研究者総覧

仲宗根 秀樹 (ナカソネ ヒデキ)

  • 総合医学第1講座 講師
Last Updated :2021/09/22

研究者情報

ホームページURL

J-Global ID

研究分野

  • ライフサイエンス / 血液、腫瘍内科学

研究活動情報

論文

  • Shunto Kawamura, Hideki Nakasone, Junko Takeshita, Shun-Ichi Kimura, Yuhei Nakamura, Masakatsu Kawamura, Nozomu YoshinoYukiko Misaki, Kazuki Yoshimura, Shimpei Matsumi, Ayumi Gomyo, Yu Akahoshi, Machiko Kusuda, Kazuaki Kameda, Aki Tanihara, Masaharu Tamaki, Shinichi Kako, Yoshinobu Kanda
    Transplantation and cellular therapy 2021年05月 
    BACKGROUND: Recipient cytomegalovirus (CMV) seropositivity is known to be a risk factor for CMV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HCT). OBJECTIVE: We explored the association of CMV-IgG titer of recipients with CMV reactivation after allo-HCT and aimed to establish a model for predicting CMV reactivation for the purpose of identifying a high-risk group. In addition, we evaluated the impact of CMV-IgG titer on survival outcomes and acute graft-versus-host-disease (GVHD). STUDY DESIGN: We retrospectively analyzed 309 patients who achieved neutrophil engraftment after allo-HCT, and evaluated whether pre-transplant recipient CMV-IgG titer was associated with transplant outcomes including CMV reactivation. Using the best cut-off value determined by a receiver operating characteristics (ROC) curve analysis, we divided cohorts into three groups, "High-titer", "Low-titer" and "Negative" groups. RESULTS: CMV reactivation frequently occurred in the "High-titer" group, followed by the "Low-titer" and "Negative-titer" groups [81%, 37% vs. 16% at 180 days after allo-HCT, P<0.01]. In a multivariate analysis, recipient CMV-IgG titer was significantly associated with subsequent CMV reactivation [HR 9.31 in the "High-titer" group, P<0.01; HR 2.91 in the "Low-titer" group, P=0.023]. CMV diseases were exclusively observed in the "High-titer" group. Overall survival (OS) in the "High-titer" group tended to be lower than those in the other two groups [2-year OS 56%, 60% vs. 80%, P=0.075], while the cumulative incidences of grade 2-4 acute graft-versus-host disease (GVHD), non-relapse mortality (NRM) and relapse were not significantly different among the three groups. In multivariate analyses, CMV-IgG titer was not associated with increased risks of these outcomes, although CMV reactivation itself was identified as a risk factor of NRM [HR 3.05, P=0.002]. CONCLUSION: We demonstrated that a higher titer of recipient CMV-IgG would predict CMV reactivation after allo-HCT. Further investigation will be required to determine how to apply these results to prophylactic or preemptive strategies against CMV, considering recipient CMV-IgG titer for effective risk stratification.
  • Koji Kawamura, Hidenori Wada, Hideki Nakasone, Yu Akahoshi, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Miki Sato, Aki Tanihara, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Transplantation and cellular therapy 27 5 436.e1-436.e8  2021年05月 
    Large outbreaks of measles or rubella occasionally occur around the world, and measles infection can be severe and even fatal in transplant patients. However, limited data are available on immunity to measles, mumps, and rubella (MMR) in adult patients after allogeneic stem cell transplantation (allo-HCT). The aim of this study was to evaluate the immune status against MMR and the effects of vaccination against MMR in adult patients after allo-HCT. A total of 135 adult patients who were alive without relapse and new malignancy at 2 years after allo-HCT were included in this study. We measured IgG antibody to MMR before allo-HCT and annually thereafter. The probabilities of being seropositive to measles, mumps or rubella after allo-HCT were estimated according to the Kaplan-Meier method and compared among groups with the log-rank test. The probability of being seropositive at 2 years after allo-HCT in patients who were seropositive before allo-HCT was 60.6% for measles, 39.7% for mumps, and 52.2% for rubella. History of chronic graft-versus-host disease tended to be a risk factor for the loss of immunity against measles (hazard ratio [HR] 1.69, P = .064) and rubella (HR 1.75, P = .056). To predict the loss of immunity against MMR at 2 years after allo-HCT, we defined the following cutoff values for the IgG index before HCT: 18.2 for measles, 5.3 for mumps, and 21.4 for rubella using a receiver-operating characteristics curve. The lower-IgG groups experienced a significant loss of seropositivity at 2 years (39% versus 82% for measles, P < .001; 13% versus 59% for mumps, P < .001; and 33% versus 90% for rubella, P < .001). After this loss of immunity, 25 patients received a single vaccination against MMR. The seroconversion rates were 64%, 36%, and 72% for measles, mumps, and rubella, respectively. Loss of immunity to MMR commonly occurs in the first several years after transplantation. In the patients who lose the immunity, the seroconversion rate after 1 dose of MMR vaccine given at ≥2 years after transplantation is suboptimal.
  • Kaito Harada, Shun-Ichi Kimura, Shigeo Fuji, Yuho Najima, Kimikazu Yakushijin, Naoyuki Uchida, Makoto Onizuka, Kazuhiro Ikegame, Shingo Yano, Naoki Shingai, Ken-Ichi Matsuoka, Yasushi Onishi, Masashi Sawa, Satoru Takada, Toshiro Kawakita, Takahiro Fukuda, Junya Kanda, Yoshiko Atsuta, Hideaki Nakasone
    Bone marrow transplantation 2021年04月 
    Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor's hazard ratio, weighted scores of 1-3 were assigned to these factors. Using the summed scores (0-8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0-2, n = 122), intermediate (3-4, n = 209), and high score (5-8, n = 110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P < 0.001), whereas the 1-year NRM was 24.1%, 43.9%, and 72.7%, respectively (P < 0.001). The prognostic value of the scoring system was confirmed in the validation cohort (n = 470). Our scoring system is useful for predicting survival after salvage SCT.
  • Masaharu Tamaki, Hideki Nakasone, Yuhei Nakamura, Masakatsu Kawamura, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shinpei Matsumi, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Kazuaki Kameda, Yu Akahoshi, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Transplantation and cellular therapy 27 4 340.e1-340.e6  2021年04月 
    Most acute leukemia patients receive consecutive intensive chemotherapy, which usually takes several months before allogeneic hematopoietic stem cell transplantation (allo-HCT). Intensive chemotherapy often induces gastrointestinal adverse events. These adverse events leave patients in a state of malnutrition, leading to a reduction in body weight. In this study, we analyzed the impact of body weight loss before allo-HCT on survival outcomes of acute leukemia patients (acute myeloid leukemia, acute lymphoid leukemia and mixed phenotype acute leukemia). A loss of body weight (LBW), which was a reduction of body weight from diagnosis or relapse to transplantation, was calculated in 182 acute leukemia patients who received first allo-HCT at our center between June 2006 and September 2019. A receiver operating characteristics curve for nonrelapse mortality (NRM) was plotted for defining the cut-off value of LBW. The cutoff value of LBW was defined as 13.2%. A higher LBW was significantly associated with inferior NRM and overall survival (OS) (2-year [2y] NRM 36.1% versus 11.5%, P = .0025; 2y-OS 39.9% versus 65.8%, P = .020). The adverse impact of LBW was also confirmed in multivariate analyses for NRM and OS (HR of NRM 2.74 [1.25-6.03], P = .0012; HR of OS 2.06 [1.00-3.07], P = .0049). The main cause of death included disease progression (n = 34) and infection (n = 35). Death cause by infection was more frequently observed in the high-LBW group (15 cases [35.7%] versus 20 cases [14.3%]; P = .0035). In addition, subgroup analyses based on a combination of the body mass index at diagnosis and LBW were performed. When the non-overweight-low LBW group (body mass index [BMI] ≤25 and LBW ≤13.2%) was used as a reference in multivariate analysis, the overweight-high LBW group (BMI >25 and LBW >13.2%) showed an increased risk of poor survival outcomes (HR of NRM 4.27 [95% confidence interval {CI}, 1.82-10.0], P < .001; HR of OS 1.93 [95%, CI 1.00-3.71], P = .050). High LBW was significantly associated with inferior survival outcomes, and the adverse effect of malnutrition might be greater than the favorable effect of the reduction in overweight.
  • Masamitsu Yanada, Naoyuki Uchida, Tatsuo Ichinohe, Takahiro Fukuda, Junya Kanda, Yoshinobu Kanda, Yoshiko Atsuta, Hideki Nakasone
    Bone marrow transplantation 2021年03月
  • Masamitsu Yanada, Takaaki Konuma, Shohei Mizuno, Masuho Saburi, Akihito Shinohara, Masatsugu Tanaka, Atsushi Marumo, Masashi Sawa, Naoyuki Uchida, Yukiyasu Ozawa, Makoto Onizuka, Satoshi Yoshioka, Hirohisa Nakamae, Tadakazu Kondo, Takafumi Kimura, Junya Kanda, Takahiro Fukuda, Yoshiko Atsuta, Hideki Nakasone, Shingo Yano
    Bone marrow transplantation 56 2 387 - 394 2021年02月 
    The aim of this study was to develop a comprehensive system for predicting non-relapse mortality after allogeneic hematopoietic cell transplantation (HCT) during first complete remission (CR) of acute myeloid leukemia (AML). After dividing 2344 eligible patients randomly into a training set and a validation set, we first identified and scored five parameters, that is, age, sex, performance status, HCT-comorbidity index (HCT-CI), and donor type, on the basis of their impact on non-relapse mortality for patients in the training set. The non-relapse mortality-J (NRM-J) index using the sum of these scores was then applied to patients in the validation set, resulting in a clear differentiation of non-relapse mortality, with expected 2-year rates of 11%, 16%, 27%, and 33%, respectively (P < 0.001). The estimated c-statistic was 0.67, which was significantly higher than that of the European Society for Blood and Marrow Transplantation score (0.60, P = 0.002) and the HCT-CI (0.57, P < 0.001). The NRM-J index showed a significant association with overall survival, but not with relapse. Our findings demonstrate that the NRM-J index is useful for predicting post-transplant non-relapse mortality for patients with AML in first CR, for whom the decision of whether to perform allogeneic HCT is critical.
  • Kaito Harada, Shigeo Fuji, Sachiko Seo, Naoyuki Uchida, Toshiro Kawakita, Shingo Yano, Yukiyasu Ozawa, Satoshi Yoshioka, Yasushi Onishi, Yuma Noguchi, Makoto Onizuka, Yoshiko Matsuhashi, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Seitaro Terakura, Hideki Nakasone
    Bone marrow transplantation 56 2 400 - 410 2021年02月 
    Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation. Although salvage cord blood transplantation (CBT) is a curative therapy for GF, the optimal immunosuppression after salvage CBT remains unknown. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage CBT using immunosuppressants, including calcineurin (CNI) alone (n = 177); CNI plus methotrexate (CNI+MTX, n = 150); and CNI plus mycophenolate mofetil (CNI+MMF, n = 161). The CNI+MMF group, in comparison with the CNI+MTX and CNI alone groups, demonstrated better neutrophil recovery at 30 days (62.7 vs. 42.7 vs. 53.1%, P < 0.001); better overall survival (OS) at 12 months (48.4 vs. 33.5 vs. 28.3%, P < 0.001); and lower non-relapse mortality (NRM) at 12 months (35.2 vs. 53.9 vs. 56.5%, P < 0.001). On multivariate analysis, CNI+MMF had the best neutrophil recovery (hazard ratio (HR), 1.71; P < 0.001) and OS (HR, 0.64; P = 0.002) and the lowest NRM (HR, 0.53; P < 0.001). Hemorrhage was relatively less frequent in the CNI+MMF group. CNI+MMF can be a promising immunosuppressant regimen after salvage CBT for GF, with better engraftment and survival outcomes, compared with CNI alone and CNI+MTX.
  • Shun-Ichi Kimura, Yuhei Nakamura, Masakatsu Kawamura, Junko Takeshita, Shunto Kawamura, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shimpei Matsumi, Ayumi Gomyo, Yu Akahoshi, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Miki Sato, Aki Tanihara, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 23 1 e13460  2021年02月 
    BACKGROUND: We retrospectively compared the impact of the areas over and under the lymphocyte curve (L_AOC vs L_AUC) on cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 301 patients met the inclusion criteria. L_AOC was calculated as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count [ALC] <700/μL). We calculated L_AOC and L_AUC from day 0 to day 15 (L_AOC15, L_AUC15) and from day 0 to day 30 (L_AOC30, L_AUC30). RESULTS: CMV antigenemia was defined as more than 3 cells/2 slides by the C10/11 method and detected in 204 cases (CMV reactivation) at a median of 39 days after HSCT. Although there were significant differences in L_AOC15, L_AOC30, L_AUC15, and L_AUC30 between patients with and without CMV reactivation, there was no difference in accuracy for predicting CMV reactivation between L_AOC and L_AUC. In a multivariate analysis, L_AOC15 and L_AUC15 were each identified as independent predictive factors for CMV reactivation, along with advanced age and CMV serostatus. However, ALC at day 14 or day 21 was as accurate as area-based indexes such as L_AOC15 and L_AUC15. L_AOC15 and L_AUC15 were significantly associated with longer duration of anti-CMV antiviral therapy while ALC was not. CONCLUSIONS: L_AOC15 and L_AUC15 had similar impacts on CMV reactivation. Although these area-based indexes were not superior to ALC for predicting CMV reactivation, they might predict patients who need longer duration of antiviral therapy more accurately.
  • Hisayuki Yokoyama, Junya Kanda, Yuta Kawahara, Naoyuki Uchida, Masatsugu Tanaka, Satoshi Takahashi, Makoto Onizuka, Yuma Noguchi, Yukiyasu Ozawa, Yuna Katsuoka, Shuichi Ota, Takanori Ohta, Takafumi Kimura, Yoshinobu Kanda, Tatsuo Ichinohe, Yoshiko Atsuta, Hideki Nakasone, Satoko Morishima
    Bone marrow transplantation 2021年01月 
    Cytomegalovirus (CMV) reactivation in cord blood transplantation (CBT) may result in the proliferation and maturation of natural killer (NK) cells. Similarly, a mismatch of the killer cell immunoglobulin-like receptor (KIR)-ligand induces NK cell activation. Therefore, if CMV reactivation occurs in the presence of KIR-ligand mismatch, it might improve CBT outcomes. We assessed the difference in the effect of CMV reactivation in the presence of KIR-ligand mismatch on disease relapse in the graft-versus-host direction. A total of 2840 patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, and chronic myeloid leukemia were analyzed. Among those with a HLA-Bw4/A3/A11 (KIR3DL-ligand) mismatch, CMV reactivation up to 100 days following CBT had a favorable impact on relapse (18.9% vs. 32.9%, P = 0.0149). However, this effect was not observed in cases without the KIR3DL-ligand mismatch or in those with or without a HLA-C1/C2 (KIR2DL-ligand) mismatch. The multivariate analysis suggested that CMV reactivation had a favorable effect on relapse only in cases with a KIR3DL-ligand mismatch (hazard ratio 0.54, P = 0.032). Moreover, the interaction effect between CMV reactivation and KIR3DL-ligand mismatch on relapse was significant (P = 0.039). Thus, our study reveals the association between KIR-ligand mismatches and CMV reactivation, which will enhance CBT outcomes.
  • Hideki Nakasone, Shinichi Kako, Takehiko Mori, Satoshi Takahashi, Makoto Onizuka, Shin-Ichiro Fujiwara, Toru Sakura, Emiko Sakaida, Akira Yokota, Nobuyuki Aotsuka, Maki Hagihara, Nobuhiro Tsukada, Yoshihiro Hatta, Kensuke Usuki, Reiko Watanabe, Moritaka Gotoh, Shin Fujisawa, Shingo Yano, Heiwa Kanamori, Shinichiro Okamoto, Yoshinobu Kanda
    Bone marrow transplantation 2021年01月 
    For patients with Philadelphia chromosome (Ph)-positive leukemia, there is no consensus regarding how long tyrosine kinase inhibitors (TKI) should be given or whether TKI could be stopped if TKI is administrated after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed relapse-free survival (RFS) in 92 allo-HCT patients who received TKI for >3 months after allo-HCT, and aimed to develop a novel indicator, called as current TKI- & relapse-free (cTRFree) achievement. TKI after allo-HCT was started as planned in 39 patients, based on measurable residual disease (MRD) in 53 at a median of 152 days after allo-HCT. There was no difference in post-TKI RFS between the planned and MRD-based starting groups (P = 0.69). Second-generation TKIs were associated with superior RFS in Ph-positive acute leukemia (HR 2.71, P = 0.031). TKI was stopped before relapse in 48 patients. Stopping TKI as a time-dependent covariate was not associated with subsequent hematological relapse (HR 1.18, P = 0.72). In the TKI-stop group, TKI administration for >6 months tended to be associated with superior RFS (HR = 0.30, P = 0.08). As an indicator of transplant success, cTRFree was 35% 5 years after starting TKI. TKI could be stopped for recipients with sustained undetectable MRD. However, further prospective studies will be required to establish clinical recommendations.
  • Katsuto Takenaka, Yasushi Onishi, Takehiko Mori, Tsuneaki Hirakawa, Yuuma Tada, Naoyuki Uchida, Takeshi Kobayashi, Yoshinobu Kanda, Yukiyasu Ozawa, Shuichi Ota, Hiroatsu Iida, Kentaro Fukushima, Takafumi Kimua, Takahiro Fukuda, Yoshiko Atsuta, Keitaro Matsuto, Hirohito Yamazaki, Hideki Nakasone
    Transplantation and cellular therapy 27 1 82.e1-82.e8  2021年01月 
    Cytomegalovirus (CMV) infection is a major infectious complication following an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent large-scale retrospective studies reported that CMV reactivation is an independent risk factor for poor post-transplant outcomes, although the development of CMV end-organ disease is suppressed by the CMV antiviral preemptive therapy, which has been mainly analyzed for hematopoietic malignancies, such as acute leukemia. However, it remains unclear whether CMV reactivation also has a negative effect on post-transplant outcomes in aplastic anemia (AA). Therefore, we evaluated the clinical relevance of CMV reactivation in patients with AA using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Adult patients with AA who underwent their first allo-HSCT between 2005 and 2017 and who survived with neutrophil engraftment until 100 days post-transplantation were analyzed (n = 672). Patients were monitored using pp65 antigenemia since the time of engraftment, and CMV reactivation in the analysis of this study was defined as the beginning of CMV preemptive or definitive therapy within 100 days post-transplantation. CMV reactivation occurred in 372 (55%) patients, including 19 with CMV end-organ disease. In time-dependent multivariate analysis, patients aged ≥40 years (hazard ratio [HR], 1.89; P = .003) who underwent transplantation from HLA-matched related peripheral blood stem cells (HR, 2.85; P = .008), HLA-matched unrelated bone marrow (BM) (HR, 2.01; P = .036), and other stem cell sources (HR, 2.32; P = .007) compared to HLA-matched related BM, CMV reactivation (HR 1.65; P = .042), grade II to IV acute graft-versus-host disease (HR 1.73; P = .013), and secondary graft failure (HR 7.09; P < .001) had independent risk factors that significantly decreased overall survival, indicating that CMV reactivation, one of the early events at post-transplantation, had a significant negative impact on the long-term prognosis at post-transplantation. This effect was more pronounced in patients aged ≥40 years who received a graft from other than HLA-matched related BM. Comparing the causes of death with and without CMV reactivation, no significant difference in the frequency of each cause of death was observed between the 2 groups (P = .453). Improvement of post-transplant CMV management that effectively suppresses CMV reactivation in the early stage at post-transplantation will be required to improve post-transplant outcomes, especially in high-risk patients.
  • Yu Akahoshi, Shun-Ichi Kimura, Yoshihiro Inamoto, Sachiko Seo, Hiroyuki Muranushi, Hiroaki Shimizu, Yukiyasu Ozawa, Masatsugu Tanaka, Naoyuki Uchida, Yoshinobu Kanda, Yuta Katayama, Souichi Shiratori, Shuichi Ota, Ken-Ichi Matsuoka, Makoto Onizuka, Takahiro Fukuda, Yoshiko Atsuta, Makoto Murata, Seitaro Terakura, Hideki Nakasone
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2020年12月 
    BACKGROUND: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a pre-emptive strategy for CMVR between 2008 and 2017. RESULTS: The cumulative incidences of grade II-IV acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (HR [hazard ratio], 1.59, 95% CI, 1.24-2.05, P < 0.001) and with G24GVHD (HR, 1.34, 95% CI, 1.06-1.70, P = 0.014), but the interaction between G24GVHD and CMVR was not significant (P = 0.326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.
  • Shun-Ichi Kimura, Yuhei Nakamura, Masakatsu Kawamura, Junko Takeshita, Shunto Kawamura, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shimpei Matsumi, Ayumi Gomyo, Yu Akahoshi, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Miki Sato, Kiriko Terasako-Saito, Aki Tanihara, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 22 6 e13409  2020年12月 
    BACKGROUND: We retrospectively evaluated the association between the D-index, which reflects both the depth and duration of neutropenia, and proven/probable invasive fungal disease (IFD) early after allogeneic hematopoietic stem cell transplantation (HSCT) at our center (n = 394). METHODS: The D-index was defined as the area over the neutrophil curve during neutropenia. The cumulative D-index from the start of neutropenia until the development of infection (c-D-index) was also evaluated as a real-time assessment of neutropenia. RESULTS: There were 19 cases of early proven/probable IFD before and within 1 week after engraftment. Fifteen cases (78.9%) were seen as breakthrough infection while on empiric (n = 7), preemptive (n = 4) or prophylactic (n = 4) antifungal administration with mold-active agents. The c-D-index and lower performance status were identified as independent significant predictive factors for IFD. A receiver operating characteristic (ROC) curve analysis showed that the D-index and c-D-index were more accurate than the simple duration of neutropenia and as accurate as the duration of profound neutropenia for predicting IFD. The sensitivity, specificity, and positive and negative predictive values of the c-D-index using an appropriate cutoff (CO) value (10 644) determined by ROC curve analysis were 73.1%, 63.2%, 9.1%, and 97.9%, respectively. The advantage of the c-D-index to cumulative days of neutropenia in terms of positive and negative predictive values seemed to be small. CONCLUSIONS: The appropriate CO value for the c-D-index for predicting IFD was as high as 10 644 in allogeneic HSCT with a more frequent use of empiric antifungal therapy. The c-D-index is useful for assessing the risk of breakthrough IFD.
  • Masaharu Tamaki, Hideki Nakasone, Tadao Aikawa, Yuhei Nakamura, Masakatsu Kawamura, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shinpei Matsumi, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Yu Akahoshi, Shun-Ichi Kimura, Shinichi Kako, Noriko Oyama-Manabe, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 12 2318 - 2322 2020年12月 
    The pulmonary function test (PFT) is an important test for risk stratification before allogeneic transplantation (allo-HCT). However, it might be preferable to avoid PFT as much as possible in the recent era of coronavirus disease 2019 (COVID-19), because PFT requires forced expirations and might produce aerosols, increasing the risk of COVID-19 transmission. Therefore, we tried to predict normal PFT results before allo-HCT based on computed tomography (CT) findings. This study included 390 allo-HCT recipients at our center for whom lung CT images and PFT results before allo-HCT were available. Abnormal CT findings were less likely to be observed in the normal PFT group (47.0% versus 67.4%, P = .015), with a high negative predictive value of 92.9%. In a multivariate analysis, normal CT was significantly associated with normal PFT (odds ratio, 2.47; 95% confidence interval, 1.22 to 4.97; P = .012). A model for predicting normal PFT was constructed based on the results of a multivariate analysis, and the area under the curve of the receiver operating characteristic analysis was 0.656, which gave a sensitivity of 45.5% and a specificity of 86.0%. The relatively high specificity of the model suggested that PFT can be omitted in patients with normal CT findings before allo-HCT.
  • Ayumi Gomyo, Hideki Nakasone, Hidenori Wada, Shunto Kawamura, Nozomu Yoshino, Junko Takeshita, Kazuki Yoshimura, Yukiko Misaki, Aki Tanihara, Yu Akahoshi, Machiko Kusuda, Masaharu Tamaki, Koji Kawamura, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Internal medicine (Tokyo, Japan) 59 19 2409 - 2414 2020年10月 [査読有り][通常論文]
     
    Autologous hematopoietic recovery after allogeneic hematopoietic cell transplantation (allo-HCT) is rare in patients who receive myeloablative conditioning (MAC). Autologous hematopoietic recovery suggests graft rejection, leading to concerns about subsequent disease relapse. We herein report a rare case of a patient with acute leukemia who experienced autologous hematopoietic recovery after cord blood transplantation (CBT) with total body irradiation-based MAC. Chromosomal abnormalities were repeatedly detected without any disease relapse for eight months. The accumulation of similar cases is required to accurately assess the incidence and clinical outcomes of autologous hematopoietic recovery after CBT with MAC.
  • Shun-Ichi Kimura, Junko Takeshita, Masakatsu Kawamura, Shunto Kawamura, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shimpei Matsumi, Ayumi Gomyo, Yu Akahoshi, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Koji Kawamura, Miki Sato, Kiriko Terasako-Saito, Aki Tanihara, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 22 5 e13387  2020年10月 [査読有り][通常論文]
     
    BACKGROUND: We evaluated the clinical impact of cytomegalovirus (CMV) reactivation calculated in terms of the area under the curve of CMV antigenemia (CMV-AUC) on the development of invasive mold infection (IMI) in the post-engraftment phase after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Among 394 consecutive patients who underwent their first allogeneic HSCT at our center between 2007 and 2018, 335 were included after excluding patients with a past history of invasive fungal disease (IFD), the development of IFD before engraftment, engraftment failure, or early death within 30 days. CMV antigenemia (CMV-AG) was monitored weekly after engraftment and 3 or more cells/2 slides were regarded as positive. CMV-AUC was calculated by the trapezoidal method using the number of CMV-AG after logarithmic transformation and the duration in weeks and was added until negative conversion. Patients with CMV reactivation were divided into low and high CMV-AUC groups using the median value of CMV-AUC as a threshold. RESULTS: There were 17 proven/probable IMIs including one mucormycosis and 16 probable invasive aspergillosis, and the 2-year cumulative incidence was 1.0% in the negative CMV-AUC group (n = 136), 3.3% in the low CMV-AUC group (n = 98) and 13.8% in the high CMV-AUC group (n = 101) (P = .001). In a multivariate analysis, grade II-IV acute GVHD (HR 3.74) and CMV-AUC (HR low 1.25, high 5.91) were identified as independent significant factors associated with a higher incidence of IMI. CONCLUSIONS: Cytomegalovirus kinetics evaluated in terms of CMV-AUC were significantly associated with the development of IMI in the post-engraftment phase after allogeneic HSCT.
  • Koji Kawamura, Yukie Tanaka, Hideki Nakasone, Yuko Ishihara, Shinichi Kako, Seiichiro Kobayashi, Yuetsu Tanaka, Tsukasa Ohmori, Kaoru Uchimaru, Sachiko Okamoto, Junichi Mineno, Hiroshi Shiku, Satoshi Nishimura, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 8 1377 - 1385 2020年08月 [査読有り][通常論文]
     
    Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by infection with human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains extremely poor. Tax, the most important regulatory protein for HTLV-1, is associated with the aggressive proliferation of host cells and is also a major target antigen for CD8+ cytotoxic T cells (CTLs). Based on our previous findings that Tax-specific CTLs with a T cell receptor (TCR) containing a unique amino-acid sequence motif exhibit strong HLA-A*24:02-restricted, Tax301-309-specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-ɑ/β genes were cloned from a previously established CTL clone and transduced into peripheral blood mononuclear cells (PBMCs) of healthy volunteers using a retroviral siTCR vector. Then the cytotoxic efficacy against HTLV-1-infected T cells or primary ATL cells was assessed both in vitro and in vivo. The redirected CTLs (Tax-siCTLs) produced a large amount of cytokines and showed strong killing activity against ATL/HTLV-1-infected T cells in vitro, although they did not have universal activity against ATL cells. Next, in a xenograft mouse model using an HTLV-1-infected T cell line (MT-2), in all mice treated with Tax-siCTLs, the tumor rapidly diminished and finally disappeared without normal tissue damage, although all mice that were untreated or treated with non-gene-modified PBMCs died because of tumor progression. Our findings confirm that Tax-siCTLs can exert strong anti-ATL/HTLV-1 effects without a significant reaction against normal cells and have the potential to be a novel immunotherapy for ATL patients.
  • Hisayuki Yokoyama, Katsuto Takenaka, Tetsuya Nishida, Sachiko Seo, Akihito Shinohara, Naoyuki Uchida, Masatsugu Tanaka, Satoshi Takahashi, Makoto Onizuka, Yasuji Kozai, Sugio Yasuhiro, Yukiyasu Ozawa, Yuna Katsuoka, Noriko Doki, Masashi Sawa, Takafumi Kimura, Junya Kanda, Takahiro Fukuda, Yoshiko Atsuta, Hideki Nakasone
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 7 1363 - 1370 2020年07月 [査読有り][通常論文]
     
    The effects of cytomegalovirus (CMV) reactivation on cord blood transplant (CBT) are unclear. We assessed the effect of CMV reactivation in adult single-unit CBT without in vivo T cell depletion. Of 3147 eligible cases, 2052 were acute myeloid leukemia (AML), 643 acute lymphoblastic leukemia (ALL), and 452 myelodysplastic syndrome (MDS). CMV reactivation up to 100 days after CBT was associated with better overall survival (OS) compared with no reactivation cases (57.3% versus 52.6% at 3 years after CBT), whereas nonrelapse mortality (NRM) was increased in ALL (16.2% versus 8.9%) and standard disease risk (17.1% versus 10.6%, P = .014) by CMV reactivation. On multivariate analysis, CMV reactivation had favorable effects on relapse in MDS (hazard ratio [HR], .55; P = .044) and high disease risk (HR, .77; P = .047). In NRM, only standard-risk cases showed adverse effects of CMV reactivation (HR, 1.56; P = .026). OS was significantly improved with CMV reactivation in a subgroup of patients with AML (HR, .84; P = .044), MDS (HR, .68; P = .048), and high disease risk (HR, .81; P = .013). This favorable effect of CMV reactivation on OS in AML and high disease risk cases was maintained even after considering the effect of grades II to IV acute graft-versus-host disease. Thus, CMV reactivation might have beneficial or adverse effects on relapse, NRM, and OS, depending on the disease type or disease risk.
  • Masaharu Tamaki, Hideki Nakasone, Masakatsu Kawamura, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Shinpei Matsumi, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Yu Akahoshi, Koji Kawamura, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 6 1131 - 1136 2020年06月 [査読有り][通常論文]
     
    Pulmonary complications are fatal adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). On the other hand, smoking is a well-known risk factor for various pulmonary diseases and also increases the incidence of pulmonary complications and overall mortality in allo-HCT recipients. In this study, we retrospectively assessed the impact of smoking intensity on survival outcomes. This study included consecutive allo-HCT recipients at our center between June 2007 and May 2019 whose smoking profiles were available (n = 408); they were divided into high (pack-years >10, n = 171) and low (pack-years ≤10, n = 231) pack-years groups. In univariate analyses, nonrelapse mortality (NRM) and overall survival (OS) were significantly inferior in the high pack-years group (1-year NRM 26.6% versus 13.9%, P < .001; 1-year OS 58.4% versus 70.1%, P = .0067). However, this association was not observed in multivariate analyses. In subgroup analyses according to sex, the survival outcomes in the high pack-years group were significantly inferior in males (NRM hazard ratio [HR], 2.24 [95% confidence interval (CI), 1.23 to 4.07], P = .0082; OS HR, 1.54 [95% CI, 1.04 to 2.28], P = .031), but not in females (NRM HR, 0.587 [95% CI, 0.241 to 1.43], P = .24; OS HR, 0.689 [95% CI, 0.400 to 1.19], P = .18). In summary, high pack-years were associated with inferior survival of allo-HCT recipients, especially in males.
  • Yukiko Misaki, Shun-Ichi Kimura, Masakatsu Kawamura, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Kazuki Yoshimura, Ayumi Gomyo, Shimpei Matsumi, Yu Akahoshi, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Koji Kawamura, Miki Sato, Kiriko Terasako-Saito, Aki Tanihara, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 22 3 e13270  2020年06月 [査読有り][通常論文]
     
    While the dose of ganciclovir (GCV) is decided base on patients' body weight (BW), that of valganciclovir (VGCV) is fixed as 900 or 1800 mg/d regardless of the patient's BW in preemptive therapy for cytomegalovirus (CMV) reactivation in hematopoietic stem cell transplantation. We analyzed the impact of the patient's BW on the effectiveness and adverse events (AEs) of VGCV. From March 2004 to February 2017, 27 patients received VGCV as a first-line treatment for CMV reactivation. As a historical control group, we extracted 17 patients who started to receive GCV at a similar timing. We used the following definitions of outcomes: speed of reduction of CMV antigenemia (CMV-AG) as a measure of effectiveness, ratios of baseline and minimum value for white blood cell (WBC) and platelet counts, and ratio of baseline and maximum values for serum creatinine (sCr) as measures of AEs. As a result, there was no significant correlation between average daily dose of VGCV with or without adjusting for the patient's BW and speed of reduction of CMV-AG. On the other hand, the decreases in WBC and platelets and the increase in sCr were significantly correlated with the cumulative dose of VGCV. However, the absolute values of the correlation coefficients did not increase when we analyzed the correlations between the BW-adjusted cumulative dose of VGCV and factors associated with adverse events. There were no significant differences in efficacies or AE parameters between the GCV and VGCV groups. In conclusion, the patient's BW did not significantly affect the effectiveness or adverse events of VGCV.
  • Masaharu Tamaki, Hideki Nakasone, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Yu Akahoshi, Koji Kawamura, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Annals of hematology 99 6 1369 - 1376 2020年06月 [査読有り][通常論文]
     
    Allogeneic hematopoietic transplantation (allo-HCT) is still associated with significant morbidity and mortality, and risk stratification is critical. In this study, we analyzed the relationship between blood pressure control early after allo-HCT and survival outcomes. All patients who survived longer than 28 days after allo-HCT at our center between June 2007 and June 2018 (n = 353) were included, and the average systolic blood pressure (asBP) from 1 to 28 days after allo-HCT was calculated. According to the results of a ROC curve analysis, an asBP of 131 mmHg was defined as a cut-off value between high and low asBP groups. Non-relapse mortality (NRM) and OS were significantly inferior in the high asBP group (2-year-NRM 28.0% vs 11.1%, P < 0.001; 2-year-OS 46.7% vs 65.7%, P = 0.001). In addition, baseline asBP before commencement of the conditioning regimen and elevation of asBP (asBP - baseline asBP) were both associated with inferior NRM. While these results were also observed in the younger patients (≤ 50 years), no relationship was observed in the older patients (> 50 years). High blood pressure within 28 days after allo-HCT was associated with inferior survival outcomes, especially in patients younger than 50 years.
  • Motohiro Kato, Hideki Nakasone, Nobuaki Nakano, Shigeo Fuji, Akihito Shinohara, Hisayuki Yokoyama, Kazuo Sakashita, Tsukasa Hori, Satoshi Takahashi, Miho Nara, Yoshinobu Kanda, Takehiko Mori, Junko Takita, Hiroshi Kawaguchi, Toshiro Kawakita, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Masao Ogata
    Bone marrow transplantation 55 6 1023 - 1028 2020年06月 [査読有り][通常論文]
     
    After primary graft failure following allogeneic hematopoietic stem cell transplantation, some patients experience autologous recovery of hematopoiesis without salvage transplantation. However, clinicians occasionally encounter unusual chromosomal abnormalities in recipient cells, not related to the original underlying diseases. In this study, through a survey based on data from the nationwide registry at the Japan Society for Hematopoietic Cell Transplantation, 42 patients were identified as having chromosomal abnormalities after autologous recovery. The complex chromosomal abnormalities were not consistent and randomly changed at each testing. Of the 42 patients, seven experienced disappearance of chromosome abnormalities without any treatment, and the probability was estimated as 17.4% (95% CI: 7.5-30.7%) at the 5-year observation. On the other hand, two patients developed hematologic malignancy at 1447 and 6202 days. Ten patients were alive without relapse or development of hematologic disorders, even though chromosomal abnormalities were continuously detected at a median of 3192 (103-4710) days. In conclusion, chromosomal abnormalities can persist for more than 10 years, and may eventually contribute to hematologic malignancy development in a small fraction of cases. Although oncogenic effects of the chromosomal abnormalities are still unclear, these findings may provide supporting evidence for late occurrence of secondary malignant neoplasms after cancer treatment.
  • Naonori Harada, Shun-Ichi Kimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Tomotaka Ugai, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Hiroyoshi Tsubochi, Yoshinobu Kanda
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 26 2 175 - 180 2020年02月 [査読有り][通常論文]
     
    OBJECTIVE: Although invasive fungal disease (IFD) is an important complication in allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of surgery, including the role of surgical resection for persistent pulmonary fungal disease prior to allogeneic HSCT in the current era with a variety of available antifungal agents, is controversial. We investigated the role of surgical resection. METHODS: We retrospectively investigated six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT between April 2007 and June 2016 at our medical center. RESULTS: We present six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT. In our case series, three of four patients who were given a presurgical diagnosis of possible IFD were given a proven diagnosis after surgery, including two cases of invasive aspergillosis (IA) and one case of mucormycosis. All surgeries were performed by video-assisted thoracic surgery (VATS) for lobectomy without major complications. Recurrence of IFD was not observed after allogeneic HSCT in any of the six patients. CONCLUSION: Our experience indicated that surgical resection of persistent localized pulmonary lesions of IFD before allogeneic HSCT was helpful for obtaining a definitive diagnosis and might be useful for reducing recurrence after HSCT.
  • Shun-Ichi Kimura, Miki Sato, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Jin Hayakawa, Yu Akahoshi, Naonori Harada, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Koji Kawamura, Kiriko Terasako-Saito, Misato Kikuchi, Aki Tanihara, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Transplant immunology 58 101262 - 101262 2020年02月 [査読有り][通常論文]
     
    We prospectively validated the previously reported L-index, which reflects both the intensity and duration of lymphopenia, and further evaluated it using a lymphocyte subset analysis after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 30). The L-index was defined as the area over the lymphocyte curve during lymphopenia (<700/μl), and calculated from the start of conditioning to day30 (L-index(30)) and day100 (L-index(100)). The lymphocyte subset including CD3, CD4, CD8, CD19 and CD56 was analyzed before and at 14, 21, 28, 42, 56, 70, and 84 days after HSCT. Cytomegalovirus (CMV) antigenemia was detected as >3 cells/2 slides by the C10/11 method in 21 cases (CMV-AG ≥3 group) at a median of 34 days. L-index(30) was significantly higher in the CMV-AG ≥3 group than in the CMV-AG <3 group (median 20,358 vs 17,235, P = .028). Recovery of the CD4+ and CD56+ cell counts between days 14 and 28 after HSCT was impaired in the CMV-AG ≥3 group. Regarding graft-versus-host disease (GVHD), grade II-IV acute GVHD was identified in 14 patients (GVHD group) at a median of 31 days. L-index(30) was significantly lower in the GVHD group (median 19,048 vs 22,256, P = .043). Recovery of CD3+ cells including both CD4+ and CD8+ cells between days 14 and 28 tended to be better in the GVHD group. In conclusion, L-index(30) was significantly associated with CMV reactivation and grade II-IV acute GVHD, but its clinical significance seemed to differ according to the results of a lymphocyte subset analysis.
  • Hideki Nakasone
    [Rinsho ketsueki] The Japanese journal of clinical hematology 61 4 379 - 386 2020年 [査読有り][通常論文]
     
    Biomarkers, which include cells, cytokines/chemokines, and genes, present in patient blood, urine, or tissues, are considered objective indicators of disease progression or treatment response. Recipients of allogeneic hematopoietic cell transplantation often develop acute and/or chronic graft-versus-host disease (GVHD). Biomarkers that could provide precise assessment of temporal inflammatory conditions in transplant recipients could help us to identify recipients at an increased risk of GVHD, determine the severity of GVHD, and decide upon treatment strategies. The current review article summarizes several established biomarkers for acute and chronic GVHD, as well as interesting and novel viewpoints. Biomarkers could be categorized as those associated with an abnormal immune reconstitution, organ damage, or poor wound healing, including inflammation and fibrosis. The investigation of biomarkers for GVHD would shed light on the complicated networks underlying allo-immune responses and is necessary for further advances in our understanding of GVHD pathophysiology. Clinical trials of preemptive interventions or novel drugs based on GVHD biomarkers are warranted. Research on potential biomarkers of GVHD would lead to further progress in diagnosis, treatment, and drug discovery.
  • Daisuke Minakata, Shin-Ichiro Fujiwara, Jin Hayakawa, Hideki Nakasone, Takashi Ikeda, Shin-Ichiro Kawaguchi, Yumiko Toda, Shoko Ito, Shin-Ichi Ochi, Takashi Nagayama, Kiyomi Mashima, Kento Umino, Hirofumi Nakano, Ryoko Yamasaki, Kaoru Morita, Yasufumi Kawasaki, Miyuki Sugimoto, Yuko Ishihara, Chihiro Yamamoto, Masahiro Ashizawa, Kaoru Hatano, Kazuya Sato, Iekuni Oh, Ken Ohmine, Kazuo Muroi, Tsukasa Ohmori, Yoshinobu Kanda
    Acta haematologica 143 3 250 - 259 2020年 [査読有り][通常論文]
     
    BACKGROUND: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. OBJECTIVES: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. METHODS: We retrospectively examined 188 patients with hematological malignancy-related DIC. RESULTS: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21-4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15-13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). CONCLUSIONS: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.
  • Chikako Ohwada, Emiko Sakaida, Aiko Igarashi, Takeshi Kobayashi, Noriko Doki, Takehiko Mori, Jun Kato, Yuya Koda, Heiwa Kanamori, Masatsugu Tanaka, Takayoshi Tachibana, Shin Fujisawa, Yuki Nakajima, Ayumi Numata, Masako Toyosaki, Yasuyuki Aoyama, Makoto Onizuka, Maki Hagihara, Satoshi Koyama, Yoshinobu Kanda, Hideki Nakasone, Hiroaki Shimizu, Seiko Kato, Reiko Watanabe, Katsuhiro Shono, Rika Sakai, Takeshi Saito, Chiaki Nakaseko, Shinichiro Okamoto
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 26 1 162 - 170 2020年01月 [査読有り][通常論文]
     
    To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.
  • Yu Akahoshi, Hideki Nakasone, Koji Kawamura, Machiko Kusuda, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Aki Tanihara, Masaharu Tamaki, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Experimental hematology 81 60 - 67 2020年01月 [査読有り][通常論文]
     
    Dasatinib, a potent tyrosine kinase inhibitor (TKI), is currently used as first-line treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, emergence of the T315I mutation has been found to be a main cause of failure after dasatinib-containing treatments. We assessed the prognostic value of small clones with the T315I mutation at specific time points using the novel technology digital polymerase chain reaction (PCR), which is more sensitive than direct sequencing. This study included 25 consecutive adult patients with Ph+ ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) following dasatinib-based chemotherapy at our center. Among six patients who experienced hematologic relapse after HSCT, four harbored the T315I mutation at relapse. However, the detection of small subclones with T315I at either diagnosis or HSCT was not associated with an increased risk of relapse. In contrast, all patients with the T315I mutation at molecular relapse after HSCT (n = 4) eventually had a hematologic relapse, and only two of the 10 patients without the T315I mutation at molecular relapse after HSCT relapsed. In conclusion, the detection of small clones with the T315I mutation at molecular relapse after HSCT, but not before HSCT, could support an early clinical decision to change treatments.
  • Masahiro Ashizawa, Yu Akahoshi, Hirofumi Nakano, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Masaharu Tamaki, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Koji Kawamura, Miki Sato, Kiriko Terasako-Saito, Aki Tanihara, Shun-Ichi Kimura, Hideki Nakasone, Shinichi Kako, Keiko Akahane, Masaru Wakatsuki, Katsuyuki Shirai, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 25 12 2461 - 2467 2019年12月 [査読有り][通常論文]
     
    Myeloablative conditioning regimens are associated with severe gonadal toxicity. To preserve ovarian function, we have been investigating ovarian shielding during total body irradiation (TBI) with a myeloablative dose. In this report, we update the clinical outcomes. Female patients with standard-risk hematologic diseases, aged 40 years or younger, who desired to have children, were included (n = 19). The conditioning regimen consisted of TBI at 12 Gy with ovarian shielding and cyclophosphamide (120 mg/kg) or cytarabine (24 g/m2). Ovarian shielding reduced the actual irradiation dose applied to the ovaries from 12 Gy to 2 to 3 Gy. The median age at hematopoietic stem cell transplantation (HSCT) was 24 years (range, 19 to 33 years). With a median follow-up period of 1449 days (range, 64 to 3694) after HSCT, 5-year overall survival and 1- and 5-year relapse rates were 67%, 17%, and 31%, respectively. Only 2 of 14 patients with acute myeloid or lymphoid leukemia in remission have relapsed thus far. The 6-month and 1-year cumulative rates of menstrual recovery were 42% and 78%, respectively. In all patients with menstrual recovery, menstruation recovered within 1 year. The serum anti-Müllerian hormone (AMH) level tended to gradually increase after menstrual recovery. Three patients with extensive chronic graft-versus-host disease experienced delayed recovery of menstruation and serum AMH. Five pregnancies in 3 patients resulted in normal delivery in 1, selective cesarean operation in 1, current pregnancy in 1, and natural abortion in 2. These results suggest that a myeloablative TBI regimen with ovarian shielding could preserve fertility after HSCT without an apparent increase in relapse in standard-risk patients. Because serum AMH recovered gradually over time, the AMH level during the early phase after HSCT may have little value as a marker of ovarian reserve.
  • Yu Akahoshi, Hideki Nakasone, Koji Kawamura, Machiko Kusuda, Shunto Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Aki Tanihara, Masaharu Tamaki, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Blood advances 3 21 3287 - 3296 2019年11月 [査読有り][通常論文]
     
    Macrophages play a crucial role in the pathogenesis of chronic graft-versus-host disease (cGVHD). We hypothesized that galectin-3, Mac-2 binding protein (M2BP), or Wisteria floribunda agglutinin (WFA)+-M2BP, called M2BP glycan isomer (M2BPGi), might contribute to macrophage activation, and fibrosis would be associated with cGVHD and nonrelapse mortality (NRM) in hematopoietic stem cell transplant (HSCT) recipients. Patients who underwent their first allogeneic HSCT and survived for >180 days without relapse were included. The predictive potential of the 3 markers for NRM was assessed using the discovery cohort (n = 55) and validation cohort 1 (n = 55). When we used the threshold determined by a receiver operating characteristics curve analysis in the discovery cohort, only M2BPGi at day +180 was significantly associated with a higher NRM in the discovery cohort (15.0% vs 0.0% at 5 years, P = .001) and in validation cohort 1 (34.0% vs 8.4% at 5 years, P = .014). This result was confirmed in validation cohort 2 (n = 50). M2BPGi was not increased in healthy individuals or in patients who received autologous HSCT. In the entire cohort (N = 110), M2BPGi was significantly related to liver cGVHD but not to other organ involvement. In multivariate analyses, M2BPGi was an independent risk factor for NRM. In immunofluorescence staining of autopsy cases, WFA+-M2BP-positive macrophages were found only in the liver sections with cGVHD. In conclusion, M2BPGi could be a promising predictor of late NRM after HSCT and was associated with liver involvement.
  • Hideki Nakasone, Misato Kikuchi, Koji Kawamura, Yu Akahoshi, Miki Sato, Shunto Kawamura, Nozomu Yoshino, Junko Takeshita, Kazuki Yoshimura, Yukiko Misaki, Ayumi Gomyo, Aki Tanihara, Machiko Kusuda, Masaharu Tamaki, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Scientific reports 9 1 16499 - 16499 2019年11月 [査読有り][通常論文]
     
    CD34-positive monocytes (CD34+mono) have recently been identified in grafts mobilized by granulocyte-colony stimulating factor. We analyzed transplant outcomes of 73 patients whose donor's peripheral blood cells were cryopreserved during mobilization. CD34+mono was detected more frequently in male donors (67% vs. 40%, P = 0.03), while the detection of CD34+mono in donors was not associated with the patient background. Although there was no significant difference in overall survival in the whole cohort, the detection of CD34+mono in donors were significantly associated with a decreased risk of non-relapse mortality (HR 0.23, P = 0.035). Fatal infectious events tended to be less frequent in donors with CD34+mono. Gene expression profile analyses of CD34+mono in humans revealed that the expressions of pro-inflammatory cytokines like IL6, CCL3, IL8, VEGFA, and IL1A were elevated in CD34+mono, and those cytokines were enriched in the immune response, especially against infectious pathogens in the gene ontology analyses. In addition, the expression of CD83 was specifically increased in CD34+mono. It might play a role of antigen presentation in the immune network, leading in a clinical benefit against infections. Further investigations will be required to confirm the biological functions and clinical roles of CD34+mono in transplantation.
  • Jin Hayakawa, Daijiro Miyamura, Shun-Ichi Kimura, Ayumi Gomyo, Masaharu Tamaki, Yu Akahoshi, Naonori Harada, Tomotaka Ugai, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Bone marrow transplantation 54 7 994 - 1003 2019年07月 [査読有り][通常論文]
     
    Quality of life of patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) temporally deteriorates and recovers over several years. We retrospectively evaluate the impact of chronic graft-versus-host disease (GVHD) and glucocorticoid on physical recovery. We included 162 patients who underwent their first allogeneic HSCT between October 2010 and December 2015 in a single hospital. All patients are planned to undergo physical function tests before and 1, 3, 12 months after allogeneic HSCT. Scores of knee extension strength and distance covered in the 6-min walk test (6MWT) recovered at the 12-month assessment. Both chronic GVHD and high dose glucocorticoid were associated with delayed recovery of body mass index (BMI), hand grip strength, knee extension strength, and duration of standing on one foot. Lung GVHD and high dose glucocorticoid had negative impact on the distance covered in the 6MWT. A multivariate analysis revealed that chronic GVHD and glucocorticoid was an independent risk factor for decreased BMI and delayed recovery of muscle strength, respectively. Our results suggest that high-risk patients who have chronic GVHD or who receive glucocorticoid therapy may require reduced dose of glucocorticoid and long-term physical support to recover physical function after transplantation.
  • Jed Paul, Hideki Nakasone, Bita Sahaf, Fang Wu, Kathy Wang, Vincent Ho, Juan Wu, Haesook Kim, Bruce Blazar, Jerome Ritz, Alan Howard, Corey Cutler, David Miklos
    Haematologica 104 7 e314-e317 - e317 2019年07月 [査読有り][通常論文]
  • Hideki Nakasone, Koji Kawamura, Kimikazu Yakushijin, Akihito Shinohara, Masatsugu Tanaka, Kazuteru Ohashi, Shuichi Ota, Naoyuki Uchida, Takahiro Fukuda, Hirohisa Nakamae, Ken-Ichi Matsuoka, Junya Kanda, Tatsuo Ichinohe, Yoshiko Atsuta, Yoshihiro Inamoto, Sachiko Seo, Fumihiko Kimura, Masao Ogata
    Blood advances 3 11 1750 - 1760 2019年06月 [査読有り][通常論文]
     
    The use of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs) and sex-mismatched hematopoietic cell transplantation (HCT), especially with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) compared with transplantation with bone marrow (BM). This raises the question of whether the use of PBSCs in FtoM HCT might affect allogeneic responses, resulting in fatal complications. Using a Japanese transplantation registry database, we analyzed 1132 patients (FtoM, n = 315; MtoF, n = 260; sex-matched, n = 557) with standard-risk diseases who underwent HCT with an HLA-matched related donor without in vivo T-cell depletion between 2013 and 2016. The impact of PBSC vs BM on transplantation outcomes was separately assessed in FtoM, MtoF, and sex-matched HCT. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years post-HCT were significantly worse in patients with PBSCs vs those with BM in FtoM HCT (2-year OS, 76% vs 62%; P = .0084; 2-year NRM, 10% vs 21%; P = .0078); no differences were observed for MtoF or sex-matched HCT. Multivariate analyses confirmed the adverse impact of PBSCs in FtoM HCT (hazard ratio [HR] for OS, 1.91; P = .025; HR for NRM, 3.70; P = .0065). In FtoM HCT, patients with PBSCs frequently experienced fatal GVHD and organ failure. In conclusion, the use of PBSCs in FtoM HCT was associated with an increased risk of NRM in the early phase, resulting in inferior survival. This suggests that, when we use female-related donors for male patients in HCT, BM may result in better outcomes than PBSCs.
  • Kazuaki Kameda, Shun-Ichi Kimura, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Machiko Kusuda, Yu Akahoshi, Tomotaka Ugai, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Aki Tanihara, Hidenori Wada, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Bone marrow transplantation 54 5 707 - 716 2019年05月 [査読有り][通常論文]
     
    Infection and inflammation can induce acute graft-vs.-host disease (aGVHD). We hypothesized that febrile neutropenia early after allogeneic hematopoietic cell transplantation (HCT) would increase the risk of aGVHD and non-relapse mortality (NRM). We retrospectively evaluated the impact of fever, C-reactive protein (CRP) concentration and blood stream infection (BSI) early after HCT on the incidence of grade II-IV aGVHD and NRM in 227 patients. Within 7 days after HCT, 91 (40.1%) patients experienced fever for at least 2 days (early-FN group). BSI occurred in 27 (11.9%) patients and the maximum CRP concentration was 2.57 mg/dl in the median. In a multivariate analysis, early-FN (hazard ratio (HR) 1.81, P = 0.007) and older recipient age (HR 1.68, P = 0.019) were significantly associated with the incidence of grade II-IV aGVHD. High-CRP and BSI were not significant risk factors for grade II-IV aGVHD. On the other hand, high-CRP was significantly associated with the incidence of NRM (HR 2.67, P = 0.004) in a multivariate analysis. In conclusion, although fever, CRP elevation and BSI are considered to be closely related events, they had different effects on the incidence of aGVHD and NRM. The development of early-FN after HCT may predict the risk of aGVHD.
  • Hideki Nakasone, Ken Tabuchi, Naoyuki Uchida, Yuju Ohno, Yoshiko Matsuhashi, Satoshi Takahashi, Yasushi Onishi, Makoto Onizuka, Hikaru Kobayashi, Takahiro Fukuda, Tatsuo Ichinohe, Minoko Takanashi, Koji Kato, Yoshiko Atsuta, Hiromasa Yabe, Yoshinobu Kanda
    British journal of haematology 185 1 166 - 169 2019年04月 [査読有り][通常論文]
  • Shinichi Kako, Ayumi Gomyo, Yu Akahoshi, Naonori Harada, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Junya Kanda, Yoshinobu Kanda
    European journal of haematology 102 3 256 - 264 2019年03月 [査読有り][通常論文]
     
    OBJECTIVES: To establish the optimal strategy for haploidentical hematopoietic stem cell transplantation (HSCT). METHODS: We performed a prospective study on haploidentical HSCT using low-dose alemtuzumab. Alemtuzumab was added at 0.25 mg/kg for 2 days. The primary outcome measure was the survival rate with the engraftment of donor cells and without grade III-IV acute graft-vs-host disease (GVHD) at 60 days after transplantation. RESULTS: Fourteen adult patients with advanced hematological disease were enrolled. The primary outcome measure was achieved in 86% of the patients. Six patients experienced relapse/progression. Non-relapse death was observed in three patients, and all of them had a history of previous allogeneic HSCT. Overall survival and progression-free survival rates at 1 year were 51% and 43%, respectively. Four patients were suspected to have herpes simplex virus infection and three had aseptic meningitis under the use of acyclovir at 200 mg. There were no deaths due to viral infection. Compared to those who underwent haploidentical HSCT using thymoglobulin, patients with alemtuzumab showed a slower recovery of CD8+ T-cells and lower incidences of GVHD and EB virus reactivation. CONCLUSIONS: Haploidentical HSCT using low-dose alemtuzumab can be performed safely. We need to overcome the high relapse/progression rate in non-remission patients.
  • Kana Sakamoto, Ryohei Katayama, Reimi Asaka, Seiji Sakata, Satoko Baba, Hideki Nakasone, Sumie Koike, Naoko Tsuyama, Akito Dobashi, Makoto Sasaki, Ryo Ichinohasama, Emi Takakuwa, Rie Yamazaki, Jun Takizawa, Takahiro Maeda, Miwako Narita, Koji Izutsu, Yoshinobu Kanda, Koichi Ohshima, Kengo Takeuchi
    Leukemia 32 12 2590 - 2603 2018年12月 [査読有り][通常論文]
     
    Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYC-BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC-BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYC-BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC-BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.
  • Shinichi Kako, Shinichiro Fujiwara, Miki Sato, Shun-Ichi Kimura, Hideki Nakasone, Kazuteru Ohashi, Toshiro Kawakita, Tetsuo Maeda, Takanobu Morishita, Ritsuro Suzuki, Takahiro Fukuda, Tatsuo Ichinohe, Mio Kurata, Yoshiko Atsuta, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24 10 2139 - 2144 2018年10月 [査読有り][通常論文]
     
    Compared with 4-times-daily infusion of intravenous busulfan (ivBU4), the safety and efficacy of once-daily infusion of ivBU (ivBU1) has not been fully clarified. We have been routinely using ivBU1 in a conditioning regimen in adult patients with myeloid malignancy who undergo allogeneic hematopoietic stem cell transplantation. In this study, a total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) in our institutions were compared with 273 control patients who received ivBU4, who were matched for age, sex, performance status, disease risk, conditioning regimen, and donor type, selected from the database of the Japanese Society for Hematopoietic Cell Transplantation using optimal matching algorithms. One-year overall survival (56.8% versus 57.1%, P = .94), disease-free survival (51.6% versus 50.8%, P = .73), relapse rate (28.5% versus 26.2%, P = .94), nonrelapse mortality (19.9% versus 23.0%, P = .71), and the incidence of graft-versus-host disease were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 versus 17, P = .001), and the incidence of veno-occlusive disease was lower (2.6% versus 17.4%, P = .04). In conclusion, ivBU1 can be safely administered with clinical outcomes similar to those with ivBU4.
  • Masaharu Tamaki, Hideki Nakasone, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Jin Hayakawa, Machiko Kusuda, Yu Akahoshi, Yuko Ishihara, Koji Kawamura, Aki Tanihara, Miki Sato, Kiriko Terasako-Saito, Kazuaki Kameda, Hidenori Wada, Misato Kikuchi, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Annals of hematology 97 10 1951 - 1960 2018年10月 [査読有り][通常論文]
     
    The optimal treatment strategy for gastrointestinal graft-versus-host disease (GI-GVHD) after allogeneic hematopoietic cell transplantation remains to be established. We retrospectively analyzed 68 cases of GI-GVHD at our institution between 2007 and 2017. The survival outcomes were significantly inferior in patients who did not respond to the first-line treatment (1-year overall survival 27.3 vs 69.2%, P = 0.0017; non-relapse mortality 50.0 vs 18.6%, P = 0.026). After subsequent treatments, 18 patients were refractory to all steroid-based treatments such as steroid pulse therapy and oral beclomethasone dipropionate (BDP). However, these steroid-refractory cases showed a gradual increase in the response rate after the initial diagnosis of steroid refractoriness. This result may be explained by the problem of evaluating the response based solely on the volume of diarrhea, i.e., severe mucosal damage due to refractory GI-GVHD may require a long recovery and sometimes be complicated with other diseases. In conclusion, patients with GI-GVHD who failed to respond to the first-line treatment had inferior survival. However, later improvement may be observed without additional immunosuppressant other than steroid among patients who initially do not respond to steroid therapy. It is important to repeat colonoscopy in patients with refractory GI-GVHD to monitor the activity of GVHD.
  • Masaharu Tamaki, Hideki Nakasone, Ayumi Gomyo, Jin Hayakawa, Yu Akahoshi, Naonori Harada, Machiko Kusuda, Yuko Ishihara, Koji Kawamura, Aki Tanihara, Miki Sato, Kiriko Terasako-Saito, Kazuaki Kameda, Hidenori Wada, Misato Kikuchi, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    International journal of hematology 108 4 423 - 431 2018年10月 [査読有り][通常論文]
     
    High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for younger myeloma patients. However, the correlation between its toxicity and renal impairment is not clear. We analyzed this relationship, focusing on estimated glomerular filtration rate (eGFR) as an index of renal function. We evaluated 78 multiple myeloma patients who underwent ASCT following high-dose melphalan at our center. Patients were divided into a higher eGFR group (eGFR ≥ 60) and a lower eGFR group (eGFR < 60). Multivariate analyses revealed that lower eGFR was independently associated with alkaline phosphatase elevation (OR 10.2, P = 0.038), mucositis (OR 10.5, P = 0.032), grade 2-4 co-elevation of both aspartate aminotransferase and alanine aminotransferase (OR 21.3, P = 0.016), delay of reticulocyte engraftment (HR 0.524, P = 0.034), and delay of platelet engraftment (HR 0.535, P = 0.0016). However, lower eGFR was not correlated with overall survival or time-to-next treatment. In summary, renal dysfunction secondary to administration of high-dose melphalan was associated with increased hepatic and mucosal toxicity and delay of hematological recovery, but did not affect survival outcomes.
  • Sarah Nikiforow, Tao Wang, Michael Hemmer, Stephen Spellman, Görgün Akpek, Joseph H Antin, Sung Won Choi, Yoshihiro Inamoto, Hanna J Khoury, Margaret MacMillan, David I Marks, Ken Meehan, Hideki Nakasone, Taiga Nishihori, Richard Olsson, Sophie Paczesny, Donna Przepiorka, Vijay Reddy, Ran Reshef, Hélène Schoemans, Ned Waller, Daniel Weisdorf, Baldeep Wirk, Mary Horowitz, Amin Alousi, Daniel Couriel, Joseph Pidala, Mukta Arora, Corey Cutler
    Haematologica 103 10 1708 - 1719 2018年10月 [査読有り][通常論文]
     
    Upper gastrointestinal acute graft-versus-host disease is reported in approximately 30% of hematopoietic stem cell transplant recipients developing acute graft-versus-host disease. Currently classified as Grade II in consensus criteria, upper gastrointestinal acute graft-versus-host disease is often treated with systemic immunosuppression. We reviewed the Center for International Blood and Marrow Transplant Research database to assess the prognostic implications of upper gastrointestinal acute graft-versus-host disease in isolation or with other acute graft-versus-host disease manifestations. 8567 adult recipients of myeloablative allogeneic hematopoietic stem cell transplant receiving T-cell replete grafts for acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome between 2000 and 2012 were analyzed. 51% of transplants were from unrelated donors. Reported upper gastrointestinal acute graft-versus-host disease incidence was 12.1%; 2.7% of recipients had isolated upper gastrointestinal acute graft-versus-host disease, of whom 95% received systemic steroids. Patients with isolated upper gastrointestinal involvement had similar survival, disease-free survival, transplant-related mortality, and relapse as patients with Grades 0, I, or II acute graft-versus-host disease. Unrelated donor recipients with isolated upper gastrointestinal acute graft-versus-host disease had less subsequent chronic graft-versus-host disease than those with Grades I or II disease (P=0.016 and P=0.0004, respectively). Upper gastrointestinal involvement added no significant prognostic information when present in addition to other manifestations of Grades I or II acute graft-versus-host disease. If upper gastrointestinal symptoms were reclassified as Grade 0 or I, 425 of 2083 patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation.
  • Yoshihiro Inamoto, Tomohiro Matsuda, Ken Tabuchi, Saiko Kurosawa, Hideki Nakasone, Hisakazu Nishimori, Satoshi Yamasaki, Noriko Doki, Koji Iwato, Takehiko Mori, Satoshi Takahashi, Hiromasa Yabe, Akio Kohno, Hirohisa Nakamae, Toru Sakura, Hisako Hashimoto, Junichi Sugita, Hiroatsu Ago, Takahiro Fukuda, Tatsuo Ichinohe, Yoshiko Atsuta, Takuya Yamashita
    Blood advances 2 15 1901 - 1913 2018年08月 [査読有り][通常論文]
     
    To characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined.
  • Koji Kawamura, Hideki Nakasone, Saiko Kurosawa, Kazuki Yoshimura, Yukiko Misaki, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Shun-Ichi Kimura, Aki Tanihara, Shinichi Kako, Heiwa Kanamori, Takehiko Mori, Satoshi Takahashi, Shuichi Taniguchi, Yoshiko Atsuta, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24 7 1521 - 1526 2018年07月 [査読有り][通常論文]
     
    The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation.
  • Machiko Kusuda, Shun-Ichi Kimura, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Tomotaka Ugai, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Aki Tanihara, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24 7 1367 - 1371 2018年07月 [査読有り][通常論文]
     
    The actual heparin concentration of harvested allogeneic bone marrow varies among harvest centers. We monitor the activated partial thromboplastin time (APTT) of the patient during bone marrow infusion and administer prophylactic protamine according to the APTT. We retrospectively reviewed the charts of consecutive patients who underwent bone marrow transplantation without bone marrow processing at our center between April 2007 and March 2016 (n = 94). APTT was monitored during marrow transfusion in 52 patients. We analyzed the relationship between the APTT ratio and several parameters related to heparin administration. As a result, the weight-based heparin administration rate (U/kg/hour) seemed to be more closely related to the APTT ratio (r = .38, P = .005) than to the total amount of heparin. There was no significant correlation between the APTT ratio and renal or liver function. Bleeding complications during and early after infusion were seen in 3 of 52 patients, and included intracranial, nasal, and punctured-skin bleeding. The APTT ratio during transfusion was over 5.88 in the former 2 patients and 2.14 in the latter. All of these patients recovered without sequelae. In conclusion, slow bone marrow infusion is recommended to decrease the weight-based heparin administration rate when the heparin concentration per patient body weight is high.
  • Hidenori Wada, Junya Kanda, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Shinichi Kako, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 23 5 271 - 276 2018年06月 [査読有り][通常論文]
     
    BACKGROUND: No standard method for measuring renal function has been established in allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: We retrospectively analyzed 80 patients with hematological diseases who underwent allo-HCT at our center. We assessed renal function using creatinine clearance (Ccr), estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcre), eGFR based on cystatin C (eGFRcys), and the average of eGFRcre and eGFRcys (eGFRave). We then evaluated the impact of pre-transplant renal function on the exacerbation of renal function and non-relapse mortality after transplantation. RESULTS: There was a significant correlation between Ccr and eGFRcre, eGFRcys, and eGFRave. eGFRave best predicted the exacerbation of renal function according to the area under the receiver-operating characteristic curve. The cumulative incidence of renal function exacerbation at 1 year was higher in the lower eGFRave group (<90 ml/min/1.73 m2) than in the higher eGFRave group (≥90 ml/min/1.73 m2; 0.85 vs. 0.39, p < 0.001), which was confirmed by a multivariate analysis (HR 2.75, p = 0.001). A lower eGFRave value was a marginally significant factor for non-relapse mortality (HR 3.29, p = 0.076). CONCLUSION: Among the four parameters, eGFRave best predicted the exacerbation of renal function in allo-HCT. Further, the marginal association between low eGFRave and high non-relapse mortality warrants further study in a prospective study in allo-HCT.
  • Anita J Kumar, Soyoung Kim, Michael T Hemmer, Mukta Arora, Stephen R Spellman, Joseph A Pidala, Daniel R Couriel, Amin M Alousi, Mahmoud D Aljurf, Jean-Yves Cahn, Mitchell S Cairo, Corey S Cutler, Shatha Farhan, Usama Gergis, Gregory A Hale, Shahrukh K Hashmi, Yoshihiro Inamoto, Rammurti T Kamble, Mohamed A Kharfan-Dabaja, Margaret L MacMillan, David I Marks, Hideki Nakasone, Maxim Norkin, Muna Qayed, Olle Ringden, Harry C Schouten, Kirk R Schultz, Melhem M Solh, Takanori Teshima, Alvaro Urbano-Ispizua, Leo F Verdonck, Robert Peter Gale, Betty K Hamilton, Navneet S Majhail, Alison W Loren
    Blood advances 2 9 1022 - 1031 2018年05月 [査読有り][通常論文]
     
    Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.
  • Yu Akahoshi, Shun-Ichi Kimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Naonori Harada, Machiko Kusuda, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Infectious diseases (London, England) 50 4 280 - 288 2018年04月 [査読有り][通常論文]
     
    BACKGROUND: Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT). METHODS: We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137). RESULTS: The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT. CONCLUSIONS: Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.
  • Hideki Nakasone, Kiriko Terasako-Saito, Teiichi Hirano, Atsushi Wake, Seiichi Shimizu, Naoki Kurita, Etsuko Yamazaki, Kensuke Usuki, Kohei Akazawa, Junya Kanda, Koichiro Minauchi, Go Yamamoto, Shiori Tanimoto, Masaharu Kamoshita, Yasuhisa Yokoyama, Etsuo Miyaoka, Shuichi Ota, Shinichi Kako, Koji Izutsu, Yoshinobu Kanda
    Hematological Oncology 36 1 202 - 209 2018年02月 [査読有り][通常論文]
     
    Complete response (CR) after treatment for multiple myeloma is associated with superior progression-free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto-HCT) between 2010 and 2012. If patients did not achieve CR after auto-HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto-HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto-HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post-HCT VGPR and in 2 of 12 patients with post-HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto-HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post-HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.
  • Yu Akahoshi, Shun-Ichi Kimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Naonori Harada, Machiko Kusuda, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Hematological oncology 36 1 276 - 284 2018年02月 [査読有り][通常論文]
     
    Delayed platelet recovery (DPR) despite prompt neutrophil engraftment is frequently observed after allogeneic hematopoietic stem cell transplantation (HSCT). However, few studies have evaluated the risk factors and long-term outcome. Therefore, we retrospectively analysed 219 adult patients who underwent their first allogenic HSCT with neutrophil engraftment. Of these 219 patients, 50 (22.8%) had DPR that was defined as relapse-free survival at day 60 after HSCT without primary platelet recovery despite neutrophil engraftment. The results of a multivariate analysis showed that a high-risk underlying disease (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.04-5.48; P = .041) and human leukocyte antigen-mismatched HSCT (OR, 2.63; 95% CI, 1.28-5.43; P = .009) were associated with an increased risk of DPR. In univariate analyses, the occurrence of DPR was significantly associated with inferior overall survival, high nonrelapse mortality, and a low incidence of chronic graft-versus-host disease (GVHD), despite a comparable relapse rate. In multivariate analyses, DPR was associated with inferior overall survival (hazard ratio [HR], 2.00; 95% CI, 1.23-3.27; P = .005) and a low incidence of chronic GVHD (HR, 0.42; 95% CI, 0.22-0.78; P = .002). In conclusion, DPR was a strong predictor of shorter survival but also less frequent chronic GVHD.
  • Hideki Nakasone, Kiriko Terasako-Saito, Teiichi Hirano, Atsushi Wake, Seiichi Shimizu, Naoki Kurita, Etsuko Yamazaki, Kensuke Usuki, Kohei Akazawa, Junya Kanda, Koichiro Minauchi, Go Yamamoto, Shiori Tanimoto, Masaharu Kamoshita, Yasuhisa Yokoyama, Etsuo Miyaoka, Shuichi Ota, Shinichi Kako, Koji Izutsu, Yoshinobu Kanda
    Hematological oncology 36 1 202 - 209 2018年02月 [査読有り][通常論文]
     
    Complete response (CR) after treatment for multiple myeloma is associated with superior progression-free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto-HCT) between 2010 and 2012. If patients did not achieve CR after auto-HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto-HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto-HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post-HCT VGPR and in 2 of 12 patients with post-HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto-HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post-HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.
  • Tamaki M, Wada H, Gomyo A, Hayakawa J, Akahoshi Y, Harada N, Kusuda M, Ishihara Y, Kawamura K, Tanihara A, Sato M, Terasako-Saito K, Kameda K, Kikuchi M, Kimura SI, Nakasone H, Kako S, Kanda Y
    International journal of hematology 107 1 117 - 121 2018年01月 [査読有り][通常論文]
     
    Donor-derived malignancy is a rare morbidity after allogeneic hematopoietic stem cell transplantation (HSCT), in which most previous cases have presented as acute leukemia or myelodysplastic syndrome. There have, however, been very few reports of donor-derived lymphoma. Here, we present a case of donor-derived mantle cell lymphoma 12 years after allogeneic HSCT, which was successfully treated with chemotherapy followed by pseudo-autologous HSCT (pASCT), i.e., an autologous HSC transplant following allogeneic HSCT in which the infused stem cell is considered to be derived from the donor cells. Although pASCT carries the risk of graft-versus-host disease (GVHD) due to the reinfusion of donor-derived peripheral blood cells, the present case did not develop GVHD without prophylaxis. The current case and a small number of previous reports suggest that the duration between allogeneic HSCT and pASCT may be important to the induction of immune tolerance, but further study in a larger number of cases is needed.
  • Kazuaki Kameda, Shinichi Kako, Jin Hayakawa, Yu Akahoshi, Yusuke Komiya, Naonori Harada, Tomotaka Ugai, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Junya Kanda, Aki Tanihara, Hidenori Wada, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Yoshinobu Kanda
    Annals of hematology 97 1 169 - 179 2018年01月 [査読有り][通常論文]
     
    We hypothesized that systemic corticosteroid administration would be safely avoided not only in grade I acute graft-versus-host disease (GVHD) but also in selected patients with grade II acute GVHD limited to the skin (grade IIs GVHD). We retrospectively evaluated risk factors for subsequent GVHD progression, defined as the involvement of other organs or progression to grade III to IV GVHD, in 50 patients with acute GVHD of grade IIs at its onset. Sixteen patients received systemic corticosteroid administration before GVHD progression. The cumulative incidence of GVHD progression at 28 days from the onset of grade IIs GVHD was 24%. Twenty-five patients did not require systemic corticosteroid administration throughout the entire episode of acute GVHD. Systemic corticosteroid administration before GVHD progression did not affect GVHD progression, chronic GVHD, or non-relapse mortality. Early onset (less than 26 days from transplantation) of grade IIs GVHD was identified as the only statistically significant risk factor for GVHD progression (hazard ratio 6.73, 95% confidence interval 1.5-31.1, P = 0.01). In conclusion, avoiding systemic corticosteroid administration for selected patients with grade IIs GVHD before GVHD progression did not compromise the transplantation outcomes. Patients with early-onset grade IIs GVHD were at high risk for GVHD progression.
  • Kazuaki Kameda, Hideki Nakasone, Yusuke Komiya, Junya Kanda, Ayumi Gomyo, Jin Hayakawa, Yu Akahoshi, Masaharu Tamaki, Naonori Harada, Machiko Kusuda, Tomotaka Ugai, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Aki Tanihara, Hidenori Wada, Kiriko Terasako-Saito, Misato Kikuchi, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 23 11 1895 - 1902 2017年11月 [査読有り][通常論文]
     
    Although a positive cytotoxic crossmatch (XM) has been reported to predict graft failure, mainly in solid organ transplantations, its significance in allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated. We retrospectively assessed the impact of positive XM on neutrophil engraftment in 41 patients who underwent HCT with an HLA-mismatched related donor. XM was positive in 22 patients. Six of these 22 patients were also positive for anti-HLA antibody, whereas only 1 was positive for donor-specific anti-HLA antibody. The cumulative incidence of engraftment at day +28 was 89.5% in patients with negative XM versus 59.1% in those with positive XM (P = .08). In particular, positive B cell warm XM was significantly associated with a lower probability of engraftment at day +28 (46.7% versus 88.5%; P = .04). In a multivariate analysis, both positive XM and positive B cell warm XM were significantly associated with delayed engraftment (hazard ratio [HR], .46; P = .02 and HR, .41; P = .01, respectively). There was no significant difference in the achievement of engraftment between those with and without detection of anti-HLA antibodies. In conclusion, positive XM might be associated with a delayed neutrophil engraftment after HCT from HLA-mismatched related donors.
  • Yuko Ishihara, Yukie Tanaka, Seiichiro Kobayashi, Koji Kawamura, Hideki Nakasone, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Naonori Harada, Machiko Kusuda, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Shun-ichi Kimura, Aki Tanihara, Shinichi Kako, Kaoru Uchimaru, Yoshinobu Kanda
    Journal of Virology 91 19 2017年10月 [査読有り][通常論文]
     
    We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donorderived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301- 309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-β chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.
  • Shun-Ichi Kimura, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Naonori Harada, Tomotaka Ugai, Machiko Kusuda, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Aki Tanihara, Yoshinobu Kanda
    Infectious diseases (London, England) 49 10 748 - 757 2017年10月 [査読有り][通常論文]
     
    BACKGROUND: We evaluated the clinical significance of repeat blood cultures in persistent and recurrent fever during neutropenia in adult acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients undergoing intensive chemotherapy. METHODS: We retrospectively reviewed the chemotherapy cycles at our centre between January 2007 and December 2015. Blood cultures obtained within three days after initial febrile neutropenia (FN) were defined as initial blood cultures and those obtained on or after day 4 were defined as repeat blood cultures. RESULTS: Overall, 321 chemotherapy cycles in 89 patients were subjected to review. FN was identified in 276 (86.0%) chemotherapy cycles. In persistent FN (134 episodes), the causative pathogens were detected by repeat blood cultures in seven episodes (5.2%), including only three episodes (2.2%) of new infection. Shaking chills and high body temperature were identified as significant predictors for bloodstream infection (BSI). In recurrent FN (85 episodes), the causative pathogens were detected in seven episodes (8.2%), and all of these were new organisms. The frequency of detecting new pathogens by repeat blood cultures in recurrent FN (7/85) was higher than that in persistent FN (3/134) (p = .0491). A history of recent BSI was identified as a significant predictor for BSI in recurrent FN. CONCLUSIONS: The diagnostic yield of repeat blood cultures for persistent FN was low in intensive chemotherapy for AML and MDS. The frequency of repeat blood cultures for persistent FN could be reduced based on predictors. On the other hand, blood cultures were considered to be essential in cases with recurrent FN.
  • Yuko Ishihara, Yukie Tanaka, Seiichiro Kobayashi, Koji Kawamura, Hideki Nakasone, Ayumi Gomyo, Jin Hayakawa, Masaharu Tamaki, Yu Akahoshi, Naonori Harada, Machiko Kusuda, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Shun-Ichi Kimura, Aki Tanihara, Shinichi Kako, Kaoru Uchimaru, Yoshinobu Kanda
    Journal of virology 91 19 2017年10月 [査読有り][通常論文]
     
    We previously reported that the T-cell receptor (TCR) repertoire of human T-cell lymphotropic virus type 1 (HTLV-1) Tax301-309-specific CD8+ cytotoxic T cells (Tax301-309-CTLs) was highly restricted and a particular amino acid sequence motif, the PDR motif, was conserved among HLA-A*24:02-positive (HLA-A*24:02+) adult T-cell leukemia/lymphoma (ATL) patients who had undergone allogeneic hematopoietic cell transplantation (allo-HSCT). Furthermore, we found that donor-derived PDR+ CTLs selectively expanded in ATL long-term HSCT survivors with strong CTL activity against HTLV-1. On the other hand, the TCR repertoires in Tax301-309-CTLs of asymptomatic HTLV-1 carriers (ACs) remain unclear. In this study, we directly identified the DNA sequence of complementarity-determining region 3 (CDR3) of the TCR-β chain of Tax301-309-CTLs at the single-cell level and compared not only the TCR repertoires but also the frequencies and phenotypes of Tax301-309-CTLs between ACs and ATL patients. We did not observe any essential difference in the frequencies of Tax301-309-CTLs between ACs and ATL patients. In the single-cell TCR repertoire analysis of Tax301-309-CTLs, 1,458 Tax301-309-CTLs and 140 clones were identified in this cohort. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was exclusively observed in all ACs and ATL patients. However, there was no correlation between PDR+ CTL frequencies and HTLV-1 proviral load (PVL). In conclusion, we have identified, for the first time, a unique amino acid sequence, PDR, as a public TCR-CDR3 motif against Tax in HLA-A*24:02+ HTLV-1-infected individuals. Further investigations are warranted to elucidate the role of the PDR+ CTL response in the progression from carrier state to ATL.IMPORTANCE ATL is an aggressive T-cell malignancy caused by HTLV-1 infection. The HTLV-1 regulatory protein Tax aggressively promotes the proliferation of HTLV-1-infected lymphocytes and is also a major target antigen for CD8+ CTLs. In our previous evaluation of Tax301-309-CTLs, we found that a unique amino acid sequence motif, PDR, in CDR3 of the TCR-β chain of Tax301-309-CTLs was conserved among ATL patients after allo-HSCT. Furthermore, the PDR+ Tax301-309-CTL clones selectively expanded and showed strong cytotoxic activities against HTLV-1. On the other hand, it remains unclear how Tax301-309-CTL repertoire exists in ACs. In this study, we comprehensively compared Tax-specific TCR repertoires at the single-cell level between ACs and ATL patients. Tax301-309-CTLs showed highly restricted TCR repertoires with a strongly biased usage of BV7, and PDR, the unique motif in TCR-β CDR3, was conserved in all ACs and ATL patients, regardless of clinical subtype in HTLV-1 infection.
  • Yu Akahoshi, Junya Kanda, Ayumu Ohno, Yusuke Komiya, Ayumi Gomyo, Jin Hayakawa, Naonori Harada, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Kimiyasu Shiraki, Yoshinobu Kanda
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 23 7 485 - 487 2017年07月 [査読有り][通常論文]
     
    We previously reported that oral low-dose acyclovir (200 mg/day) for the prevention of herpes simplex virus (HSV) infections after allogenic hematopoietic stem cell transplantation (HSCT) is effective without the emergence of acyclovir-resistant HSV infections. However, HSV infections are of significant concern because the number of allogeneic HSCT with T-cell depletion, which is a risk factor of the emergence of drug-resistant HSV infections, has been increasing. We experienced a 25-year-old female who received allogenic HSCT from an unrelated donor with 1-antigen mismatch using anti-thymocyte globulin. Despite acyclovir prophylaxis (200 mg/day), she developed the right palatal ulcer that was positive for HSV-1 specific antigen by fluorescent antibody on day 20 and developed new hypoglossal and tongue ulcers on day 33. Replacement of acyclovir with foscarnet improved her ulcers. We isolated 2 acyclovir-resistant and foscarnet-sensitive strains from the right palatal and hypoglossal ulcers, which had the same frame shift mutation in the thymidine kinase genes. The rate of proliferation of the isolate from the hypoglossal ulcer was faster than that from the right palatal ulcer in the plaque reduction assay. HSV strains that acquired acyclovir-resistant mutations at the right palatal ulcer with larger plaque might spread to the hypoglossal ulcer as the secondary site of infection because of better growth property. Second-line antiviral agents should be considered when we suspect treatment failure of HSV infection, especially in HSCT with T-cell depletion. Further studies are required whether low-dose acyclovir prophylaxis leads to the emergence of virological resistance.
  • Ryoko Yamasaki, Junya Kanda, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Koji Kawamura, Yuko Ishihara, Kana Sakamoto, Miki Sato, Masahiro Ashizawa, Tomohito Machishima, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Shinichi Kako, Junji Nishida, Yoshinobu Kanda
    International journal of hematology 105 6 835 - 840 2017年06月 [査読有り][通常論文]
     
    Levofloxacin (LVFX) is widely used for antibacterial prophylaxis during neutropenia. Garenoxacin (GRNX), which has been investigated in Japan, has stronger antibacterial activity than LVFX against gram-positive bacteria; however, no studies have compared the effectiveness of LVFX and GRNX. We retrospectively analyzed 42 patients with acute leukemia and 32 patients who underwent hematopoietic cell transplantation. Thirty-one patients before September 2009 received GRNX, and subsequent 43 patients received LVFX. We compared the cumulative incidences of positive blood and stool cultures. There was no significant difference in the incidence of bacteremia between the GRNX and LVFX groups. However, while gram-negative bacteria were detected in 80% of the patients with bacteremia in the GRNX group, they were detected in only 33% of the patients with bacteremia in the LVFX group. Patients in the GRNX group more frequently experienced positive stool cultures than those in the LVFX group, and this was confirmed by a multivariate analysis. Gram-negative bacteria accounted for 100 and 67% of the stool culture results in the GRNX and LVFX groups, respectively. While both fluoroquinolones may be appropriate antibacterial prophylactic agents for neutropenia patients with hematological malignancies, vigilance for gram-negative bacterial infections should be exercised when GRNX is used as prophylaxis.
  • Shinichi Kako, Yu Akahoshi, Naonori Harada, Hirofumi Nakano, Kazuaki Kameda, Tomotaka Ugai, Ryoko Yamasaki, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 22 3 129 - 135 2017年04月 [査読有り][通常論文]
     
    OBJECTIVES: To clarify optimal strategies for human leukocyte antigen (HLA)-mismatched haploidentical hematopoietic stem cell transplantation (HSCT). METHODS: Twelve patients who underwent HSCT from a haploidentical related donor using low-dose thymoglobulin were analyzed retrospectively. Thymoglobulin was added to conditioning regimens at 2.5 mg/kg/day for 2 days (days -4 and -3). Prophylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine and methotrexate. RESULTS: The median age of the patients was 33 years. Six patients had previous allogeneic HSCT, and HSCT was performed in non-remission for nine patients. All patients but one, who died due to early infection, achieved neutrophil engraftment at a median of 17 days with complete donor-type chimerism. Acute and chronic GVHD were observed in six and five patients, respectively, but no patients died of GVHD-associated complication. No one developed cytomegalovirus disease, but Epstein-Barr virus-related lymphoproliferative disorder was observed in one patient. Long-term survival in remission without immunosuppressive agents are observed in two patients who underwent HSCT in remission, but the majority of patients who underwent HSCT in non-remission experienced disease progression. CONCLUSION: Haploidentical HSCT could be performed with thymoglobulin at 5 mg/kg, with the balance between GVHD and relapse rate. The dose reduction of thymoglobulin may be considered for advanced hematological malignancy.
  • Shun-Ichi Kimura, Ayumi Gomyo, Jin Hayakawa, Yu Akahoshi, Naonori Harada, Tomotaka Ugai, Yusuke Komiya, Kazuaki Kameda, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Junya Kanda, Shinichi Kako, Aki Tanihara, Yoshinobu Kanda
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 23 3 148 - 153 2017年03月 [査読有り][通常論文]
     
    BACKGROUND: We examined the clinical characteristics and predictive factors for mortality in coryneform bacteria bloodstream infection in hematological patients. METHODS: We searched for hematological patients who had positive blood cultures for coryneform bacteria at our center between April 2007 and January 2016. Patients with definite bloodstream infections were included. We started species identification in April 2014. RESULTS: Twenty of twenty-eight cases with a positive blood culture for coryneform bacteria were regarded as definite infections. Sixteen and two patients were allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients, respectively. Corynebacterium striatum was identified in all nine of the cases tested and one patient was co-infected with Corynebacterium amycolatum. None of the patients died directly due to coryneform bacteria infection. The survival rates at 30, 60 and 180 days were 100%, 73.7% and 51.3%, respectively. Causes of mortality included progression of the underlying disease (n = 6), other infections (n = 4) and HSCT complications (n = 2). Mixed infection (hazard ratio (HR) 5.47, 95% confidence interval (CI) 1.30-23.0), renal impairment (HR 6.31, 95% CI 1.06-37.4) and absence of a central venous (CV) catheter at the onset (HR 6.39, 95% CI 1.04-39.45) were identified as predictive factors for mortality. CONCLUSION: Most of the coryneform bacteria bloodstream infections occurred in HSCT recipients. Contamination seemed to be less common when coryneform bacteria were detected in blood in hematological patients. Although coryneform bacteria bloodstream infection seemed to mostly be manageable, the prognosis was not desirable, particularly in patients with mixed infection, renal impairment and absence of a CV catheter.
  • Hideki Nakasone, Shigeo Fuji, Kimikazu Yakushijin, Makoto Onizuka, Akihito Shinohara, Kazuteru Ohashi, Koichi Miyamura, Naoyuki Uchida, Minoko Takanashi, Tatsuo Ichinohe, Yoshiko Atsuta, Takahiro Fukuda, Masao Ogata
    American journal of hematology 92 2 171 - 178 2017年02月 [査読有り][通常論文]
     
    Total body irradiation (TBI) has been thought to promote donor cell engraftment in allogeneic hematopoietic cell transplantation (HCT) from alternative donors. However, recent progress in HCT strategies may affect the clinical significance of TBI on neutrophil engraftment. With the use of a Japanese transplant registry database, we analyzed 3933 adult recipients (>15 y.o.) who underwent HCT between 2006 and 2013 from an 8/8 HLA-matched unrelated bone marrow donor (MUD, n = 1367), an HLA-mismatched unrelated bone marrow donor (MMUD, n = 1102), or unrelated cord blood (CBT, n = 1464). Conditioning regimens were divided into five groups: High-TBI-(>8Gy), Low-TBI- (≤8Gy), and no-TBI-myeloablative conditioning (MAC), and Low-TBI- and no-TBI-reduced-intensity conditioning (RIC). In both MUD and MMUD, neutrophil engraftment rate was >90% in each of the five conditioning groups, and TBI was not associated with prompt neutrophil engraftment in multivariate analyses. Conversely, in CBT, TBI regimens had a higher rate of day-30 neutrophil engraftment than no-TBI-regimens: 78% in High-TBI-MAC, 83% in Low-TBI-MAC, and 76% in Low-TBI-RIC versus 65% in No-TBI-MAC, and 68% in No-TBI-RIC (P < .001). Multivariate analyses in CBT demonstrated that TBI-regimens were significantly associated with a higher rate of neutrophil engraftment. Subsequently focusing on CBT patients alone, TBI-regimens were significantly associated with a higher rate of neutrophil engraftment in patients who received CBT with a 4/6 or less HLA allele-match, or who had anti-HLA antibodies. In summary, TBI-regimens had no impact on neutrophil engraftment in the current practice of unrelated bone marrow transplantation. However, in CBT, TBI is still necessary to enhance engraftment.
  • Yoshihiro Inamoto, Fumihiko Kimura, Junya Kanda, Junichi Sugita, Kazuhiro Ikegame, Hideki Nakasone, Yasuhito Nannya, Naoyuki Uchida, Takahiro Fukuda, Kosuke Yoshioka, Yukiyasu Ozawa, Ichiro Kawano, Yoshiko Atsuta, Koji Kato, Tatsuo Ichinohe, Masami Inoue, Takanori Teshima
    Haematologica 101 12 1592 - 1602 2016年12月 [査読有り][通常論文]
     
    Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.
  • Yoshiko Atsuta, for the, Akihiro Hirakawa, Hideki Nakasone, Saiko Kurosawa, Kumi Oshima, Rika Sakai, Kazuteru Ohashi, Satoshi Takahashi, Takehiko Mori, Yukiyasu Ozawa, Takahiro Fukuda, Heiwa Kanamori, Yasuo Morishima, Koji Kato, Hiromasa Yabe, Hisashi Sakamaki, Shuichi Taniguchi, Takuya Yamashita
    Biology of Blood and Marrow Transplantation 22 9 1702 - 1709 2016年09月 [査読無し][通常論文]
     
    We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up.
  • Yoshiko Atsuta, Akihiro Hirakawa, Hideki Nakasone, Saiko Kurosawa, Kumi Oshima, Rika Sakai, Kazuteru Ohashi, Satoshi Takahashi, Takehiko Mori, Yukiyasu Ozawa, Takahiro Fukuda, Heiwa Kanamori, Yasuo Morishima, Koji Kato, Hiromasa Yabe, Hisashi Sakamaki, Shuichi Taniguchi, Takuya Yamashita
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22 9 1702 - 1709 2016年09月 [査読有り][通常論文]
     
    We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up.
  • Yu Akahoshi, Junya Kanda, Ayumi Gomyo, Jin Hayakawa, Yusuke Komiya, Naonori Harada, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22 9 1678 - 1683 2016年09月 [査読有り][通常論文]
     
    Secondary failure of platelet recovery (SFPR), a late decrease in the platelet count after primary platelet recovery that is not due to relapse or graft rejection, occasionally occurs after allogeneic hematopoietic stem cell transplantation (HSCT). The risk factors and impact of SFPR on transplantation outcomes are not well known in the clinical setting. Therefore, we retrospectively evaluated 184 adult patients who underwent their first allogeneic HSCT and achieved primary platelet recovery. The cumulative incidence of SFPR, defined as a decrease in the platelet count to below 20,000/µL for more than 7 days, was 12.2% at 3 years, with a median onset of 81 days (range, 39 to 729) after HSCT. Among patients who developed SFPR (n = 23), 19 (82.6%) showed recovery to a sustained platelet count of more than 20,000/µL without transfusion support, and the median duration of SFPR was 23 days (range, 7 to 1048 days). A multivariate analysis showed that in vivo T cell depletion (hazard ratio [HR], 6.92; 95% confidence interval [CI], 2.31 to 20.7; P < .001), grades II to IV acute graft-versus-host disease (HR, 3.99; 95% CI, 1.52 to 10.5; P = .005), and the use of ganciclovir or valganciclovir (HR, 2.86; 95% CI, 1.05 to 7.77; P = .039) were associated with an increased risk for SFPR. The occurrence of SFPR as a time-dependent covariate was significantly associated with inferior overall survival (HR, 2.29; 95% CI, 1.18 to 4.46; P = .015) in a multivariate analysis. These findings may help to improve the management and treatment strategy for SFPR.
  • Nakano H, Ashizawa M, Akahoshi Y, Ugai T, Wada H, Yamasaki R, Ishihara Y, Kawamura K, Sakamoto K, Sato M, Terasako-Saito K, Kimura S, Kikuchi M, Nakasone H, Kako S, Kanda J, Yamazaki R, Tanihara A, Nishida J, Kanda Y
    International journal of hematology 104 1 110 - 6 2016年07月 [査読有り][通常論文]
     
    Conditioning regimens that include cyclophosphamide (CY) and total body irradiation (TBI) induce severe gonadal toxicity and permanent infertility in approximately 90 % of female patients who undergo hematopoietic stem cell transplantation (HSCT). However, the use of ovarian shielding or non-myeloablative regimens may preserve ovarian function. To evaluate the ovarian reserve, serum anti-Müllerian hormone (AMH) levels were retrospectively measured in 11 female HSCT recipients aged less than 40 years, including seven with acute leukemia (AL) and four with aplastic anemia (AA), who received a myeloablative conditioning regimen with ovarian shielding or a reduced-intensity conditioning regimen. In most patients, menstruation had stopped and AMH level had decreased to an undetectable level (<0.1 ng/ml) after HSCT. Most patients showed a recovery of regular menstruation, but AMH levels did not increase immediately after the resumption of menstruation. However, in three AL patients and two AA patients who were evaluable for long-term recovery, AMH level increased gradually beyond 1 year after HSCT. In conclusion, recovery of the serum AMH level may be delayed after HSCT, and the AMH level early after HSCT may not accurately reflect ovarian reserve. A prospective study is required to address the usefulness of measuring the AMH level in HSCT recipients.
  • 後明 晃由美, 賀古 真一, 早川 仁, 小宮 佑介, 原田 尚憲, 亀田 和明, 鵜飼 知嵩, 和田 英則, 石原 優子, 河村 浩二, 坂本 佳奈, 佐藤 美樹, 斎藤 桐子, 木村 俊一, 菊地 美里, 仲宗根 秀樹, 諫田 淳也, 森口 正人, 神田 善伸
    臨床血液 57 6 784  (一社)日本血液学会-東京事務局 2016年06月 [査読無し][通常論文]
  • Yu Akahoshi, Shun-Ichi Kimura, Hirofumi Nakano, Naonori Harada, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Junya Kanda, Shinichi Kako, Junji Nishida, Yoshinobu Kanda
    Clinical transplantation 30 6 703 - 8 2016年06月 [査読有り][通常論文]
     
    Patients with hematological malignancies show a high prevalence of asymptomatic colonization with Clostridium difficile (CD colonization). Therefore, it is difficult to distinguish CD colonization with diarrhea induced by a conditioning regimen from true Clostridium difficile infection (CDI) in hematopoietic stem cell transplantation (HSCT) recipients. We retrospectively analyzed 308 consecutive patients who underwent a CD toxin A/B enzyme immunoassay test for diarrhea within 100 d after HSCT from November 2007 to May 2014. Thirty patients (9.7%) had positive CD toxin results, and 11 of these had positive results in subsequent tests after an initial negative result. Allogeneic HSCT, total body irradiation, stem cell source, acute leukemia, and the duration of neutropenia were significantly correlated with positive CD toxin results. In a logistic regression model, allogeneic HSCT was identified as a significant risk factor (odds ratio 18.6, p < 0.01). In an analysis limited to within 30 d after the conditioning regimen, the duration of neutropenia was the sole risk factor (odds ratio 10.4, p < 0.01). There were no distinctive clinical features for CDI, including the onset or duration of diarrhea. In conclusion, although CDI may be overdiagnosed in HSCT recipients, it is difficult to clinically distinguish between CDI and CD colonization.
  • Jed Paul, Bita Sahaf, Spenser Perloff, Kelsi Schoenrock, Fang Wu, Hideki Nakasone, John Coller, David Miklos
    Journal of immunological methods 432 57 - 64 2016年05月 [査読有り][通常論文]
     
    Enzyme-linked immunosorbent assays (ELISAs) have traditionally been used to detect alloantibodies in patient plasma samples post hematopoietic cell transplantation (HCT); however, protein microarrays have the potential to be multiplexed, more sensitive, and higher throughput than ELISAs. Here, we describe the development of a novel and sensitive microarray method for detection of allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome, called HY antigens. Six microarray surfaces were tested for their ability to bind recombinant protein and peptide HY antigens. Significant allogeneic immune responses were determined in male patients with female donors by considering normal male donor responses as baseline. HY microarray results were also compared with our previous ELISA results. Our overall goal was to maximize antibody detection for both recombinant protein and peptide epitopes. For detection of HY antigens, the Epoxy (Schott) protein microarray surface was both most sensitive and reliable and has become the standard surface in our microarray platform.
  • Yuki Teramura, Kazuaki Kameda, Junya Kanda, Ayumi Gomyo, Jin Hayakawa, Yu Akahoshi, Yusuke Komiya, Naonori Harada, Tomotaka Ugai, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Hidenori Wada, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Yoshinobu Kanda
    [Rinsho ketsueki] The Japanese journal of clinical hematology 57 5 597 - 601 2016年05月 [査読有り][通常論文]
     
    The patient was a 62-year-old woman with CD5(+) diffuse large B-cell lymphoma. Treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) was started. On the eleventh day of the third cycle, headache and low grade fever developed. Her consciousness gradually deteriorated. Seven days after symptom onset, she was brought to the emergency department of our hospital. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 25/μl, and a protein level of 188 mg/dl. Antibacterial and antiviral agents were administered based on a diagnosis of acute meningitis. She showed no improvement. We performed another lumbar puncture and intrathecal chemotherapy, a combination of methotrexate and dexamethasone, was administered because we suspected central nervous system involvement of lymphoma. She showed transient improvement. On day 12, we started the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine). However, fever and disturbance of consciousness persisted. On day 20, we empirically started anti-tuberculosis treatment. Four days later, tubercle bacilli were confirmed by CSF culture after a 23-day incubation. We ultimately confirmed a diagnosis of tuberculous meningitis. Impaired cellular immunity in lymphoma patients increases the risk of tuberculosis. It is important to consider tuberculous meningitis in the differential diagnosis of a lymphoma patient presenting with meningitis.
  • Kana Sakamoto, Hideki Nakasone, Yuki Togashi, Seiji Sakata, Naoko Tsuyama, Satoko Baba, Akito Dobashi, Reimi Asaka, Chien-Chen Tsai, Shih-Sung Chuang, Koji Izutsu, Yoshinobu Kanda, Kengo Takeuchi
    International journal of hematology 103 4 399 - 408 2016年04月 [査読有り][通常論文]
     
    Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+LBCL) is a rare, aggressive B-cell lymphoma with ALK fusion genes. Histopathologically, the ALK immunohistochemical staining pattern is suggestive of the fusion partner of ALK. Here, we examined an ALK+LBCL case showing a unique diffuse cytoplasmic ALK staining pattern and identified EML4-ALK, which has not previously been reported in ALK+LBCL. Furthermore, to clarify whether the prognosis differs depending on the staining pattern, we reviewed 112 previously reported cases, and analyzed immunohistochemical markers and clinical data stratified by the staining pattern. We found that ALK staining can be classified into a granular cytoplasmic staining (GCS) or a non-GCS patterns. Sixty-four adult cases for which both the ALK staining pattern and survival time were reported were further analyzed for survival trends. The non-GCS pattern was significantly associated with inferior overall survival (P = 0.031). This difference remained significant after adjusting for age and clinical stage (hazard ratio 5.08, 95 % CI 1.88-13.7, P = 0.0013). Given that the ALK immunohistochemical staining pattern is associated with the ALK fusion partner, the present results suggest that the prognosis for ALK+LBCL differs depending on the ALK fusion partner.
  • Kameda K, Kimura SI, Akahoshi Y, Nakano H, Harada N, Ugai T, Wada H, Yamasaki R, Ishihara Y, Kawamura K, Sakamoto K, Ashizawa M, Sato M, Terasako-Saito K, Nakasone H, Kikuchi M, Yamazaki R, Kanda J, Kako S, Tanihara A, Nishida J, Kanda Y
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22 2 371 - 377 2016年02月 [査読有り][通常論文]
     
    Bloodstream infections (BSI) are still important complications after allogeneic hematopoietic stem cell transplantation (allo-SCT). Patients who are receiving corticosteroid therapy can develop BSI without fever. The utility of surveillance blood cultures in these situations is controversial. We retrospectively analyzed 74 patients who received a corticosteroid consisting of ≥.5 mg/kg prednisolone or equivalent after allo-SCT. In principle, we performed surveillance blood culture weekly for these patients. Sixteen patients (21.6%) developed definite BSI. In a multivariate analysis, a myeloablative conditioning regimen, high-risk disease status at allo-SCT, and the presence of a central venous catheter at the initiation of corticosteroid therapy were identified as independent significant risk factors for the development of definite BSI. At the first definite BSI episode, 7 patients (46.7%) were afebrile and diagnosed by surveillance blood culture. However, 6 of these 7 afebrile patients showed various signs that could be attributed to infection at the time of positive blood culture. In conclusion, patients receiving corticosteroid therapy after allo-SCT frequently develop afebrile BSI. Although surveillance blood culture might be beneficial in these situations, it also seems important to not miss the signs of BSI, even when patients are afebrile.
  • Yuko Ishihara, Shun-ichi Kimura, Yu Akahoshi, Naonori Harada, Hirofumi Nakano, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Shinichi Kako, Aki Tanihara, Junji Nishida, Kensuke Usuki, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 21 1 19 - 25 2016年01月 [査読有り][通常論文]
     
    OBJECTIVES: The D-index and the L-index, calculated as the area over the neutrophil and lymphocyte curves, respectively, reflect both the intensity and duration of cytopenia. We, retrospectively, investigated the impact of these indexes on pulmonary infection (PI) in induction chemotherapy for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). METHODS: We included 92 patients (ALL 83, LBL 9) from two institutions. We calculated the D-index and cumulative D-index until the development of PI (c-D-index), which enables real-time risk assessment for infection. We also calculated the L-index (35), defined as the area over the lymphocyte curve during lymphopenia (<700/µl) until day 35 and the cumulative-L-index until the development of PI (c-L-index). RESULTS: Eight patients developed PI on day 20 (median). Two patients were strongly suspected to have bacterial pneumonia, and the others were suspected to have pulmonary fungal infection. The D-index and the L-index (35) in patients with PI were higher than those in patients without PI (7230 ± 4734 vs. 4519 ± 3416, P = 0.041 and 15 458 ± 5243 vs. 8920 ± 5901, P = 0.018), while the c-D-index and the c-L-index were not significantly different. Although the c-L-index did not have predictive value for PI, c-D-index, when treated as a dichotomous variable with a cutoff value of 5589 as determined by a receiver operating characteristic curve analysis, showed a significant difference between two groups (P = 0.045). This association became clearer when we focused on suspected pulmonary fungal infection. DISCUSSION AND CONCLUSION: In induction chemotherapy for ALL/LBL, c-D-index with a cutoff value of 5589 might have predictive value for the development of PI.
  • Y Arai, J Kanda, H Nakasone, T Kondo, N Uchida, T Fukuda, K Ohashi, K Kaida, K Iwato, T Eto, Y Kanda, H Nakamae, T Nagamura-Inoue, Y Morishima, M Hirokawa, Y Atsuta, M Murata
    Bone marrow transplantation 51 1 96 - 102 2016年01月 [査読有り][通常論文]
     
    Hepatic acute GvHD (aGvHD) is associated with high mortality owing to poor response to immunosuppressive therapy. The pathogenesis of hepatic aGvHD differs from that of other lesions, and specific risk factors related to pre-transplant liver conditions should be determined. We conducted a cohort study by using a Japanese transplant registry database (N=8378). Of these subjects, 1.5% had hepatitis C virus Ab (HCV-Ab) and 9.4% had liver dysfunction (elevated transaminase or bilirubin levels) before hematopoietic cell transplantation (HCT). After HCT, the cumulative incidence of hepatic aGvHD was 6.7%. On multivariate analyses, HCV-Ab positivity (hazard ratio (HR), 1.93; P=0.02) and pre-transplant liver dysfunction (HR, 1.85; P<0.01), as well as advanced HCT risk, unrelated donors, HLA mismatch and cyclosporine as GvHD prophylaxis, were significant risk factors for hepatic aGvHD, whereas hepatitis B virus surface Ag was not. Hepatic aGvHD was a significant risk factor for low overall survival and high transplant-related mortality in all aGvHD grades (P<0.01). This study is the first to show the relationship between pre-transplant liver conditions and hepatic aGvHD. A prospective study is awaited to validate the results of this study and establish a new strategy especially for high-risk patients.
  • Shinichi Kako, Yu Akahoshi, Naonori Harada, Hirofumi Nakano, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Junji Nishida, Yoshinobu Kanda
    Annals of hematology 95 1 87 - 92 2016年01月 [査読有り][通常論文]
     
    The effects of intensive regimens and the roles of drugs used might differ between T- and B-lineage acute lymphoblastic leukemia (ALL). We performed a literature search for clinical studies published from January 1998 to March 2013. Studies were eligible for inclusion in the analyses if they included more than 80 patients with adult ALL who were treated with a uniform regimen and compared T- and B-lineage ALL. Studies that included only adolescent or elderly patients were excluded. We identified 11 clinical studies, which included a total of 381 and 1366 patients with T- and B-lineage ALL, respectively, and performed meta-analyses using the selected studies. Nine studies included patients with Philadelphia chromosome-positive (Ph+) ALL. A meta-analysis using the random-effect model demonstrated superior survival in patients with T-lineage ALL compared to those with B-lineage ALL (hazard ratio 1.78, 95 % confidence interval 1.50-2.11), though the inclusion of patients with Ph+ ALL in B-lineage ALL must have influenced this result strongly. We performed meta-regression analyses, adjusted according to whether or not patients with Ph+ ALL were included in each study. Use of dexamethasone (Dex), higher dose of methotrexate (MTX), and higher dose of L-asparaginase (L-asp) were associated with a significant trend toward a better outcome in T-lineage ALL. A meta-regression analysis including Dex and the dose of L-asp or MTX together as covariates showed that these factors were independently significant. In conclusion, the use of Dex and high-dose L-asp or MTX may improve the outcome of T-lineage ALL. This hypothesis should be tested in a prospective study including only patients with Ph-negative ALL.
  • Hideki Nakasone, Bita Sahaf, Lu Tian, Tao Wang, Michael D Haagenson, Kelsi Schoenrock, Spenser Perloff, Christine E Ryan, Fang Wu, Stephen R Spellman, Stephanie J Lee, Jerome Ritz, David B Miklos
    Haematologica 101 1 e30-3 - E33 2016年01月 [査読有り][通常論文]
  • Kazuaki Kameda, Hideki Nakasone
    INTERNAL MEDICINE 55 17 2519 - 2519 2016年 [査読有り][通常論文]
  • Tomotaka Ugai, Kohei Hamamoto, Shun-ichi Kimura, Yu Akahoshi, Hirofumi Nakano, Naonori Harada, Kazuaki Kameda, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Tomohisa Okochi, Junya Kanda, Shinichi Kako, Osamu Tanaka, Yoshinobu Kanda
    European journal of radiology 84 12 2663 - 70 2015年12月 [査読有り][通常論文]
     
    OBJECTIVE: The purpose of this study was to review the high-resolution computed tomography (CT) findings in patients with pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT), and to evaluate the relationship between CT findings and clinical outcomes. PATIENTS AND METHODS: We collected the clinical data in 96 consecutive patients who underwent CT scan for pulmonary complications after allogeneic HSCT and analyzed the relationships among these clinical characteristics, CT findings and clinical responses. Radiologists who were blinded to clinical information evaluated the CT findings. RESULTS: In multivariate analyses, the presence of chronic graft-versus-host disease (GVHD) and non-segmental multiple consolidations were significantly associated with a poor response to antimicrobial therapies, and the disease risk was significantly associated with a poor corticosteroid response. In addition, the existence of cavity formation and pleural effusion were significantly associated with a fatal prognosis. Twenty-five patients underwent bronchoscopic examination and 4 of them also underwent transbronchial lung biopsy (TBLB), but diagnostic information was not obtained in 15 patients. There was no significant association between specific CT findings and the diagnosis based on bronchoscopic examination. CONCLUSIONS: No specific CT finding was identified as a predictor for either an antimicrobial response or for a corticosteroid response in this study. The presence of cavity formation and pleural effusion may predict a poor prognosis.
  • Hideki Nakasone, Mats Remberger, Lu Tian, Petter Brodin, Bita Sahaf, Fang Wu, Jonas Mattsson, Robert Lowsky, Robert Negrin, David B Miklos, Everett Meyer
    Haematologica 100 11 1477 - 85 2015年11月 [査読有り][通常論文]
     
    Sex-mismatched hematopoietic cell transplantation is linked to increased graft-versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reduced-intensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with anti-thymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus-leukemia effect resulted in superior overall survival in recipients of sex-mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex-matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection.
  • Yu Akahoshi, Shinichi Kako, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Junji Nishida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 20 7 410 - 5 2015年08月 [査読有り][通常論文]
     
    OBJECTIVES: Limited data are available on the effect of how cyclophosphamide (CY) and total body irradiation (TBI) are administered. We analyzed the effect of the interval from TBI to hematopoietic stem cell transplantation (HSCT) on the outcome of HSCT. METHODS: Adult patients who underwent HSCT using myeloablative conditioning consisting of TBI and CY were retrospectively analyzed. They were divided into three groups according to the duration between the start of TBI and HSCT (Group A: 2-4 days, Group B: 5-8 days, Group C: 9-10 days). RESULTS: Seventy-five adult patients were included. The 3-year overall survival rate was 56, 47, and 77% in Groups A, B, and C, respectively (P = 0.14). Similarly, there was no significant difference among the three groups with respect to progression-free survival (57, 47, and 72%, P = 0.17), relapse rate (32, 37, and 16%, P = 0.29), or non-relapse mortality (8, 14, and 12%, P = 0.81). In addition, we observed no significant difference among the three groups with respect to the incidence of grade II-IV acute graft-versus-host disease (GVHD) (31, 47, and 32%, respectively, P = 0.56) and that of chronic GVHD (23, 23, and 22%, respectively, P = 0.97). DISCUSSION AND CONCLUSION: Although recipient immune system at HSCT might be affected by the timing of TBI, the duration between the start of TBI and HSCT did not influence the outcome of HSCT using myeloablative conditioning with TBI and CY.
  • Koji Kawamura, Jin Hayakawa, Yu Akahoshi, Naonori Harada, Hirofumi Nakano, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Shinichi Kako, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    International journal of hematology 102 2 230 - 7 2015年08月 [査読有り][通常論文]
     
    Limited data are available on prophylaxis for herpes simplex virus (HSV) and varicella zoster virus (VZV) disease following autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively reviewed the clinical charts of 105 consecutive patients who underwent their first auto-HCT at our institution between September 2007 and June 2014. Before August 2009, 30 patients received oral acyclovir at 1000 mg/day until engraftment, whereas after September 2009, 69 patients received oral acyclovir at 200 mg/day. After engraftment, acyclovir was continued at 200 mg/day at the discretion of the attending physicians in both groups. The cumulative incidence of HSV disease at 1 year after auto-HCT was 7.7 and 4.5 % in patients who received oral acyclovir at 1000 and 200 mg/day, respectively (P = 0.75). Patients were next divided into three groups according to the timing at which acyclovir prophylaxis was stopped after auto-HCT; at engraftment, between engraftment and 1 year after auto-HCT, and later than 1 year. The cumulative incidence of VZV disease was 25.8, 7.7, and 0.0 % at 1 year, respectively. This study suggests that low-dose acyclovir prophylaxis may be effective for preventing HSV and VZV disease after auto-HCT. Our findings support the recommendation of acyclovir prophylaxis within the first year after auto-HCT.
  • Hideki Nakasone, Lu Tian, Bita Sahaf, Takakazu Kawase, Kelsi Schoenrock, Spenser Perloff, Christine E Ryan, Jed Paul, Rakesh Popli, Fang Wu, Joanne M Otani, John Coller, Edus H Warren 3rd, David B Miklos
    Blood 125 20 3193 - 201 2015年05月 [査読有り][通常論文]
     
    Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HY-Ab was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant.
  • Miki Sato, Shinichi Kako, Kana Matsumoto, Kumi Oshima, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Ryoko Yamasaki, Hidenori Wada, Yuko Ishihara, Kana Sakamoto, Koji Kawamura, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-Ichi Kimura, Hideki Nakasone, Misato Kikuchi, Aki Tanihara, Rie Yamazaki, Yukie Tanaka, Junya Kanda, Junji Nishida, Kunihiko Morita, Yoshinobu Kanda
    International Journal of Hematology 101 5 497 - 504 2015年05月 [査読有り][通常論文]
     
    In Japan, intravenous busulfan (ivBu) is usually given four times per day as an infusion at 0.8 mg/kg over 2 h. However, as this requires a midnight administration, a once-daily infusion of ivBu at 3.2 mg/kg over 3 h has been investigated as a more convenient and safer method. In this study, 20 Japanese patients received once-daily ivBu in conditioning regimens before allogeneic hematopoietic stem cell transplantation (HSCT), and blood samples were obtained just before, and 3, 3.5, 5, 7, 10, and 24 h after the initiation of ivBu infusion. The outcomes of HSCT were evaluated prospectively. The median area under the plasma concentration versus time curve (AUC) of Bu was 5272 μmol × min/L (range 3491–6284 μmol × min/L), and was similar to those in previous once-daily ivBu studies and to the estimated daily AUC in previous 4-times-daily ivBu studies. All of the patients but two, who died early due to infection, achieved neutrophil engraftment at a median of 25 days after transplantation. No patient was diagnosed with veno-occlusive disease according to the criteria established by Jones. No regimen-related toxicity was significantly associated with AUC. In conclusion, once-daily administration of ivBu has a stable pharmacokinetic profile, and was safely performed in Japanese patients.
  • S-I Kimura, T Murata, Y Akahoshi, H Nakano, T Ugai, H Wada, R Yamasaki, Y Ishihara, K Kawamura, K Sakamoto, M Ashizawa, M Sato, K Terasako-Saito, H Nakasone, M Kikuchi, R Yamazaki, S Kako, J Kanda, A Tanihara, J Nishida, Y Kanda
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 34 5 951 - 61 2015年05月 [査読有り][通常論文]
     
    We compared the expected medical costs of empirical and preemptive treatment strategies for invasive fungal infection in neutropenic patients with hematological diseases. Based on the results of two clinical trials with different backgrounds reported by Oshima et al. [J Antimicrob Chemother 60(2):350-355; Oshima study] and Cordonnier et al. [Clin Infect Dis 48(8):1042-1051; PREVERT study], we developed a decision tree model that represented the outcomes of empirical and preemptive treatment strategies, and estimated the expected medical costs of medications and examinations in the two strategies. We assumed that micafungin was started in the empirical group at 5 days after fever had developed, while voriconazole was started in the preemptive group only when certain criteria, such as positive test results of imaging studies and/or serum markers, were fulfilled. When we used an incidence of positive test results of 6.7 % based on the Oshima study, the expected medical costs of the empirical and preemptive groups were 288,198 and 150,280 yen, respectively. Even in the case of the PREVERT study, in which the incidence of positive test results was 32.9 %, the expected medical costs in the empirical and preemptive groups were 291,871 and 284,944 yen, respectively. A sensitivity analysis indicated that the expected medical costs in the preemptive group would exceed those in the empirical group when the incidence of positive test results in the former was over 34.4 %. These results suggest that a preemptive treatment strategy can be expected to reduce medical costs compared with empirical therapy in most clinical settings.
  • Miki Sato, Shinichi Kako, Kana Matsumoto, Kumi Oshima, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Ryoko Yamasaki, Hidenori Wada, Yuko Ishihara, Kana Sakamoto, Koji Kawamura, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-Ichi Kimura, Hideki Nakasone, Misato Kikuchi, Aki Tanihara, Rie Yamazaki, Yukie Tanaka, Junya Kanda, Junji Nishida, Kunihiko Morita, Yoshinobu Kanda
    International journal of hematology 101 5 497 - 504 2015年05月 [査読有り][通常論文]
     
    In Japan, intravenous busulfan (ivBu) is usually given four times per day as an infusion at 0.8 mg/kg over 2 h. However, as this requires a midnight administration, a once-daily infusion of ivBu at 3.2 mg/kg over 3 h has been investigated as a more convenient and safer method. In this study, 20 Japanese patients received once-daily ivBu in conditioning regimens before allogeneic hematopoietic stem cell transplantation (HSCT), and blood samples were obtained just before, and 3, 3.5, 5, 7, 10, and 24 h after the initiation of ivBu infusion. The outcomes of HSCT were evaluated prospectively. The median area under the plasma concentration versus time curve (AUC) of Bu was 5272 μmol × min/L (range 3491-6284 μmol × min/L), and was similar to those in previous once-daily ivBu studies and to the estimated daily AUC in previous 4-times-daily ivBu studies. All of the patients but two, who died early due to infection, achieved neutrophil engraftment at a median of 25 days after transplantation. No patient was diagnosed with veno-occlusive disease according to the criteria established by Jones. No regimen-related toxicity was significantly associated with AUC. In conclusion, once-daily administration of ivBu has a stable pharmacokinetic profile, and was safely performed in Japanese patients.
  • Shun-Ichi Kimura, Yu Akahoshi, Hirofumi Nakano, Naonori Harada, Kazuaki Kameda, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Junya Kanda, Shinichi Kako, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    The Journal of infection 70 5 520 - 40 2015年05月 [査読有り][通常論文]
     
    OBJECTIVES: We evaluated the incidence of and risk factors for false-positive Aspergillus galactomannan (GM) antigenemia in allogeneic hematopoietic stem cell transplantation (HSCT). We also focused on the GM index value and its kinetics. METHODS: Patients who underwent their first allogeneic HSCT at our center between June 2007 and December 2012 were included (n = 172). Episodes of positive GM tests were classified as either "true-positive", which fulfilled the EORTC criteria for proven or probable invasive aspergillosis (IA), or "false-positive", which was not accompanied by clinical findings. The remaining cases were regarded as "inconclusive". RESULTS: The one-year cumulative incidences of IA and positive GM tests were 10.1% and 48.1%, respectively. Among 148 episodes of positive GM tests, 97(65.5%), 23(15.5%), and 28(19.0%) were classified as false-positive, true-positive and inconclusive, respectively. In the first episodes of positive GM tests in each patient (false-positive = 67, others = 30), an increase in the GM value in the first two measurements, neutropenia, and use of anti-mold agents at positive GM episode were associated with a significantly lower possibility of false-positive results according to a multivariate analysis. CONCLUSIONS: A false-positive GM test was frequently seen after allogeneic HSCT. An increase in the GM value may increase its positive predictive value.
  • Hideki Nakasone, Bita Sahaf, David B Miklos
    International journal of hematology 101 5 438 - 51 2015年05月 [査読有り][通常論文]
     
    Allogeneic hematopoietic cell transplantation (allo-HCT) can be a curative strategy for hematological diseases, and the indications for allo-HCT have broadened widely due to recent progress in supportive strategies. However, patients must overcome various complications and chronic graft-versus-host disease (cGVHD) remains the most common allo-HCT cause of long-term morbidity and mortality. cGVHD is difficult to biologically assess due to the heterogeneity of cGVHD symptoms, and the pathogenesis of cGVHD has yet to be established. Recent experimental model progress has suggested that B-cells play a critical role in cGVHD development. Consistent with these experimental results, some clinical studies investigating B-cell depletion and modulation of B-cell signaling pathways have decreased cGVHD incidence and provided some therapeutic benefit. However, randomized control studies are necessary to confirm the efficacy of B-cell targeting drugs for cGVHD. Here, we review the pathophysiology of cGVHD, especially focusing on the role of B-cell immunity, and discuss the efficacy of both B-cell depletion and modulation of B-cell signaling pathways in human cGVHD prevention, initial treatment, and salvage treatment.
  • H. Nakasone, T. Fukuda, J. Kanda, T. Mori, S. Yano, T. Kobayashi, K. Miyamura, T. Eto, H. Kanamori, K. Iwato, N. Uchida, S. Mori, T. Nagamura-Inoue, T. Ichinohe, Y. Atsuta, T. Teshima, M. Murata
    Bone Marrow Transplantation 50 4 559 - 565 2015年04月 [査読無し][通常論文]
     
    The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P< 0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P< 0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.
  • H Nakasone, T Fukuda, J Kanda, T Mori, S Yano, T Kobayashi, K Miyamura, T Eto, H Kanamori, K Iwato, N Uchida, S Mori, T Nagamura-Inoue, T Ichinohe, Y Atsuta, T Teshima, M Murata
    Bone marrow transplantation 50 4 559 - 65 2015年04月 [査読有り][通常論文]
     
    The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (P<0.001). In a multivariate analysis, TBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, P<0.01), whereas TBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.
  • Koji Kawamura, Rie Yamazaki, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Shun-ichi Kimura, Misato Kikuchi, Hideki Nakasone, Junya Kanda, Shinichi Kako, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 20 2 77 - 82 2015年03月 [査読有り][通常論文]
     
    BACKGROUND: Previous studies have shown that most patients lose immunity to measles, mumps, and rubella (MMR) during long-term follow-up after allogeneic hematopoietic stem cell transplantation (HSCT), and immunizations against them have been investigated. However, these previous studies mainly targeted pediatric patients and information in adult patients is still insufficient. METHODS: We evaluated the immunity to MMR in 45 adult allogeneic HSCT patients. None of these patients received vaccination after HSCT. RESULTS: The seropositive rates at six years after allogeneic HSCT were estimated to be less than 44% for measles, less than 10% for mumps, and less than 36% for rubella. Thirteen of the 16 female patients who were 16-39 years old were negative or equivocal for rubella. Patients who developed grade II-IV acute graft-versus-host disease tended to become seronegative for measles and rubella at two years after HSCT, although the difference was not statistically significant. CONCLUSIONS: This study showed that most adult patients lost immunity to MMR after allogeneic HSCT. Although we did not evaluate the safety and efficacy of vaccination in this study, most HSCT guidelines recommend vaccination for HSCT recipients without active chronic graft-versus-host disease or ongoing immunosuppressive therapy at 24 months after HSCT. Immunization against rubella is especially important for female patients of reproductive age. Further studies will be necessary to evaluate the effect of vaccination on the antibody response in adult allogeneic HSCT recipients.
  • Misato Kikuchi, Hideki Nakasone, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Kana Sakamoto, Koji Kawamura, Yuko Ishihara, Miki Sato, Masahiro Ashizawa, Kiriko Terasako-Saito, Shun-ichi Kimura, Rie Yamazaki, Shinichi Kako, Junya Kanda, Junji Nishida, Naohiro Sekiguchi, Satoshi Noto, Michiko Kida, Akira Hangaishi, Kensuke Usuki, Yoshinobu Kanda
    Journal of chemotherapy (Florence, Italy) 27 2 99 - 105 2015年02月 [査読有り][通常論文]
     
    Elderly patients with non-Hodgkin lymphoma (NHL) have a poor prognosis. Owing to treatment-related toxicities, there is no standard chemotherapy for the elderly patients, especially those aged 70 years or older. In this study, we retrospectively evaluated the efficacy and toxicity of reduced-dose (two-thirds) R-CHOP chemotherapy as an initial chemotherapy for 45 patients aged 70 years or older with B-cell NHL. The WHO classification of NHL included diffuse large B-cell lymphoma (DLBCL) (31), mantle cell lymphoma (5), follicular lymphoma (4), extranodal marginal zone lymphoma (1), Burkitt lymphoma (1), and B-cell lymphoma whose further types were unclassified (3). The incidences of grade 4 neutropenia and febrile neutropenia (FN) were 51.1 and 15.6%, respectively. Efficacy was evaluated in patients with DLBCL. The overall and complete response (CR) rates were 96.7 and 90.0%, respectively. Two-year event-free survival (EFS) and overall survival (OS) were 84.4 and 89.2%, respectively. There was no treatment-related mortality. In conclusion, two-thirds R-CHOP chemotherapy is a promising treatment for elderly patients with B-cell NHL in terms of its efficacy and toxicity.
  • K Terasako-Saito, H Nakasone, Y Tanaka, R Yamazaki, M Sato, K Sakamoto, Y Ishihara, K Kawamura, Y Akahoshi, J Hayakawa, H Wada, N Harada, H Nakano, K Kameda, T Ugai, R Yamasaki, M Ashizawa, S-I Kimura, M Kikuchi, A Tanihara, J Kanda, S Kako, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 16 6 930 - 40 2014年12月 [査読有り][通常論文]
     
    BACKGROUND: Cytomegalovirus (CMV)-specific CD8(+) cytotoxic T lymphocytes (CMV-CTLs) play a crucial role in preventing CMV disease. However, the actual in vivo dynamics of CMV-CTL clones after allogeneic hematopoietic stem cell transplantation (alloHCT) are still unclear. METHODS: Using a single-cell T-cell receptor repertoire analysis, we monitored clones and chimerism of CMV-CTLs in 3 CMV-seropositive alloHCT recipients from CMV-seronegative donors, with or without CMV reactivation. RESULTS: Nearly all of the CMV-CTLs during follow-up were CD45RA(-) CCR7(-) effector memory/CD45RA(+) CCR7(-) effector T cells, and were highly matured. In each case, the use of BV gene families was restricted, especially in BV5, 7, 28, and 29. Although no common predominant CMV-CTL clones were found, several shared motifs of complementarity-determining region-3 were identified among the 3 cases; QGA in all, TGE and TDT in Case 1 and Case 2, and RDRG in Case 2 and Case 3. In all cases, CMV-CTL clones that were detected for the first time after alloHCT persisted as the dominant clones. In Case 1, without CMV reactivation, recipient-derived CMV-CTLs exclusively persisted as a dominant clone, while all CMV-CTLs in the other 2 cases, with CMV reactivation, were donor derived. CONCLUSION: Clone monitoring and chimerism analyses should help to further clarify novel aspects of immuno-reconstitution after alloHCT.
  • R. Yamazaki, Y. Tanaka, H. Nakasone, M. Sato, K. Terasako-Saito, K. Sakamoto, Y. Akahoshi, H. Nakano, T. Ugai, R. Yamasaki, H. Wada, Y. Ishihara, K. Kawamura, M. Ashizawa, S. I. Kimura, M. Kikuchi, S. Kako, J. Kanda, A. Tanihara, J. Nishida, Y. Kanda
    Transplant Infectious Disease 16 6 904 - 913 2014年12月 [査読有り][通常論文]
     
    Background: Cytomegalovirus (CMV) reactivation still remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT). Patients and methods: In this study, we analyzed an immunoglobulin allotype, IgG1m(f), in CMV-seropositive HSCT recipients and their donors to distinguish donor-derived antibody from recipient-derived antibody. Eight donor-recipient pairs were informative regarding the appearance of donor-derived immunoglobulin-G (IgG), as the recipients were homozygous null for the IgG1m(f) allotype and the donors were IgG1m(f) positive. In these patients, total IgG, IgM, and allotype-specific IgG against CMV were measured by enzyme-linked immunosorbent assay. All subjects were monitored for at least 9 months after HSCT with (n = 5) or without (n = 3) CMV reactivation. Results: Donor-derived CMV IgG tended to be elevated earlier in patients with CMV-seropositive donors than in those with CMV-seronegative donors. In 1 patient with a CMV-negative donor, donor-derived CMV IgG was not detected until late CMV reactivation. In 3 patients without CMV reactivation, donor-derived CMV IgG was also elevated within 1-6 months after HSCT. Conclusion: In conclusion, the CMV serostatus of the donor may be related to the timing of the appearance of donor-derived CMV IgG and the reconstitution of humoral immunity against CMV, regardless of the CMV antigenemia level after HSCT.
  • Yuko Ishihara, Junya Kanda, Kaori Tanaka, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Shinichi Kako, Junji Nishida, Kunitomo Watanabe, Yoshinobu Kanda
    International journal of hematology 100 6 607 - 10 2014年12月 [査読有り][通常論文]
     
    We report a case of severe oral infection with a high fever due to Lactobacillus rhamnosus during induction chemotherapy for acute myeloid leukemia. The patient did not improve on treatment with meropenem, clindamycin, or vancomycin until neutrophil recovery. Since L. rhamnosus GG is used in dairy products, and the patient ingested dairy products daily before starting chemotherapy, we suspected an association between the ingestion of dairy products and the development of infection. Pulsed-field gel electrophoresis using two different restriction enzymes showed that the strain isolated from the patient was identical to the L. rhamnosus GG strain isolated from dairy products and ATCC #53103. This was confirmed by a PCR assay with species-specific L. rhamnosus GG primers. Since Lactobacillus infection, particularly L. rhamnosus infection, can be fatal in immunocompromised hosts, we should consider Lactobacillus as a causative organism when Gram-positive rods are detected during treatment with broad-spectrum antibiotics and vancomycin. The causal association between the ingestion of dairy products containing Lactobacillus and Lactobacillus infection in immunocompromised hosts warrants further study.
  • R Yamazaki, Y Tanaka, H Nakasone, M Sato, K Terasako-Saito, K Sakamoto, Y Akahoshi, H Nakano, T Ugai, R Yamasaki, H Wada, Y Ishihara, K Kawamura, M Ashizawa, S-I Kimura, M Kikuchi, S Kako, J Kanda, A Tanihara, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 16 6 904 - 13 2014年12月 [査読有り][通常論文]
     
    BACKGROUND: Cytomegalovirus (CMV) reactivation still remains a major problem following allogeneic hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: In this study, we analyzed an immunoglobulin allotype, IgG1m(f), in CMV-seropositive HSCT recipients and their donors to distinguish donor-derived antibody from recipient-derived antibody. Eight donor-recipient pairs were informative regarding the appearance of donor-derived immunoglobulin-G (IgG), as the recipients were homozygous null for the IgG1m(f) allotype and the donors were IgG1m(f) positive. In these patients, total IgG, IgM, and allotype-specific IgG against CMV were measured by enzyme-linked immunosorbent assay. All subjects were monitored for at least 9 months after HSCT with (n = 5) or without (n = 3) CMV reactivation. RESULTS: Donor-derived CMV IgG tended to be elevated earlier in patients with CMV-seropositive donors than in those with CMV-seronegative donors. In 1 patient with a CMV-negative donor, donor-derived CMV IgG was not detected until late CMV reactivation. In 3 patients without CMV reactivation, donor-derived CMV IgG was also elevated within 1-6 months after HSCT. CONCLUSION: In conclusion, the CMV serostatus of the donor may be related to the timing of the appearance of donor-derived CMV IgG and the reconstitution of humoral immunity against CMV, regardless of the CMV antigenemia level after HSCT.
  • K. Terasako-Saito, H. Nakasone, Y. Tanaka, R. Yamazaki, M. Sato, K. Sakamoto, Y. Ishihara, K. Kawamura, Y. Akahoshi, J. Hayakawa, H. Wada, N. Harada, H. Nakano, K. Kameda, T. Ugai, R. Yamasaki, M. Ashizawa, S. -I. Kimura, M. Kikuchi, A. Tanihara, J. Kanda, S. Kako, J. Nishida, Y. Kanda
    TRANSPLANT INFECTIOUS DISEASE 16 6 930 - 940 2014年12月 [査読有り][通常論文]
     
    BackgroundCytomegalovirus (CMV)-specific CD8(+) cytotoxic T lymphocytes (CMV-CTLs) play a crucial role in preventing CMV disease. However, the actual in vivo dynamics of CMV-CTL clones after allogeneic hematopoietic stem cell transplantation (alloHCT) are still unclear. MethodsUsing a single-cell T-cell receptor repertoire analysis, we monitored clones and chimerism of CMV-CTLs in 3 CMV-seropositive alloHCT recipients from CMV-seronegative donors, with or without CMV reactivation. ResultsNearly all of the CMV-CTLs during follow-up were CD45RA(-)CCR7(-) effector memory/CD45RA(+)CCR7(-) effector T cells, and were highly matured. In each case, the use of BV gene families was restricted, especially in BV5, 7, 28, and 29. Although no common predominant CMV-CTL clones were found, several shared motifs of complementarity-determining region-3 were identified among the 3 cases; QGA in all, TGE and TDT in Case 1 and Case 2, and RDRG in Case 2 and Case 3. In all cases, CMV-CTL clones that were detected for the first time after alloHCT persisted as the dominant clones. In Case 1, without CMV reactivation, recipient-derived CMV-CTLs exclusively persisted as a dominant clone, while all CMV-CTLs in the other 2 cases, with CMV reactivation, were donor derived. ConclusionClone monitoring and chimerism analyses should help to further clarify novel aspects of immuno-reconstitution after alloHCT.
  • Ishihara Yuko, Kimura Shun-ichi, Akahoshi Yu, Nakano Hirofumi, Ugai Tomotaka, Wada Hidenori, Yamasaki Ryoko, Kawamura Koji, Sakamoto Kana, Ashizawa Masahiro, Sato Miki, Terasako Kiriko, Kikuchi Misato, Nakasone Hideki, Yamazaki Rie, Kanda Junya, Kako Shinichi, Nishida Junji, Usuki Kensuke, Kanda Yoshinobu
    臨床血液 55 9 1374  (一社)日本血液学会-東京事務局 2014年09月 [査読無し][通常論文]
  • Sato Miki, Kako Shinichi, Matsumoto Kana, Oshima Kumi, Akahoshi Yu, Nakano Hirofumi, Ugai Tomotaka, Yamasaki Ryoko, Wada Hidenori, Ishihara Yuko, Sakamoto Kana, Kawamura Koji, Ashizawa Masahiro, Saito Kiriko, Kimura Jun-ichi, Nakasone Hideki, Kikuchi Misato, Yamazaki Rie, Tanaka Yukie, Kanda Jyunya, Nishida Jyunji, Morita Kunihiko, Kanda Yoshinobu
    臨床血液 55 9 1328  (一社)日本血液学会-東京事務局 2014年09月 [査読無し][通常論文]
  • Shun-ichi Kimura, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    The Journal of infection 69 1 13 - 25 2014年07月 [査読有り][通常論文]
     
    OBJECTIVES: We performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients. METHODS: We collected reports from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, along with references cited therein. We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. RESULTS: Seventeen trials with 1453 autologous and allogeneic HSCT recipients were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotics in two trials. Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones. One trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95%CI 0.09-0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22-0.63) and bacteremia (OR 0.31; 95%CI 0.16-0.59) without significantly affecting all-cause mortality or infection-related mortality. CONCLUSIONS: Systemic antibiotic prophylaxis successfully reduced the incidence of infection. However, there was no significant impact on mortality. The clinical benefits of prophylaxis with fluoroquinolones were inconclusive because of the small number of clinical trials evaluated.
  • Rakesh Popli, Bita Sahaf, Hideki Nakasone, Joyce Yeuk Yu Lee, David B Miklos
    Immunologic research 58 2-3 249 - 58 2014年05月 [査読有り][通常論文]
     
    H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.
  • M Sato, H Nakasone, K Terasako-Saito, K Sakamoto, R Yamazaki, Y Tanaka, Y Akahoshi, H Nakano, T Ugai, H Wada, R Yamasaki, Y Ishihara, K Kawamura, M Ashizawa, S-i Kimura, M Kikuchi, A Tanihara, J Kanda, S Kako, J Nishida, Y Kanda
    Bone marrow transplantation 49 4 553 - 60 2014年04月 [査読有り][通常論文]
     
    We previously reported that the baseline C-reactive protein level did not predict infectious events after hematopoietic cell transplantation (HCT). Procalcitonin (PCT) has recently emerged as a powerful biomarker for the early diagnosis of bacterial infection. We evaluated the ability of the baseline PCT level to predict early infectious events after HCT in 79 recipients who received HCT between 2008 and 2012. The high-PCT group (≥ 0.07 ng/mL, n=27) frequently experienced documented infection (DI) (21.2% vs 44.4% at day 30, P=0.038) and bloodstream infection (BSI) (15.4% vs 37.0% at day 30, P=0.035). In a multivariate analysis, however, the baseline PCT level was not significantly associated with DI (HR 2.01, P=0.089) or BSI (HR 2.28, P=0.084). Localized infection, such as anal canal problems, before the start of conditioning was seen in 26 patients. When we stratified the patients according to the presence of elevated PCT and localized infection, the group with elevated PCT and localized infection (n=17) was significantly associated with increased DI (HR 3.40, P=0.0074) and BSI (HR 3.59 P=0.0078) after HCT. A larger prospective observation is warranted to confirm the impact of the baseline PCT level and clinical features on the outcome of HCT.
  • Kana Sakamoto, Hideki Nakasone, Shigeharu Tsurumi, Ko Sasaki, Kinuko Mitani, Michiko Kida, Akira Hangaishi, Kensuke Usuki, Ayako Kobayashi, Ken Sato, Mariko Karasawa-Yamaguchi, Koji Izutsu, Yasushi Okoshi, Shigeru Chiba, Yoshinobu Kanda
    Journal of thrombosis and thrombolysis 37 3 279 - 86 2014年04月 [査読有り][通常論文]
     
    High-dose dexamethasone (HDD) has been shown to be an effective initial treatment for immune thrombocytopenia (ITP), but it is not clear whether HDD offers any advantages over conventional-dose prednisone (PSL). We retrospectively compared the efficacy and toxicity of HDD and PSL for newly diagnosed ITP. The response was evaluated according to the International Working Group (IWG) criteria. We analyzed data from 31 and 69 patients in the HDD and PSL groups, respectively. There were no significant differences in patient characteristics between the two groups except for the incidence of the eradication of Helicobacter pylori. The response rate was better in the HDD group (42.7 vs. 28.4 %), and this difference was statistically significant when adjusted for other factors including the eradication of H. pylori. In the HDD group, a response was achieved earlier (28 vs. 152 days in median) and steroids were more frequently discontinued at 6 months (64.5 vs. 37.7 %). Among patients who achieved a response, there was no significant difference in the incidence of loss of response. There were no significant differences in the rate of adverse events, transition to chronic ITP, and splenectomy. In conclusion, HDD might enable the early cessation of steroids without a loss of response.
  • Hideki Nakasone, Kiriko Terasako-Saito, Rie Yamazaki, Miki Sato, Yukie Tanaka, Kana Sakamoto, Masakazu Kurita, Ryoko Yamasaki, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Tomohito Machishima, Masahiro Ashizawa, Shun-ichi Kimura, Misato Kikuchi, Aki Tanihara, Junya Kanda, Shinichi Kako, Junji Nishida, Shigeki Yamada, Yoshinobu Kanda
    EXPERIMENTAL HEMATOLOGY 42 4 261 - 273 2014年04月 [査読有り][通常論文]
     
    Adiponectin has been shown to play a critical role in immunity. Recently, we reported that the adiponectin levels after allogeneic stem cell transplantation were higher in recipients with chronic graft-versus-host disease (cGVHD). However, the effects of adiponectin on extracellular matrix (ECM) and regulatory factors in dermal fibroblasts remain unclear. We compared the messenger RNA (mRNA) levels of collagen typel (COL1A), fibronectin 1 (FN1), matrix metalloproteinase (MMP)1, MMP3, tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, transforming growth factor-beta (TGF-beta), and TGF-beta receptor 2 (TGF-beta R2 in human normal dermal fibroblasts cultured with and without adiponectin, and we assessed the degree of synthesis of ECMs by immunolluorescent microscopy. Furthermore, we also assessed these mRNA levels after blocking of TGF-beta R2. Adiponectin induced higher mRNA levels of FN1, MMP1, MMP3, TIMP1, TIMP3, and TGF-beta R2 in a dose-dependent manner, but did not significantly affect COL1A or TGF-beta. In addition, adiponectin was shown to upregulate FN1, MMPs, and TIMPs after blocking of TGF-beta R2. Immunofluorescent microscopy revealed that adiponectin promoted a greater synthesis of ECMs than in the control in vitro. The finding that adiponectin upregulated ECM-associated factors might mean that high levels of adiponectin could modulate dermal fibrosis was observed in recipients with cGVHD. Further basic investigation is warranted to elucidate whether the adiponectin-pathway could be a target for the treatment of sclerotic cGVHD.(C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
  • M. Sato, H. Nakasone, K. Terasako-Saito, K. Sakamoto, R. Yamazaki, Y. Tanaka, Y. Akahoshi, H. Nakano, T. Ugai, H. Wada, R. Yamasaki, Y. Ishihara, K. Kawamura, M. Ashizawa, S-i Kimura, M. Kikuchi, A. Tanihara, J. Kanda, S. Kako, J. Nishida, Y. Kanda
    BONE MARROW TRANSPLANTATION 49 4 553 - 560 2014年04月 [査読有り][通常論文]
     
    We previously reported that the baseline C-reactive protein level did not predict infectious events after hematopoietic cell transplantation (HCT). Procalcitonin (PCT) has recently emerged as a powerful biomarker for the early diagnosis of bacterial infection. We evaluated the ability of the baseline PCT level to predict early infectious events after HCT in 79 recipients who received HCT between 2008 and 2012. The high-PCT group (>= 0.07 ng/ mL, n = 27) frequently experienced documented infection (DI) (21.2% vs 44.4% at day 30, P = 0.038) and bloodstream infection (BSI) (15.4% vs 37.0% at day 30, P = 0.035). In a multivariate analysis, however, the baseline PCT level was not significantly associated with DI (HR 2.01, P = 0.089) or BSI (HR 2.28, P = 0.084). Localized infection, such as anal canal problems, before the start of conditioning was seen in 26 patients. When we stratified the patients according to the presence of elevated PCT and localized infection, the group with elevated PCT and localized infection (n = 17) was significantly associated with increased DI (HR 3.40, P = 0.0074) and BSI (HR 3.59 P = 0.0078) after HCT. A larger prospective observation is warranted to confirm the impact of the baseline PCT level and clinical features on the outcome of HCT.
  • Yukie Tanaka, Rie Yamazaki, Kiriko Terasako-Saito, Hideki Nakasone, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Shun-ichi Kimura, Misato Kikuchi, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Immunol. Lett. 158 1-2 120 - 125 2014年03月 [査読有り][通常論文]
     
    Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax301-309-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-β chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) ATL patients. Therefore, in this study, we prepared an HTLV-1 Tax301-309 peptide-specific CTL clone (HT-9) expressing PDR-mo
  • Shun-ichi Kimura, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Ryoko Yamasaki, Masahiro Ashizawa, Tomohito Machishima, Miki Sato, Kiriko Terasako, Hideki Nakasone, Misato Kikuchi, Shinya Okuda, Shinichi Kako, Junya Kanda, Rie Yamazaki, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 19 2 107 - 12 2014年03月 [査読有り][通常論文]
     
    The D-index is calculated as the area over the neutrophil curve during neutropenia. We investigated the impact of the D-index on pulmonary infection in 33 acute myeloid leukemia patients undergoing consolidation chemotherapy with high-dose cytarabine. There was no difference in the D-index between chemotherapies with and without pulmonary infection. The cumulative D-index (c-D-index) until the development of infection exceeded 4000 in four of five patients with pulmonary infection. Although there was no difference in the total D-index throughout the overall consolidation chemotherapy, the total D-index from induction to consolidation and the D-index at induction chemotherapy were higher in patients with pulmonary infection during consolidation than in those without it (P = 0.014 and 0.019, respectively). Our results showed that the cumulative effect of neutropenia might determine the risk of pulmonary infection in consolidation chemotherapy. We are planning a clinical trial of c-D-index-guided preemptive antifungal therapy.
  • Tanaka Y, Yamazaki R, Terasako-Saito K, Nakasone H, Akahoshi Y, Nakano H, Ugai T, Wada H, Yamasaki R, Ishihara Y, Kawamura K, Sakamoto K, Ashizawa M, Sato M, Kimura S, Kikuchi M, Kako S, Kanda J, Tanihara A, Nishida J, Kanda Y
    Immunology letters 158 1-2 120 - 125 2014年03月 [査読有り][通常論文]
     
    Adult T cell leukemia/lymphoma (ATL) is an aggressive mature T cell malignancy that is causally associated with human T cell lymphotropic virus type 1 (HTLV-1) infection. The HTLV-1 regulatory protein Tax aggressively accelerates the proliferation of host cells and is also an important target antigen for CD8(+) cytotoxic T cells (CTLs). We previously reported that several predominant HLA-A*24:02-restricted HTLV-1 Tax(301-309)-specific CTL clones commonly expressed a particular amino acid sequence motif (P-D-R) in complementarity-determining region 3 of T-cell receptor (TCR)-beta chain among unrelated ATL patients who underwent allogeneic stem cell transplantation (allo-HSCT). Furthermore, a PDR-motif(+) CTL clone persistently existed in a long-term survivor as a central CTL clone with strong CTL activities after HSCT. Although a larger analysis of the relationship between PDR-motif(+) CTLs and the clinical course is required, the expression of PDR-motif(+) TCR on CD8(+) T cells may play a critical role in the management of anti-HTLV-1 activities for HLA-A24:02(+) An patients. Therefore, in this study, we prepared an HTLV-1 Tax(301-309) peptide-specific CTL clone (HT-9) expressing PDR-motif(+) TCR isolated from a long-term survivor after HSCT, and evaluated its CTL activity against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients. Before the assay of CTL function, we confirmed that HT-9 expressed less-differentiated effector-memory phenotypes (CD45RA(-)CCR7(-)CD27(+)CD28(+/-)CD57(+/-)) and T-cell exhaustion marker PD-1(+). In assays of CTL function, HT-9 recognized HTLV-1 Tax in an HLA-restricted fashion and demonstrated strong CTL activities against a variety of HTLV-1-infected T-cells from HLA-A*24:02(+) ATL patients regardless of whether the sources were autologous or allogeneic, but not normal cells. These data indicate that PDR-motif(+) TCR could be an important TCR candidate for TCR-gene immunotherapy for HLA-A24:02(+) ATL patients, provided that the CTL activities against HTLV-1 are reproduced in in vivo experiments using mouse models. (C) 2013 Elsevier B.V. All rights reserved.
  • Masahiro Ashizawa, Yu Akahoshi, Hirofumi Nakano, Tomotaka Ugai, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Kiriko Terasako, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Shinichi Kako, Junya Kanda, Rie Yamazaki, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    International journal of hematology 99 3 311 - 7 2014年03月 [査読有り][通常論文]
     
    Conditioning regimens consisting of reduced-dose cyclophosphamide (CY) and fludarabine (FDR) have been investigated for use in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aplastic anemia to reduce the toxicities associated with CY. However, the ideal dose of CY has not been identified. In addition, little information is available regarding donor cell chimerism after allo-HSCT with these regimens. Therefore, we retrospectively analyzed 13 patients who underwent allo-HSCT with half-dose CY (100 mg/kg in total), FDR, and anti-thymocyte globulin at total doses of 2.5-10 mg/kg at our center. All the patients except one, who died due to encephalopathy on day 20, achieved neutrophil engraftment a median of 18.5 days after HSCT with complete donor-type chimerism. Two patients who received a graft from an HLA-matched donor subsequently developed mixed chimerism (MC) associated with transfusion-dependent cytopenia. One became transfusion-independent after donor lymphocyte infusion, but continues to exhibit MC. The other regained complete donor-type chimerism after the cessation of cyclosporine, but remains transfusion-dependent. These findings suggest that a conditioning regimen with half-dose CY and FDR is effective for achieving neutrophil engraftment and complete donor-type chimerism. However, subsequent MC may be observed, especially after HLA-matched HSCT.
  • Hideki Nakasone, Takahiro Fukuda, Junya Kanda, Takehiko Mori, Takanori Teshima, Shingo Yano, Naoyuki Uchida, Kazuhiko Kakihana, Tetsuya Eto, Shin-Ichiro Mori, Tokiko Nagamura, Tatsuo Ichinohe, Yoshiko Atsuta, Makoto Murata
    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 20 2 S275 - S276 2014年02月 [査読無し][通常論文]
  • Yoshinobu Kanda, Hidenori Wada, Ryoko Yamasaki, Koji Kawamura, Yuko Ishihara, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Tomohito Machishima, Kiriko Terasako-Saito, Shun-Ichi Kimura, Hideki Nakasone, Misato Kikuchi, Rie Yamazaki, Junya Kanda, Shinichi Kako, Junji Nishida, Hidekazu Tsunoda, Yoshio Omori, Masanori Nakazawa, Osamu Tanaka
    Annals of hematology 93 2 287 - 92 2014年02月 [査読有り][通常論文]
     
    To prevent ovarian dysfunction due to total body irradiation, we started ovarian shielding at our center (Saitama Medical Center, Jichi Medical University (SMC-JMU)) with a long source axis distance, which is different from the original method used at the University of Tokyo Hospital (UTH). We retrospectively analyzed the outcome of eight patients with a median age of 20.5 years from SMC-JMU and compared the results with the published data for eight patients with a median age of 22 years from UTH. The recovery of ovarian function was observed in five and six patients, respectively. The cumulative incidence of ovarian recovery, while treating relapse and death without ovarian recovery as competing risks, was 68.8 % at 2 years after transplantation in the total population, and there was no statistically significant difference between the two institutions (p = 0.85). Age and the history of previous chemotherapy did not affect the incidence of ovarian recovery. Two patients from each center had a relapse of leukemia. Overall, among the 11 patients who have survived without relapse, only one has not achieved ovarian recovery. In conclusion, ovarian shielding with both methods strongly protected ovarian function. However, we should continue to monitor the relapse rate among patients who undergo this procedure.
  • J Kanda, H Nakasone, Y Atsuta, T Toubai, H Yokoyama, T Fukuda, S Taniguchi, K Ohashi, H Ogawa, T Eto, K Miyamura, Y Morishima, T Nagamura-Inoue, H Sakamaki, M Murata
    Bone marrow transplantation 49 2 228 - 35 2014年02月 [査読有り][通常論文]
     
    Few studies have evaluated the risk factors for chronic GVHD and organ involvement associated with different graft types, including unrelated cord blood (U-CB). We retrospectively studied 4818 adult patients who received their first allogeneic transplantation and survived for at least 100 days. The incidence of chronic GVHD at 2 years was 37%. The following factors were associated with the development of chronic GVHD: female donor/male recipient, CMV-Ab seropositivity, matched related peripheral blood grafts vs matched related BM grafts, no in vivo T-cell depletion and the occurrence of grade II-IV acute GVHD. Among these factors, the association with acute GVHD occurrence was consistently significant across donor subtypes. The use of U-CB was not associated with chronic GVHD, but was associated with a low incidence of extensive chronic GVHD. Chronic GVHD patients who had received U-CB transplants showed less frequent involvement of the oral cavity (28% vs 55%), eye (12% vs 26%), liver (20% vs 44%), lung (11% vs 25%) and joint (0% vs 6%) than those with matched related BM grafts. In conclusion, we found that U-CB transplants were associated with a low incidence of extensive chronic GVHD and less frequent involvement of the oral cavity, eye, liver, lung and joints.
  • Koji Kawamura, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Tomohito Machishima, Kiriko Terasako, Shun-Ichi Kimura, Misato Kikuchi, Hideki Nakasone, Rie Yamazaki, Junya Kanda, Shinichi Kako, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 19 26 - 32 2014年02月 [査読有り][通常論文]
     
    OBJECTIVES: To evaluate the prophylactic role of long-term ultra-low-dose acyclovir for varicella zoster virus (VZV) disease after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: We evaluated 141 patients who were planned to receive acyclovir at 200mg/day until the end of immunosuppressive therapy and for at least 1 year after HSCT in our center between June 2007 and June 2012. RESULTS: The cumulative incidence of VZV disease after HSCT was 4.5% at 1 year and 18.3% at 2 years. Protocol violation was the only independent significant factor that increased the incidence of VZV disease (hazard ratio (HR) 7.50, 95% confidence interval (CI) 3.60-15.63). Excluding patients with protocol violation, the discontinuation of acyclovir was the only significant factor for the development of VZV disease (HR 5.90, 95% CI 1.56-22.37). Six patients experienced breakthrough VZV disease, but four of these six had not taken acyclovir for several weeks before breakthrough VZV disease. On the other hand, the cumulative incidence of VZV disease after the cessation of acyclovir was 28.4% at 1 year and 38.0% at 2 years. The proportion of disseminated VZV disease was only 7% and no patient died directly of VZV disease. CONCLUSIONS: This study shows that long-term ultra-low-dose acyclovir appears to be effective for preventing VZV disease, especially disseminated VZV disease, after allogeneic HSCT. We recommend continuing acyclovir until the end of immunosuppressive therapy and for at least 1 year after HSCT, but additional strategies such as the administration of varicella vaccine may be needed to eradicate VZV disease.
  • H Nakasone, Y Tanaka, R Yamazaki, K Terasako, M Sato, K Sakamoto, R Yamasaki, H Wada, Y Ishihara, K Kawamura, T Machishima, M Ashizawa, S-I Kimura, M Kikuchi, A Tanihara, J Kanda, S Kako, J Nishida, Y Kanda
    Bone Marrow Transplant. 49 1 87 - 94 2014年 [査読有り][通常論文]
     
    Cellular immunity is important for the control of CMV infection after allogeneic hematopoietic cell transplantation (Allo-HCT). However, the actual in vivo dynamics of CMV-specific cytotoxic T cell (CMV-CTL) clones are still unclear. We conducted clone monitoring of tetramer(+) CMV-CTLs in HLA-A*2402-positive donor-patient pairs, using a direct single-cell analysis that enabled the simultaneous identification and quantification of CTL clones. Clone dynamics were assessed in three cases with or without CMV reactivation. In Case-1 without CMV reactivation, despite the long-term use of systemic steroid, dominant clones of Donor-1 persisted and remained dominant. The CMV-CTLs at 1 year after Allo-HCT included a high proportion of CD45RA(+)CCR7(-) effector and CD27(-)CD57(+)mature T cells. On the other hand, in Cases-2 and -3 with CMV reactivation, novel clones appeared and became dominant during the follow-up. Their CMV-CTLs included more CD27(+) immature T cells at 1 year after Allo-HCT. With regard to clonotypes, HLA-A*2402-restricted CMV-CTLs tended to select BV7 and BJ1-1 genes for complementarity-determining region 3 (CDR3) of T-cell receptor (TCR)-β. Specific amino-acid sequence
  • Nakasone H, Tanaka Y, Yamazaki R, Terasako K, Sato M, Sakamoto K, Yamasaki R, Wada H, Ishihara Y, Kawamura K, Machishima T, Ashizawa M, Kimura SI, Kikuchi M, Tanihara A, Kanda J, Kako S, Nishida J, Kanda Y
    Bone marrow transplantation 49 1 87 - 94 2014年01月 [査読有り][通常論文]
     
    Cellular immunity is important for the control of CMV infection after allogeneic hematopoietic cell transplantation (Allo-HCT). However, the actual in vivo dynamics of CMV-specific cytotoxic T cell (CMV-CTL) clones are still unclear. We conducted clone monitoring of tetramer(+) CMV-CTLs in HLA-A*2402-positive donor-patient pairs, using a direct single-cell analysis that enabled the simultaneous identification and quantification of CTL clones. Clone dynamics were assessed in three cases with or without CMV reactivation. In Case-1 without CMV reactivation, despite the long-term use of systemic steroid, dominant clones of Donor-1 persisted and remained dominant. The CMV-CTLs at 1 year after Allo-HCT included a high proportion of CD45RA(+)CCR7(-) effector and CD27(-)CD57(+)mature T cells. On the other hand, in Cases-2 and -3 with CMV reactivation, novel clones appeared and became dominant during the follow-up. Their CMV-CTLs included more CD27(+) immature T cells at 1 year after Allo-HCT. With regard to clonotypes, HLA-A*2402-restricted CMV-CTLs tended to select BV7 and BJ1-1 genes for complementarity-determining region 3 (CDR3) of T-cell receptor (TCR)-β. Specific amino-acid sequences of CDR3 of TCR-β were found in each case. Patterns of clone reconstitution and phenotype would be different according to CMV reactivation. In vivo clone monitoring of CMV-CTLs could provide insight into the mechanism of immunological reconstitution following Allo-HCT.
  • Koji Kawamura, Misato Kikuchi, Kiriko Terasako, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Tomohito Machishima, Shun-ichi Kimura, Hideki Nakasone, Shinya Okuda, Rie Yamazaki, Junya Kanda, Shinichi Kako, Yukie Tanaka, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 49 2 334 - 40 2013年10月 [査読有り][通常論文]
     
    Peripheral blood stem cell (PBSC) collection using granulocyte colony-stimulating factor (G-CSF) alone is superior to the combination of chemotherapy and G-CSF in terms of low morbidity, short duration of mobilization and low cost. We retrospectively compared the results of PBSC collection using G-CSF alone in 11 patients with malignant lymphoma (ML), 23 patients with plasma cell neoplasms (PCN) and 48 healthy donors. The geometric mean number of CD34(+) cells/kg obtained on the first day of collection was 0.99 × 10(6)/kg in ML patients, 2.26 × 10(6)/kg in PCN patients, and 3.36 × 10(6)/kg in healthy donors. The probability of collecting at least 1 × 10(6)/kg CD34(+) cells/kg during a single course of apheresis was 90.9% in ML patients, 95.7% in PCN patients, and 100% in healthy donors. In a multiple regression analysis of the CD34(+) cell yields on the first day of apheresis, we identified disease, the baseline white blood cell count (WBC), platelet count, and lactate dehydrogenase as independent significant variables. Particularly, disease was strongly associated with the CD34(+) cell yield, probably due to the difference in the number of previous chemotherapy cycles. In conclusion, the minimal dose of CD34(+) cells for autologous transplantation was collected in almost all patients with hematological malignancies. However, patients who have received repeated cycles of chemotherapy, such as patients with ML, and those who have low WBC counts and/or platelet counts may be at higher risk for poor mobilization.
  • K Kawamura, H Wada, R Yamasaki, Y Ishihara, K Sakamoto, M Ashizawa, M Sato, T Machishima, K Terasako, S I Kimura, M Kikuchi, H Nakasone, R Yamazaki, J Kanda, S Kako, A Tanihara, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 15 5 457 - 65 2013年10月 [査読有り][通常論文]
     
    BACKGROUND: Currently, acyclovir (ACV) at 1000 mg/day is widely used as prophylaxis in the early phase of hematopoietic stem cell transplant (HSCT) in Japan. However, low-dose ACV (200 mg/day) has been shown to prevent varicella zoster virus reactivation in the middle and late phases of HSCT. METHODS: Therefore, in this study, we decreased the dose of ACV to 200 mg/day in the early phase after HSCT. We analyzed 93 consecutive herpes simplex virus (HSV)-seropositive patients who underwent allogeneic HSCT for the first time in our center between June 2007 and December 2011. RESULTS: Before August 2009, 38 patients received oral ACV at 1000 mg/day (ACV1000) until day 35 after HSCT, whereas 55 patients received oral ACV at 200 mg/day (ACV200) after September 2009. We compared the cumulative incidence of HSV infection in the 2 groups. Oral ACV was changed to intravenous administration because of intolerance in 66% and 45% of the patients in the ACV1000 and ACV200 groups, respectively (P = 0.060). The probability of severe stomatitis (Bearman grade II-III) was 76% and 60% in the ACV1000 and ACV200 groups, respectively (P = 0.12). The number of patients who developed HSV disease before day 100 after HSCT was 0 in the ACV1000 group and 2 in the ACV200 group, with a cumulative incidence of 3.6% (P = 0.43). HSV disease in the latter 2 patients was limited to the lips and tongue and was successfully treated with ACV or valacyclovir at a treatment dose. CONCLUSION: ACV at 200 mg/day appeared to be effective for preventing HSV disease in the early phase after HSCT.
  • H Nakasone, M Onizuka, N Suzuki, N Fujii, S Taniguchi, K Kakihana, H Ogawa, K Miyamura, T Eto, H Sakamaki, H Yabe, Y Morishima, K Kato, R Suzuki, T Fukuda
    Bone marrow transplantation 48 10 1317 - 23 2013年10月 [査読有り][通常論文]
     
    Cryptogenic organizing pneumonia (COP), previously known as bronchiolitis obliterans organizing pneumonia (BOOP), is a significant complication after allogeneic hematopoietic SCT (HCT). However, the pathogenesis of this complication has not yet been elucidated. Therefore, we identified the pre-transplant risk factors for the development of COP/BOOP using the Japan transplant registry database between 2005 and 2009. Among 9550 eligible recipients, 193 experienced COP/BOOP (2%). HLA disparity (odds ratio (OR) 1.51, P=0.05), female-to-male HCT (OR 1.53, P=0.023), and PBSC transplant (OR 1.84, P=0.0076) were significantly associated with an increased risk of COP/BOOP. On the other hand, BU-based myeloablative conditioning (OR 0.52, P=0.033), or fludarabine-based reduced-intensity conditioning (OR 0.50, P=0.0011) in comparison with a TBI-based regimen and in vivo T-cell depletion (OR 0.46, P=0.055) were associated with a lower risk. Of the 193 patients with COP/BOOP, 77 died, including non-relapse death in 46 (59%). Pulmonary failure and fatal infection accounted for 41% (n=19) and 26% (n=12) of the non-relapse death. Allogeneic immunity and conditioning toxicity could be associated with COP/BOOP. Prospective studies are required to elucidate the true risk factors for COP/BOOP and to develop a prophylactic approach.
  • Masahiro Ashizawa, Shun-ichi Kimura, Hidenori Wada, Kana Sakamoto, Miki Sato, Kiriko Terasako, Misato Kikuchi, Hideki Nakasone, Shinya Okuda, Shinichi Kako, Rie Yamazaki, Kumi Oshima, Katsuhiko Matsuura, Tsukasa Ohmori, Seiji Madoiwa, Junji Nishida, Jun Mimuro, Kaoru Tabei, Yoichi Sakata, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 18 5 300 - 4 2013年09月 [査読有り][通常論文]
     
    A mixing test is useful for distinguishing between coagulation factor deficiency and the presence of inhibitor as the cause of coagulopathy. However, we experienced a patient with acquired factor V (FV) inhibitor whose mixing test showed a coagulation factor deficiency pattern. A 65-year-old man with a tendency for bleeding was referred to our center. The laboratory data showed remarkable prolongation of prothrombin time and activated partial thromboplastin time (APTT). FV activity was less than 3%. A mixing test showed a coagulation factor deficiency pattern. However, neither the tendency for bleeding nor the coagulation tests were corrected by transfusion of fresh frozen plasma. A few days later, a positive test for FV inhibitor of 3 Bethesda units was obtained. Therefore, we started prednisolone and plasma exchange, and the coagulation test results normalized after 6 weeks. Although an incubation period is generally not considered necessary in a mixing test for FV inhibitor, we repeated mixing tests with various incubation periods and confirmed an incubation period-dependent prolongation of the APTT. Therefore, a mixing test with an incubation period is recommended for the detection of FV inhibitor, since a mixing test without an incubation period may show a coagulation factor deficiency pattern when the titer of FV inhibitor is low.
  • Tomohito Machishima, Shinichi Kako, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Miki Sato, Masahiro Ashizawa, Kiriko Terasako, Shun-ichi Kimura, Misato Kikuchi, Hideki Nakasone, Junya Kanda, Rie Yamazaki, Junji Nishida, Yoshinobu Kanda
    CLINICAL TRANSPLANTATION 27 5 749 - 756 2013年09月 [査読有り][通常論文]
     
    Cyclosporine (CsA) is the most widely used immunosuppressive agent for the prevention of acute graft-versus-host disease (GVHD). In a previous report, the incidence of acute GVHD was decreased by increasing the target blood concentration of CsA during a continuous infusion from 300 to 500ng/mL without excessive toxicities. To confirm these results, we retrospectively analyzed 69 patients who received a continuous infusion of CsA at a higher target CsA level between 450 and 550ng/mL (CsA500 group) and compared the clinical outcome with 29 patients who received CsA with a lower target concentration between 250 and 350ng/mL (CsA300 group). The target concentration was determined based on the status of background diseases. Multivariate analysis revealed that the incidence of grade III-IV acute GVHD was significantly lower in the CsA500 group, although the incidence of grade II-IV acute GVHD was not different. Toxicities were equivalently observed between the two groups. Concomitant administration of voriconazole or itraconazole and higher hematocrit were identified as independent significant factors for higher concentration/dose ratio of CsA. The average dose of CsA to maintain CsA level around 500ng/mL was higher compared with the previous study (3.4mg/kg vs. 2.7mg/kg at three wk), probably due to the difference in measuring method of CsA concentration. We conclude that continuous infusion of CsA with a target level between 450 and 550ng/mL is a feasible and effective GVHD prophylaxis, but caution should be paid for the difference in measuring method.
  • M Sato, H Nakasone, H Wada, R Yamasaki, Y Ishihara, K Sakamoto, K Kawamura, M Ashizawa, T Machishima, K Terasako, S-I Kimura, M Kikuchi, A Tanihara, R Yamazaki, Y Tanaka, J Kanda, S Kako, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 15 4 E169-71 - E171 2013年08月 [査読有り][通常論文]
  • Makoto Murata, Hideki Nakasone, Junya Kanda, Takahiko Nakane, Tatsuo Furukawa, Takahiro Fukuda, Takehiko Mori, Shuichi Taniguchi, Tetsuya Eto, Kazuteru Ohashi, Masayuki Hino, Masami Inoue, Hiroyasu Ogawa, Yoshiko Atsuta, Tokiko Nagamura-Inoue, Hiromasa Yabe, Yasuo Morishima, Hisashi Sakamaki, Ritsuro Suzuki
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 19 8 1183 - 9 2013年08月 [査読有り][通常論文]
     
    Systemic corticosteroid therapy is recommended as a first-line treatment for acute graft-versus-host disease (GVHD). We performed a retrospective study to identify the factors affecting the response of grade II to IV acute GVHD to systemic corticosteroid therapy using the Japanese national registry data for patients who received first allogeneic hematopoietic cell transplantation with bone marrow (BM) (n = 1955), peripheral blood stem cells (PBSCs) (n = 642), or umbilical cord blood (UCB) (n = 839). Of 3436 patients, 2190 (63.7%) showed improvement of acute GVHD to first-line therapy with corticosteroids. Various factors were identified to predict corticosteroid response. Interestingly, UCB (versus HLA-matched related BM) transplantation was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement. HLA-matched related PBSC transplantation was not significantly different from HLA-matched related BM transplantation. Patients without improvement from corticosteroid therapy had a 2.5-times higher nonrelapse mortality and a .6-times lower overall survival rate. The present study demonstrated, for the first time, a higher probability of improvement in grade II to IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. A prospective study is warranted.
  • M. Sato, H. Nakasone, H. Wada, R. Yamasaki, Y. Ishihara, K. Sakamoto, K. Kawamura, M. Ashizawa, T. Machishima, K. Terasako, S. I. Kimura, M. Kikuchi, A. Tanihara, R. Yamazaki, Y. Tanaka, J. Kanda, S. Kako, J. Nishida, Y. Kanda
    Transplant Infectious Disease 15 4 E169 - E171 2013年08月 [査読有り][通常論文]
  • Misato Kikuchi, Hideki Nakasone, Kinuko Mitani, Moritaka Gotoh, Ayako Kobayashi, Naoki Kurita, Takeshi Saito, Ken Sato, Yoshinobu Kanda
    Scandinavian journal of infectious diseases 45 7 531 - 6 2013年07月 [査読有り][通常論文]
     
    BACKGROUND: Invasive aspergillosis (IA) is a critical complication in neutropenic patients. Recurrent IA is especially associated with high mortality. Therefore, secondary prophylaxis is important in patients with a history of IA. We retrospectively assessed the effect of secondary prophylaxis for IA. METHODS: We reviewed the medical records of 46 hematology patients who developed possible, probable, or proven IA according to the EORTC/MSG criteria between 2005 and 2009, and who subsequently underwent chemotherapy (n = 30) or stem cell transplantation (n = 16). RESULTS: Ten patients developed recurrent IA within 10 days after recovery from neutropenia. None of the 15 patients who achieved complete response (CR) of IA experienced recurrent IA. Among patients who did not achieve CR of IA, multivariate analysis identified the following independent risk factors: female sex (hazard ratio (HR) 7.23, 95% confidence interval (CI) 2.38-21.9, p = 0.00047), high serum C-reactive protein level (≥ 1 mg/dl) at the beginning of subsequent therapy (HR 4.46, 95% CI 1.51-13.2, p = 0.007), and the use of micafungin (HR 12.0, 95% CI 2.03-71.2, p = 0.0061) or amphotericin B (HR 16.5, 95% CI 1.56-174, p = 0.020) for secondary prophylaxis (reference: voriconazole). CONCLUSIONS: Three risk factors for recurrent IA were identified. However, a prospective controlled trial is required to evaluate the impact of secondary prophylactic regimens.
  • Rie Yamazaki, Hideki Nakasone, Yukie Tanaka, Miki Sato, Kiriko Terasako, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Tomohito Machishima, Shun-Ichi Kimura, Misato Kikuchi, Shinya Okuda, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 19 7 1013 - 20 2013年07月 [査読有り][通常論文]
     
    Varicella-zoster virus (VZV) reactivation is a frequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Although previous studies have revealed that cellular immunity is important for suppressing reactivation, the role of humoral immunity against VZV has been poorly evaluated. We analyzed inherited polymorphisms in the immunoglobulin G (IgG) heavy chain constant regions of 50 HSCT recipient-donor pairs to distinguish donor-derived and recipient-derived antibodies. Twelve pairs were informative regarding the origin of IgG, since either the donors (n = 3) or recipients (n = 9) were homozygous null for the IgG1m(f) allotype. In these 9 homozygous-null recipients, allotype-specific IgG against VZV were measured by enzyme-linked immunosorbent assay and compared with measles-IgG. All 9 homozygous-null recipients were monitored for more than 1 year after HSCT, with (n = 4, localized zoster) or without (n = 5) clinical VZV disease. In 3 patients with VZV disease, donor-derived IgG against VZV was elevated between 500 to 700 days after HSCT after the episode of VZV disease. In 1 patient who suffered from VZV disease just before HSCT, donor-derived VZV IgG was elevated within 3 months after HSCT. On the other hand, 2 patients who received reduced-intensity conditioning (RIC) transplantation from an IgG1m(f) null donor maintained recipient-derived IgG against VZV for more than 1 year, whereas it was decreased within 3 months in 1 recipient who received conventional conditioning. In conclusion, the production of anti-VZV IgG by recipient plasma cells persists long after RIC. In patients without symptomatic VZV reactivation, donor-derived anti-VZV IgG did not reach titers comparable to those measured in healthy virus carriers.
  • Hideki Nakasone, Saiko Kurosawa, Kimikazu Yakushijin, Shuichi Taniguchi, Makoto Murata, Kazuhiro Ikegame, Takeshi Kobayashi, Tetsuya Eto, Koichi Miyamura, Hisashi Sakamaki, Yasuo Morishima, Tokiko Nagamura, Ritsuro Suzuki, Takahiro Fukuda
    American journal of hematology 88 6 477 - 84 2013年06月 [査読有り][通常論文]
     
    The impact of hepatitis C virus (HCV) infection on outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a matter of debate. We have retrospectively examined the significance of HCV infection among recipients who received allogeneic HCT, using a Japan transplant outcome registry database between 2006 and 2009. Among 7,831 recipients, 136 were HCV-positive. The rate of hematopoietic recovery was lower in the HCV-positive group (neutrophil recovery of 500 × 10(6) /L or higher: 79% vs. 87% at Day 30, P = 0.087; platelet recovery of 50 × 10(9) /L or higher: 57% vs. 65% at Day 60, P = 0.012). The HCV-positive group had a significantly higher incidence of nonrelapse mortality 38% vs. 25% at 2 years, P < 0.01) and inferior overall survival (41% vs. 51% at 2 years, P < 0.01). A multivariate analysis revealed that HCV seropositivity was associated with an independent risk for higher nonrelapse mortality (hazard ratio: 1.65, P < 0.01) and inferior overall survival (hazard ratio: 1.39, P < 0.01). The incidences of death due to hepatic problems (8% vs. 2%, P < 0.01), bacterial infection (10% vs. 4%, P < 0.01), or graft failure (5% vs. 2%, P = 0.084) tended to be higher in the HCV-positive group. HCV infection had an adverse impact on the clinical outcome following HCT, especially in the setting of unrelated transplantation. Careful evaluation before embarking on HCT and intensive assessment against complications are warranted in HCV-infected recipients.
  • Hideki Nakasone, Junya Kanda, Shingo Yano, Yoshiko Atsuta, Hiroatsu Ago, Takahiro Fukuda, Kazuhiko Kakihana, Tatsuya Adachi, Toshiaki Yujiri, Shuichi Taniguchi, Jun Taguchi, Yasuo Morishima, Tokiko Nagamura, Hisashi Sakamaki, Takehiko Mori, Makoto Murata
    Transplant international : official journal of the European Society for Organ Transplantation 26 6 631 - 9 2013年06月 [査読有り][通常論文]
     
    Bronchiolitis obliterans syndrome (BOS) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, the pathogenesis and risks for the development of BOS have remained unclear. Therefore, a case-control study was conducted to investigate the risk factors for the development of BOS, which included the largest number of BOS cases; 196 patients with BOS were identified and compared with 1960 control recipients. The following were identified as significantly higher risk factors for the development of BOS: female recipients (OR 1.47, P = 0.019), ABO-mismatch HSCT (minor mismatch, OR 1.67, P = 0.015; major mismatch, OR 1.73, P = 0.012; bidirectional mismatch, OR 1.96, P = 0.018), busulfan+cyclophosphamide-based myeloablative conditioning (OR 1.74, P = 0.016), and acute graft-versus-host disease (GVHD) involving the skin (OR 1.55, P = 0.011). On the other hand, the risk for the development of BOS was significantly lower in patients receiving cord blood transplantation (OR 0.26, P = 0.0011). With respect to other target organs of chronic GVHD, ocular involvement was significantly associated with BOS (OR 2.53, P < 0.001). Prospective studies are required to elucidate the risk factors for the development of BOS, and future investigations should focus on finding a prophylactic approach against BOS based on these findings.
  • M. Sato, H. Nakasone, K. Oshima, Y. Ishihara, H. Wada, K. Sakamoto, K. Kawamura, M. Ashizawa, T. MacHishima, K. Terasako, S. Kimura, M. Kikuchi, S. Okuda, A. Tanihara, R. Yamazaki, Y. Tanaka, J. Kanda, S. Kako, J. Nishida, Y. Kanda
    Bone Marrow Transplantation 48 5 698 - 702 2013年05月 [査読有り][通常論文]
     
    Various biomarkers have been investigated with regard to their ability to predict the outcome of allogeneic hematopoietic SCT (HSCT). In this study, we retrospectively reviewed 90 recipients who received HSCT between 2007 and 2011 in our institution, and evaluated the predictive value of the baseline serum C-reactive protein (CRP) levels just before the initiation of conditioning for transplant-related complications after allogeneic HSCT. A receiver-operating characteristic curve revealed that the baseline serum CRP levels had an excellent predictive value for non-relapse mortality (NRM), with an area under the curve of 0.83. The sensitivity and specificity for NRM were 80% and 87%, respectively, with a cutoff of 0.6 mg/dL. With this cutoff value, multivariate analyses revealed that a higher baseline CRP level was an independent risk factor for NRM (HR 6.21, P< 0.01), grade III-IV acute GVHD (HR 3.91, P=0.03) and poor overall survival (HR 3.27, P=0.0018). On the other hand, the baseline CRP level did not predict infectious events. These findings suggested that CRP levels before conditioning may be a useful predictive biomarker for poor survival. © 2013 Macmillan Publishers Limited All rights reserved.
  • M Sato, H Nakasone, K Oshima, Y Ishihara, H Wada, K Sakamoto, K Kawamura, M Ashizawa, T Machishima, K Terasako, S Kimura, M Kikuchi, S Okuda, A Tanihara, R Yamazaki, Y Tanaka, J Kanda, S Kako, J Nishida, Y Kanda
    Bone marrow transplantation 48 5 698 - 702 2013年05月 [査読有り][通常論文]
     
    Various biomarkers have been investigated with regard to their ability to predict the outcome of allogeneic hematopoietic SCT (HSCT). In this study, we retrospectively reviewed 90 recipients who received HSCT between 2007 and 2011 in our institution, and evaluated the predictive value of the baseline serum C-reactive protein (CRP) levels just before the initiation of conditioning for transplant-related complications after allogeneic HSCT. A receiver-operating characteristic curve revealed that the baseline serum CRP levels had an excellent predictive value for non-relapse mortality (NRM), with an area under the curve of 0.83. The sensitivity and specificity for NRM were 80% and 87%, respectively, with a cutoff of 0.6 mg/dL. With this cutoff value, multivariate analyses revealed that a higher baseline CRP level was an independent risk factor for NRM (HR 6.21, P<0.01), grade III-IV acute GVHD (HR 3.91, P=0.03) and poor overall survival (HR 3.27, P=0.0018). On the other hand, the baseline CRP level did not predict infectious events. These findings suggested that CRP levels before conditioning may be a useful predictive biomarker for poor survival.
  • M Ashizawa, K Oshima, H Wada, Y Ishihara, K Kawamura, K Sakamoto, M Sato, K Terasako, T Machishima, S Kimura, M Kikuchi, H Nakasone, S Okuda, S Kako, J Kanda, R Yamazaki, A Tanihara, J Nishida, Y Kanda
    Bone marrow transplantation 48 1 94 - 8 2013年01月 [査読有り][通常論文]
     
    Hyperbilirubinemia in the early phase after allogeneic hematopoietic SCT (HSCT) is due to various causes. One of the most important causes of hyperbilirubinemia is veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS). However, the prognosis of patients who are clinically diagnosed as SOS varies. We retrospectively evaluated 82 patients who underwent their first allogeneic HSCT. GVHD prophylaxis was a combination of short-term MTX and CsA (n=77) or tacrolimus (n=5). Thirty-three patients developed hyperbilirubinemia, with a bilirubin level of at least 2 mg/dL, within 20 days after HSCT. Of these patients, 24 were diagnosed as VOD/SOS using the modified Seattle criteria. Twenty-six recovered to a bilirubin level of <2 mg/dL. We focused on the serum alkaline phosphatase/total bilirubin ratio (ALP/TB) at the onset of hyperbilirubinemia and found that it significantly predicted the recovery from hyperbilirubinemia. OS was significantly higher in patients with a lower ALP/TB ratio (P=0.00056). In addition, a lower ALP/TB ratio was associated with better survival even in patients who were clinically diagnosed as SOS (P<0.001). The ALP/TB ratio at the onset of hyperbilirubinemia may be a useful predictor for the prognosis of hyperbilirubinemia and SOS early after HSCT.
  • Kana Sakamoto, Hideki Nakasone, Hidenori Wada, Ryoko Yamasaki, Yuko Ishihara, Koji Kawamura, Masahiro Ashizawa, Miki Sato, Kiriko Terasako-Saito, Tomohito Machishima, Shun-ichi Kimura, Misato Kikuchi, Shinichi Kako, Junya Kanda, Rie Yamazaki, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    PloS one 8 9 e73754  2013年 [査読有り][通常論文]
     
    BACKGROUND: Preemptive therapy with ganciclovir (GCV) based on the results of a cytomegalovirus (CMV) antigenemia assay is a standard strategy for preventing CMV disease after allogeneic hematopoietic cell transplantation (HCT). However, the appropriate threshold of antigenemia-positive cells for deciding when to start GCV remains unclear. PATIENTS: This retrospective study included 80 recipients who received HCT from an alternative donor between 2007 and 2011. In 2009, we switched the threshold from 3 (3A group, n=24) to 20 (20A group, n=56) antigenemia-positive cells per two slides for preemptive therapy after HCT from an alternative donor. RESULTS: Early CMV disease within 100 days after HCT was observed in one patient in the 20A group. Antiviral agents including GCV, val-GCV, and foscarnet were given in 17 (71%) and 36 (64%) patients in the 3A and 20A groups, respectively (p=0.23). In 13 (23%) patients in the 20A group, the initiation of preemptive therapy was avoided because of the change in the cutoff value for CMV antigenemia. However, the total dose of GCV was not different between the two groups. The use of steroid was significantly associated with CMV antigenemia of at least 20 positive cells among patients with low-level antigenemia at the first detection. CONCLUSION: The increased threshold up to 20 positive cells for starting preemptive therapy was not associated with a significant increase in CMV disease, but the total dose of GCV was not reduced and there was one early CMV disease in the 20A group. We should explore how to identify patients who are at high risk for increased antigenemia among patients with low-level antigenemia, but at least, preemptive therapy should not be withheld in patients who are already receiving systemic steroid.
  • Yukie Tanaka, Hideki Nakasone, Rie Yamazaki, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Tomohito Machishima, Miki Sato, Kiriko Terasako, Shun-ichi Kimura, Misato Kikuchi, Shinya Okuda, Shinichi Kako, Junya Kanda, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Journal of clinical immunology 32 6 1340 - 52 2012年12月 [査読有り][通常論文]
     
    PURPOSE: Adult T cell leukemia/lymphoma (ATL) is a highly aggressive malignancy of T cells caused by human T cell lymphotropic virus type 1 (HTLV-1). Recent clinical studies have suggested that allogeneic stem cell transplantation (HSCT) improves the clinical course of ATL by harnessing a graft-versus-ATL effect, and that donor-derived HTLV-1 Tax-specific CD8(+) cytotoxic T cells (CTLs) contribute to the graft-versus-ATL effect after HSCT. However, little is known about the immunological characteristics of Tax-specific CTLs in ATL patients who underwent HSCT. METHODS: We serially analyzed frequencies, differentiation, functions and clonal dynamics of Tax-specific CTLs in paired samples of peripheral blood (PB) and bone marrow (BM) from an ATL patient after HSCT at the single-cell level. We used flowcytometric and single-cell T cell receptor (TCR) repertoire analysis methods without culture steps. RESULTS: Donor-derived Tax-specific CTLs effectively suppressed HTLV-1 replication in both PB and BM at least during chronic graft-versus-host disease after HSCT. Furthermore, Tax-specific CTLs had comparable properties between BM and PB, except for preferential accumulation in BM rather than PB. Tax-specific CTLs persistently existed as less-differentiated CD45RA(-)CCR7(-) effector memory CTLs based on predominant phenotypes of CD27(+), CD28(+/-) and CD57(+/-). Our approach using single-cell TCR repertoire analysis method showed highly restricted oligoclonal responses of Tax-specific CTLs, and TCR BV7- or BV30- expressing two predominant CTL clones persistently existed and maintained strong cytotoxic activities against HTLV-1 in both PB and BM over three years after HSCT. CONCLUSIONS: These findings about Tax-specific CTLs provide insights into future directions for studies on immunotherapy against ATL.
  • Terasako Kiriko, Nakasone Hideki, Tanaka Yukie, Sato Miki, Yamazaki Rie, Wada Hidenori, Ishihara Yuko, Kawamura Koji, Sakamoto Kana, Ashizawa Masahiro, Machishima Tomohito, Kimura Shun-ichi, Kikuchi Misato, Okuda Shinya, Kako Shinichi, Kanda Jyunya, Nishida Jyunji, Kanda Yoshinobu
    臨床血液 53 9 1113  (一社)日本血液学会-東京事務局 2012年09月 [査読無し][通常論文]
  • S. I. Kimura, H. Wada, K. Sakamoto, M. Ashizawa, M. Sato, K. Terasako, H. Nakasone, M. Kikuchi, S. Okuda, S. Kako, R. Yamazaki, K. Oshima, Y. Tanaka, A. Tanihara, J. Nishida, Y. Kanda
    Transplant Infectious Disease 14 4 364 - 373 2012年08月 [査読有り][通常論文]
     
    We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/μL). We calculated the L-index from the start of conditioning to day 30 - L-index(30) - and to day 100 - L-index(100) - after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III-IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation. © 2012 John Wiley & Sons A/S.
  • J Suzuki, M Ashizawa, S Okuda, H Wada, K Sakamoto, K Terasako, M Sato, S-I Kimura, M Kikuchi, H Nakasone, S Kako, R Yamazaki, K Oshima, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 14 4 E7-12 - E12 2012年08月 [査読有り][通常論文]
     
    Although the reactivation of varicella zoster virus (VZV) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), VZV meningoencephalitis is a rare life-threatening infectious disease after HSCT. We describe here a patient who developed VZV meningoencephalitis 2 years after human leukocyte antigen-matched unrelated HSCT for acute myeloblastic leukemia. She developed chronic graft-versus-host disease, and cyclosporine (CSA) was continued until 17 months after HSCT. Low-dose acyclovir (ACV) at 200 mg/day was administered to prevent the reactivation of VZV from day -7 to the termination of CSA. At 22 months, she suddenly developed fever, loss of consciousness, and seizure, with generalized skin rash. A high level of VZV DNA was detected in her cerebrospinal fluid (CSF). She was diagnosed to have VZV meningoencephalitis. Intravenous ACV at 30 mg/kg/day was given for 2 months. Although loss of consciousness was quickly resolved, some neurologic symptoms persisted. She did not have any known risk factors for VZV reactivation. Therefore, we should keep in mind that any HSCT recipient may develop VZV meningoencephalitis, and examination of CSF for VZV infection with an empiric administration of ACV may be recommended for HSCT recipients with central nervous system symptoms, even in the absence of skin manifestations.
  • S-I Kimura, H Wada, K Sakamoto, M Ashizawa, M Sato, K Terasako, H Nakasone, M Kikuchi, S Okuda, S Kako, R Yamazaki, K Oshima, Y Tanaka, A Tanihara, J Nishida, Y Kanda
    Transplant infectious disease : an official journal of the Transplantation Society 14 4 364 - 73 2012年08月 [査読有り][通常論文]
     
    We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/μL). We calculated the L-index from the start of conditioning to day 30 - L-index(30) - and to day 100 - L-index(100) - after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III-IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation.
  • Shinichi Kako, Hideki Nakasone, Hiroshi Endo, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako, Misato Kikuchi, Shun-ichi Kimura, Shinya Okuda, Rie Yamazaki, Kumi Oshima, Aki Tanihara, Junji Nishida, Kensuke Usuki, Yoshinobu Kanda
    Hematological oncology 30 2 82 - 8 2012年06月 [査読有り][通常論文]
     
    Patients with aplastic anemia (AA) or myelodysplastic syndrome (MDS) often have persistent severe neutropenia and are susceptible to infectious complications. We retrospectively reviewed the clinical course of patients with AA or MDS who had neutropenia (neutrophil count < 500/µl) for more than 25 days. A total of 46 patients, 11 with AA and 35 with MDS, were included. Twenty-three patients had infectious events (IE), and the cumulative incidence of IE was 30% at 6 months and 51% at 1 year. The cumulative incidence of IE was 67% at 1 year in 30 patients who experienced very severe neutropenia of less than 200/µl. Overall survival in all patients was 76% at 6 months and 65% at 1 year. In a multivariate analysis, male sex, underlying diseases, and a neutrophil count of less than 200/µl as a time-dependent covariate significantly affected IE. In analyses that excluded patients with AA, male sex was the only factor. In conclusion, severe neutropenia was significantly associated with IE in patients with AA or MDS, and IE might be lethal. When we only considered patients with MDS, the neutrophil count alone could not be used to predict the prognosis.
  • Masahiro Ashizawa, Shinichi Kako, Hidenori Wada, Kana Sakamoto, Miki Sato, Kiriko Terasako, Shun-ichi Kimura, Misato Kikuchi, Hideki Nakasone, Shinya Okuda, Rie Yamazaki, Kumi Oshima, Junji Nishida, Yoshinobu Kanda
    Hematological oncology 30 1 50 - 2 2012年03月 [査読有り][通常論文]
  • Kiriko Terasako, Kumi Oshima, Hidenori Wada, Yuko Ishihara, Koji Kawamura, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Tomohito Machishima, Hideki Nakasone, Shun-ichi Kimura, Misato Kikuchi, Shinya Okuda, Shinichi Kako, Rie Yamazaki, Kengo Takeuchi, Junji Nishida, Shigeki Yamada, Osamu Tanaka, Yoshinobu Kanda
    Internal medicine (Tokyo, Japan) 51 4 405 - 11 2012年 [査読有り][通常論文]
     
    Disseminated adenovirus disease after allogeneic hematopoietic stem cell transplantation (HSCT) is lethal in most cases, especially when it develops as fulminant hepatic failure. We encountered a patient who developed fulminant hepatic failure caused by adenovirus infection. She did not show manifestations of graft-versus-host disease and the results of serum tests for viral infection were all negative. Abdominal computed tomography (CT) findings were consistent with peliosis hepatitis. She died of fulminant hepatic failure, however, and pathological examinations of the liver specimen obtained after her death revealed adenovirus infection. In this report, we review the clinical characteristics and imaging findings of fulminant hepatic failure caused by adenovirus infection.
  • Rie Yamazaki, Hideki Nakasone, Hidenori Wada, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako, Misato Kikuchi, Shun-Ichi Kimura, Shinya Okuda, Shinichi Kako, Yukie Tanaka, Aki Tanihara, Kumi Oshima, Junji Nishida, Yoshinobu Kanda
    Experimental hematology 39 12 1119 - 23 2011年12月 [査読有り][通常論文]
     
    Myelodysplastic syndrome (MDS) is known to be associated with functional abnormalities of B cells, including hypergammaglobulinemia and monoclonal gammopathy (MG). However, the pathogenesis of these immunological disorders has not been clarified. We report a patient who developed donor-derived MDS followed by leukemic transformation after cord blood transplantation for MDS with MG. Interestingly, MG reappeared before development of donor-derived MDS. We analyzed the immunoglobulin allotype gene polymorphisms to determine whether the MG after cord blood transplantation was of recipient origin or donor origin. Results of genetic analysis and enzyme-linked immunosorbent assay of IgG1 allotype revealed that the MG after cord blood transplantation was of donor origin. Although the mechanism of donor-derived MG remains unclear, the persistent presence of recipient's antigen presenting cells might have induced the abnormal immunoglobulin production.
  • Hideki Nakasone, Phan Nguyen Thanh Binh, Rie Yamazaki, Yukie Tanaka, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako, Shun-ichi Kimura, Misato Kikuchi, Shinichi Kako, Shinya Okuda, Kumi Oshima, Aki Tanihara, Junji Nishida, Yasunori Abe, Yoshinobu Kanda
    Blood 117 12 3469 - 72 2011年03月 [査読有り][通常論文]
     
    Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 ± 11.0 vs 9.1 ± 6.1 μg/mL in females, P < .001; and 10.1 ± 6.8 vs 4.3 ± 2.9 μg/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (β-coefficient 8.2, P < .0001) and the severity of cGVHD (β-coefficient 6.6, 12.7, and 15.6, P < .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD.
  • H. Nakasone, Binh P. N. T, R. Yamazaki, Y. Tanaka, K. Sakamoto, M. Ashizawa, M. Sato, K. Terasako, S. - Kimura, M. Kikuchi, S. Kako, S. Okuda, K. Oshima, A. Tanihara, J. Nishida, Y. Abe, Y. Kanda
    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION 17 2 S338 - S338 2011年02月 [査読有り][通常論文]
  • Shun-Ichi Kimura, Shinichi Kako, Hidenori Wada, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Kiriko Terasako, Misato Kikuchi, Hideki Nakasone, Shinya Okuda, Rie Yamazaki, Kumi Oshima, Junji Nishida, Takuro Watanabe, Yoshinobu Kanda
    Leukemia research 35 1 e11-2 - E12 2011年01月 [査読有り][通常論文]
  • Shun-Ichi Kimura, Kumi Oshima, Ken Sato, Miki Sato, Kiriko Terasako, Hideki Nakasone, Misato Kikuchi, Shinya Okuda, Shinichi Kako, Rie Yamazaki, Yukie Tanaka, Aki Tanihara, Junji Nishida, Yoshinobu Kanda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 16 10 1355 - 61 2010年10月 [査読有り][通常論文]
     
    We investigated the impact of neutropenia on the development of early bloodstream and pulmonary infections in hematopoietic stem cell transplantation (HSCT) recipients, and evaluated the utility of an index (D-index) that reflects both the intensity and duration of neutropenia. Fifty-eight patients (23 autologous, 35 allogeneic HSCT recipients) were enrolled in this retrospective study. The D-index was defined as the area over the neutrophil curve during neutropenia. We also evaluated the utility of the cumulative D-index from the start of neutropenia until the development of infection (c-D-index), which may enable real-time assessment of the risk for infection. The patients showed 12 and 7 episodes of bloodstream and pulmonary infection, respectively. The D-index, days of neutropenia (<500/microL) and days of profound neutropenia (<100/microL) had at least a nearly significant impact on the development of both bloodstream and pulmonary infections. On the other hand, the c-D-index, cumulative days of neutropenia, and cumulative days of profound neutropenia significantly affected pulmonary infection, but not bloodstream infection. The c-D-index had a high negative predictive value of 97.4% for pulmonary infection with a cutoff of 5500, but the area under the receiver operating characteristic curve was similar to that of the cumulative days of neutropenia and profound neutropenia. Our results showed that although the c-D-index may be useful for identifying patients who are at low risk for early pulmonary infection after HSCT, its performance was similar to that of the simple duration of neutropenia.
  • Yoko Ishida, Kiriko Terasako, Kumi Oshima, Kana Sakamoto, Masahiro Ashizawa, Miki Sato, Misato Kikuchi, Shun-Ichi Kimura, Hideki Nakasone, Shinya Okuda, Shinichi Kako, Rie Yamazaki, Junji Nishida, Yoshinobu Kanda
    International journal of hematology 92 3 542 - 6 2010年10月 [査読有り][通常論文]
     
    Although allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), the prognosis of patients who relapse after allogeneic HSCT has been extremely poor. Dasatinib, a second-generation tyrosine kinase inhibitor, is a promising agent for the treatment of Ph-ALL. We report on a Ph-ALL patient who relapsed early after the first allogeneic HSCT, but achieved complete molecular remission with dasatinib alone. She remains in molecular remission 12 months after the second allogeneic HSCT. Dasatinib was generally well tolerated, but she developed myalgia, nausea and positive cytomegalovirus antigenemia. In addition, sudden-onset bloody diarrhea was observed 10 days after the second HSCT, which was possibly associated with the use of dasatinib in addition to the effect of the conditioning regimen and graft-versus-host disease. In conclusion, dasatinib is an effective agent for Ph-ALL with a poor prognosis, but may be associated with specific adverse events including opportunistic infection and gastrointestinal bleeding.
  • Yukie Tanaka, Hideki Nakasone, Rie Yamazaki, Ken Sato, Miki Sato, Kiriko Terasako, Shun-Ichi Kimura, Shinya Okuda, Shinichi Kako, Kumi Oshima, Aki Tanihara, Junji Nishida, Toshiaki Yoshikawa, Tetsuya Nakatsura, Haruo Sugiyama, Yoshinobu Kanda
    Cancer Research 70 15 6181 - 6192 2010年08月 [査読有り][通常論文]
     
    Adult T-cell leukemia (ATL) is a lymphoproliferative malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. Recently, it has been shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for ATL, and that HTLV-1 Tax-specific CD8+ cytotoxic T cells (CTL) contribute to the graft-versus-ATL effect. In the present study, we, for the first time, analyzed the T-cell receptor (TCR) repertoire of isolated Tax301-309 (SFHSLHLLF)-specific CTLs in HLA-A*2402+ ATL patients before and after allo-HSCT by single-cell reverse transcription-PCR. The Tax301-309-specific CTLs in bone marrow and peripheral blood showed highly restricted oligoclonal diversity. In addition, a unique conserved amino acid motif of "P-D/P-R" in TCR-β complementarity-determining region 3 in either BV7- or BV18-expressing CTLs was observed not only in all of the samples from ATL patients, but also in samples from the same patient before and after HSCT. Furthermore, the P-D/P-R motif-bearing CTL clones established from peripheral blood samples after HSCT exhibited strong killing activity against the HTLV-1-infected T cells of the patient. CTL clones were not established in vitro from samples prior to allo-HSCT. In addition, CTL clones with a strong killing activity were enriched in vivo after HSCT in the patient. Hence, Tax 301-309-specific CTLs in ATL patients might have a preference for TCR construction and induce strong immune responses against the HTLV-1-infected T cells of patients, which contribute to the graft-versus-ATL effects after allo-HSCT. However, further analyses with a larger number of patients and more frequent sampling after allo-HSCT is required to confirm these findings. ©2010 AACR.
  • Yukie Tanaka, Hideki Nakasone, Rie Yamazaki, Ken Sato, Miki Sato, Kiriko Terasako, Shun-ichi Kimura, Shinya Okuda, Shinichi Kako, Kumi Oshima, Aki Tanihara, Junji Nishida, Toshiaki Yoshikawa, Tetsuya Nakatsura, Haruo Sugiyama, Yoshinobu Kanda
    Cancer research 70 15 6181 - 92 2010年08月 [査読有り][通常論文]
     
    Adult T-cell leukemia (ATL) is a lymphoproliferative malignancy associated with human T-cell lymphotropic virus type 1 (HTLV-1) infection. Recently, it has been shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for ATL, and that HTLV-1 Tax-specific CD8(+) cytotoxic T cells (CTL) contribute to the graft-versus-ATL effect. In the present study, we, for the first time, analyzed the T-cell receptor (TCR) repertoire of isolated Tax(301-309) (SFHSLHLLF)-specific CTLs in HLA-A*2402(+) ATL patients before and after allo-HSCT by single-cell reverse transcription-PCR. The Tax(301-309)-specific CTLs in bone marrow and peripheral blood showed highly restricted oligoclonal diversity. In addition, a unique conserved amino acid motif of "P-D/P-R" in TCR-beta complementarity-determining region 3 in either BV7- or BV18-expressing CTLs was observed not only in all of the samples from ATL patients, but also in samples from the same patient before and after HSCT. Furthermore, the P-D/P-R motif-bearing CTL clones established from peripheral blood samples after HSCT exhibited strong killing activity against the HTLV-1-infected T cells of the patient. CTL clones were not established in vitro from samples prior to allo-HSCT. In addition, CTL clones with a strong killing activity were enriched in vivo after HSCT in the patient. Hence, Tax(301-309)-specific CTLs in ATL patients might have a preference for TCR construction and induce strong immune responses against the HTLV-1-infected T cells of patients, which contribute to the graft-versus-ATL effects after allo-HSCT. However, further analyses with a larger number of patients and more frequent sampling after allo-HSCT is required to confirm these findings.
  • Kiriko Terasako, Ken Sato, Miki Sato, Shun-Ichi Kimura, Hideki Nakasone, Shinya Okuda, Shinichi Kako, Yukie Tanaka, Rie Yamazaki, Kumi Oshima, Aki Tanihara, Takakazu Higuchi, Junji Nishida, Yoshinobu Kanda
    Hematology 15 3 165 - 169 2010年06月 [査読有り][通常論文]
     
    Anti-thymocyte globulin (ATG) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia. However, there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome. Therefore, in this study, we retrospectively compared the effect of two different rabbit ATG preparations [Thymoglobulin (ATG-G) and ATG-Fresenius (ATG-F)] on immune recovery and cytomegalovirus infection after transplantation. The conditioning regimen was a combination of fludarabine, cyclophosphamide, and ATG. Low dose total body irradiation was added in alternative donor transplantation. Four patients received ATG-F at 5 mg/kg/day from day -7 to day -3, whereas ATG-G was given at 2•5 mg/kg/day from day -5 to day -2 in three patients. There was no graft rejection and no grade II-IV acute graft-versus-host disease. All three patients in the ATG-G group developed positive cytomegalovirus antigenemia including two with high-grade antigenemia, whereas two of the four patients in the ATG-F group were persistently negative. Immunological evaluation on day 60 revealed that both CD4+ and CD8+ T-cell recoveries were delayed in the ATG-G group. These findings suggested that ATG-G has a stronger immunosuppressive activity than the ATG-F with a dose ratio of 1:2•5. © 2010 Maney Publishing.
  • S Kimura, K Oshima, S Okuda, K Sato, M Sato, K Terasako, H Nakasone, S Kako, R Yamazaki, Y Tanaka, A Tanihara, T Higuchi, J Nishida, Y Kanda
    Bone marrow transplantation 45 6 1088 - 94 2010年06月 [査読有り][通常論文]
     
    We investigated the serial changes in the blood CsA concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (n=12). The microemulsion form of CsA, Neoral, was started at twice the last dose in intravenous infusion in two equally divided doses. The area under the concentration-time curve during oral administration (AUC(PO)) was significantly higher than the AUC during intravenous infusion (AUC(IV)) (median 7508 vs 6705 ng/ml x h, P=0.050). The median bioavailability of Neoral, defined as (AUC(PO)/DOSE(PO)) divided by (AUC(IV)/DOSE(IV)), was 0.685 (range, 0.45-1.04). Concomitant administration of oral voriconazole (n=4) significantly increased the bioavailability of Neoral (median 0.87 vs 0.54, P=0.017), probably due to the inhibition of gut CYP3A4 by voriconazole. Although the conversion from intravenous to oral administration of CsA at a ratio of 1:2 seemed to be appropriate in most patients, a lower conversion ratio may be better in patients taking oral voriconazole. To obtain a similar AUC, the target trough concentrations during twice-daily oral administration should be halved compared with the target concentration during continuous infusion.
  • H Nakasone, Y Kanda, H Takasaki, C Nakaseko, T Sakura, S Fujisawa, A Yokota, S Yano, K Usuki, A Maruta, D Abe, T Hoshino, S Takahashi, H Kanamori, S Okamoto
    Leukemia 24 6 1236 - 9 2010年06月 [査読有り][通常論文]
  • Kiriko Terasako, Ken Sato, Miki Sato, Shun-ichi Kimura, Hideki Nakasone, Shinya Okuda, Shinichi Kako, Yukie Tanaka, Rie Yamazaki, Kumi Oshima, Aki Tanihara, Takakazu Higuchi, Junji Nishida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 15 3 165 - 9 2010年06月 [査読有り][通常論文]
     
    Anti-thymocyte globulin (ATG) is widely used in the conditioning regimen before allogeneic stem cell transplantation for aplastic anemia. However, there are several different preparations of ATG and little is known about the difference of their effects on transplantation outcome. Therefore, in this study, we retrospectively compared the effect of two different rabbit ATG preparations [Thymoglobulin (ATG-G) and ATG-Fresenius (ATG-F)] on immune recovery and cytomegalovirus infection after transplantation. The conditioning regimen was a combination of fludarabine, cyclophosphamide, and ATG. Low dose total body irradiation was added in alternative donor transplantation. Four patients received ATG-F at 5 mg/kg/day from day -7 to day -3, whereas ATG-G was given at 2.5 mg/kg/day from day -5 to day -2 in three patients. There was no graft rejection and no grade II-IV acute graft-versus-host disease. All three patients in the ATG-G group developed positive cytomegalovirus antigenemia including two with high-grade antigenemia, whereas two of the four patients in the ATG-F group were persistently negative. Immunological evaluation on day 60 revealed that both CD4+ and CD8+ T-cell recoveries were delayed in the ATG-G group. These findings suggested that ATG-G has a stronger immunosuppressive activity than the ATG-F with a dose ratio of 1:2.5.
  • H Nakasone, A Ito, H Endo, M Kida, I Koji, K Usuki
    Bone marrow transplantation 45 3 590 - 2 2010年03月 [査読有り][通常論文]
  • Miki Sato, Shinichi Kako, Kumi Oshima, Ken Sato, Kiriko Terasako, Shun-Ichi Kimura, Hideki Nakasone, Shinya Okuda, Rie Yamazaki, Takakazu Higuchi, Junji Nishida, Yoshinobu Kanda
    Scandinavian journal of infectious diseases 42 2 97 - 101 2010年 [査読有り][通常論文]
     
    We retrospectively evaluated the serum high-sensitivity C-reactive protein (CRP) level before chemotherapy for the prediction of infectious events during neutropenia in patients with acute myeloid leukaemia. Thirty-eight patients who underwent first induction chemotherapy and 37 patients who underwent first consolidation chemotherapy were analyzed separately. A receiver-operating characteristic (ROC) curve revealed that the serum CRP level just before the first consolidation chemotherapy, but not just before the induction chemotherapy, had a significant predictive value for febrile neutropenia (FN) at a cut-off value of 0.19 mg/dl and documented infection (DI) at a cut-off value of 0.26 mg/dl. The high-sensitivity CRP measurement enabled the detection of slight increases in the serum CRP level, which might reflect a minute inflammation by occult infection, and discriminated high-risk patients for infectious events.
  • Hideki Nakasone, Yoshinobu Kanda, Tomoki Ueda, Kenji Matsumoto, Naomi Shimizu, Jiro Minami, Rika Sakai, Maki Hagihara, Akira Yokota, Kumi Oshima, Yuiko Tsukada, Takayoshi Tachibana, Chiaki Nakaseko, Shin Fujisawa, Shingo Yano, Hiroyuki Fujita, Satoshi Takahashi, Heiwa Kanamori, Shinichiro Okamoto
    American journal of hematology 84 12 809 - 14 2009年12月 [査読有り][通常論文]
     
    The combination of cyclophosphamide and granulocyte-colony stimulating factor (G-CSF) has widely been used to mobilize hematopoietic stem cells (HSCs) for autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Recently, however, alternative approaches such as G-CSF alone or etoposide followed by G-CSF have been investigated. We, therefore, retrospectively analyzed the effects of these mobilization methods on collection yield and disease outcome in ASCT for MM. We reviewed 146 MM patients from whom we intended to collect stem cells. For mobilization, 67, 58, and 21 patients received cyclophosphamide and G-CSF, etoposide and G-CSF, and G-CSF alone (including nonmyelosuppressive chemotherapy followed by G-CSF), respectively. Among them, 136 achieved the target number of HSCs (at least 2 x 10(6)/kg). Lower creatinine and higher albumin levels at diagnosis were significantly associated with successful yield. A lower number of infused HSCs, use of the etoposide for mobilization and high ISS were associated with delayed hematopoietic recovery. The mobilization methods did not significantly affect either the successful collection of more than 2 x 10(6) CD34-positive cells/kg or PFS after ASCT. G-CSF alone was sufficient for stem cell mobilization for a single ASCT. The optimal approach to collect HSCs in MM remains to be elucidated.
  • Hideki Nakasone, Shinichi Kako, Hiroshi Endo, Ayumu Ito, Miki Sato, Kiriko Terasako, Shinya Okuda, Yukie Tanaka, Rie Yamazaki, Kumi Oshima, Aki Tanihara, Michiko Kida, Takakazu Higuchi, Koji Izutsu, Junji Nishida, Akio Urabe, Kensuke Usuki, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 14 6 361 - 5 2009年12月 [査読有り][通常論文]
     
    The incidence of autoimmune hemolytic anemia (AIHA) is highest among the elderly, and thus it is frequently associated with co-morbidities such as diabetes mellitus (DM). However, there have been few reports on the impact of these co-morbidities on survival in patients with AIHA. Therefore, we retrospectively reviewed the records of 53 consecutive AIHA patients and assessed the impact of DM on survival. Eighteen of the 53 patients had DM. The estimated 4-year overall survival (4y-OS) for all patients was 84.9%. Infection was the most frequent cause of death, and fatal infections were exclusively observed in patients with DM. The deaths in DM patients occurred frequently within 1 year, to give significantly poor survival (4y-OS; 69.3% versus 93.6%, P=0.0064). The presence of DM was identified as the only significant risk factor for survival. A large prospective investigation is warranted to assess the impact of co-morbidities on survival in patients with AIHA.
  • Shinichi Kako, Kumi Oshima, Miki Sato, Kiriko Terasako, Shinya Okuda, Hideki Nakasone, Rie Yamazaki, Yukie Tanaka, Aki Tanihara, Yutaka Kawamura, Hirokazu Kiyosaki, Takakazu Higuchi, Junji Nishida, Fumio Konishi, Yoshinobu Kanda
    Leukemia & lymphoma 50 10 1618 - 24 2009年10月 [査読無し][通常論文]
     
    The clinical features and outcome of small intestinal lymphoma remain unclear. We retrospectively analyzed 23 patients who had non-Hodgkin lymphoma with a small intestinal lesion. With a median follow-up of 37 months, the 5-year overall survival and failure-free survival (FFS) were 64% and 60%, respectively. In a univariate analysis, a worse performance status at the start of treatment and the occurrence of abdominal symptoms or perforation during treatment were associated with poor survival. Perforation often resulted in a dismal prognosis in patients with uncontrollable lymphoma, but not in patients with lymphoma in remission. The role of surgery in small intestinal lymphoma remains equivocal. In the current study, surgery before other therapies favorably influenced FFS, and all patients who underwent complete resection of the small intestinal lesion had extremely favorable results. Further studies are warranted to establish optimal therapeutic strategies.
  • Fumiya Miyamura, Shinichi Kako, Hiroko Yamagami, Ken Sato, Miki Sato, Kiriko Terasako, Shun-Ichi Kimura, Hideki Nakasone, Satoko Aoki, Shinya Okuda, Rie Yamazaki, Kumi Oshima, Kentaro Yoshinaga, Takakazu Higuchi, Junji Nishida, Toshio Demitsu, Akihiro Kakehashi, Yoshinobu Kanda
    International journal of hematology 90 3 397 - 401 2009年10月 [査読有り][通常論文]
     
    Only some carriers of human T cell lymphotropic virus type I (HTLV-1) develop adult T cell leukemia/lymphoma (ATLL) after a long latency period, and an association has been reported between chronic refractory eczema, known as infective dermatitis, and young-onset ATLL. A 25-year-old female developed ATLL and underwent allogeneic hematopoietic stem cell transplantation (HSCT) in non-remission. She had chronic refractory eczema and corneal injury at the onset of ATLL. Remission of ATLL was achieved, and the HTLV-1 proviral load decreased after HSCT. In addition, her pre-existing eczema and corneal injuries almost disappeared. More than a year has passed since the transplantation was performed, and she has had no recurrence of either ATLL or lesions in the skin and eye. Her clinical course suggests a possible association between skin and eye lesions and HTLV-1 infection. Changes in the immunological condition after HSCT might play a key role. Special attention is needed when HTLV-1 carriers develop eye or skin lesions.
  • Kumi Oshima, Miki Sato, Shinya Okuda, Kiriko Terasako, Hideki Nakasone, Shinichi Kako, Rie Yamazaki, Yukie Tanaka, Aki Tanihara, Takakazu Higuchi, Junji Nishida, Ikuo Nakamura, Yukio Yoshida, Yoshinobu Kanda
    Hematology (Amsterdam, Netherlands) 14 2 73 - 5 2009年04月 [査読有り][通常論文]
     
    The appearance of hepatitis B surface antigen (HBsAg) in patients previously positive for antibody to this antigen (HBsAb) is called reverse seroconversion, a rare complication after hematopoietic stem cell transplantation (HSCT), which occurs almost exclusively after HSCT from an HBsAb-negative donor and the development of chronic graft-versus-host disease (CGVHD). However, we experienced a patient who developed reverse seroconversion 23 months after unrelated HSCT even in the absence of immunosuppressants use or CGVHD. Serum immunoglobulin level was persistently normal. Therefore, all HBsAb-positive recipients should be considered to be at risk for HBV reactivation, even in patients without any risk factors.
  • Shinya Okuda, Kiriko Terasako, Kumi Oshima, Miki Sato, Hideki Nakasone, Shinichi Kako, Rie Yamazaki, Yukie Tanaka, Aki Tanihara, Takakazu Higuchi, Junji Nishida, Yoshinobu Kanda
    American journal of hematology 84 3 167 - 9 2009年03月 [査読有り][通常論文]
     
    Allogeneic hematopoietic stem cell transplantation for severe aplastic anemia from an alternative donor is associated with higher risks of graft rejection and severe graft-versus-host disease. We developed a conditioning regimen consisting of rabbit anti-thymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Two adult female patients with transfusion-dependent very severe aplastic anemia underwent 1-locus mismatched transplantation using this regimen. Both patients achieved stable engraftment and the clinical course thereafter was uneventful with persistently normal ovarian function. This novel conditioning regimen may be suitable for alternative donor transplantation for severe aplastic anemia, especially in young female patients.
  • Shinichi Kako, Kumi Oshima, Miki Sato, Kiriko Terasako, Shinya Okuda, Hideki Nakasone, Rie Yamazaki, Yukie Tanaka, Aki Tanihara, Yutaka Kawamura, Hirokazu Kiyosaki, Takakazu Higuchi, Junji Nishida, Fumio Konishi, Yoshinobu Kanda
    LEUKEMIA & LYMPHOMA 50 10 1618 - 1624 2009年 [査読有り][通常論文]
     
    The clinical features and outcome of small intestinal lymphoma remain unclear. We retrospectively analyzed 23 patients who had non-Hodgkin lymphoma with a small intestinal lesion. With a median follow-up of 37 months, the 5-year overall survival and failure-free survival (FFS) were 64% and 60%, respectively. In a univariate analysis, a worse performance status at the start of treatment and the occurrence of abdominal symptoms or perforation during treatment were associated with poor survival. Perforation often resulted in a dismal prognosis in patients with uncontrollable lymphoma, but not in patients with lymphoma in remission. The role of surgery in small intestinal lymphoma remains equivocal. In the current study, surgery before other therapies favorably influenced FFS, and all patients who underwent complete resection of the small intestinal lesion had extremely favorable results. Further studies are warranted to establish optimal therapeutic strategies.
  • Hideki Nakasone, Koji Izutsu, Satoshi Wakita, Hiroki Yamaguchi, Michiko Muramatsu-Kida, Kensuke Usuki
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 14 11 1262 - 9 2008年11月 [査読有り][通常論文]
     
    Although core-binding factor acute myeloid leukemia (CBF-AML) is generally considered to be a low-risk form of AML, the survival rate is still 50% to 60%. To evaluate the effectiveness of autologous stem cell transplantation (ASCT) with a PCR-negative graft we analyzed a series of consecutive CBF-AML patients. Between 1997 and 2006, 18 patients aged<60 years were referred under a diagnosis of CBF-AML. Peripheral blood stem cells (PBSC) were collected after a second or further course of postremission therapy. When >2.0x10(6)/kg CD34-positive cells with minimal residual disease (MRD) undetectable by nested polymerase chain reaction (PCR) had been collected, ASCT was performed with busulfan, etoposide, and cytarabine combined with granulocyte colony-stimulating factor. Event-free survival (EFS) and complications of ASCT were then assessed. Fourteen of the 18 patients received ASCT. The median observation period was 4.4 years. The 5-year EFS was 93% for ASCT patients, despite the presence of adverse factors. In 8 of 10 patients who had detectable MRD in the bone marrow before ASCT, MRD became undetectable after ASCT. Neutrophils recovered promptly within 2 weeks, but platelets recovered relatively slowly. Half of the patients suffered from varicella zoster virus infection. Although 1 case of myelodysplastic syndrome occurred, there was no case of relapse. ASCT with a PCR-negative graft was associated with excellent EFS. For patients with CBF-AML, especially with adverse factors or remnant MRD in the bone marrow, this strategy is the treatment of choice.
  • Hideki Nakasone, Kimiko Iijima, Hiroki Asano, Fumihiko Nakamura, Michiko Kida, Koji Izutsu, Akio Urabe, Kensuke Usuki
    [Rinsho ketsueki] The Japanese journal of clinical hematology 49 7 498 - 504 2008年07月 [査読有り][通常論文]
     
    Immunosuppressive therapy (IST) for paroxysmal nocturnal hemoglobinuria (PNH) has been infrequently reported. Four PNH cases were treated with antithymocyte globulin (ATG) at our center. We assessed and reviewed the efficacy and safety of IST for PNH. ATG therapy was performed for progression of cytopenia in 3 classical-type and 1 marrow failure-type PNH cases. ATG was administered at a dose of 15 mg/kg for 5 consecutive days. Hydration and anticoagulant therapy were given as prophylaxis for thrombosis during ATG therapy. Cyclosporine was also given to the 3 classical-type PNH patients. Three patients showed hemolytic exacerbation and thrombocytopenia during ATG administration, and all needed to receive transfusions of red blood cells and platelets; however, renal failure and thrombosis did not occur. Anemia improved in all cases within 1 year, but thereafter, recurred in 2 cases. ATG therapy is a choice of treatment for PNH, although its mechanism remains unknown.
  • Yuki Asano-Mori, Yoshinobu Kanda, Kumi Oshima, Shinichi Kako, Akihito Shinohara, Hideki Nakasone, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
    American journal of hematology 83 6 472 - 6 2008年06月 [査読有り][通常論文]
     
    To evaluate the efficacy of long-term prophylaxis with ultra-low-dose acyclovir against varicella-zoster virus (VZV) reactivation, we analyzed the records of 242 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2006 at our hospital. We started long-term oral acyclovir at 200 mg/day in July 2001. Acyclovir was continued until the end of immunosuppressive therapy and at least 1 year after transplantation. Sixty-six patients developed VZV reactivation at a median of 248 days after HSCT, with a cumulative incidence of 34.7%. Only one breakthrough reactivation occurred during long-term acyclovir, which responded well to therapeutic dose of valacyclovir. The use of long-term acyclovir was the only independent determinant that significantly decreased the overall incidence of VZV reactivation (20% vs. 50%, P < 0.0001). With this prophylaxis, visceral dissemination and serious complications other than post-herpetic neuralgia was completely eliminated, and thereby need for hospitalization was significantly reduced (21% vs. 71%, P = 0.0034). Fifteen of the 57 patients who discontinued acyclovir developed VZV reactivation, with a cumulative incidence of 32.1%. VZV reactivation following discontinuation tended to occur in patients who were receiving immunosuppressive therapy at the cessation of acyclovir. These findings suggested that long-term prophylaxis of ultra-low-dose acyclovir resulted in a successful prevention of severe VZV-related symptoms and death, with a significantly decreased overall incidence of VZV reactivation. Prolongation of prophylactic acyclovir on profound immunosuppression might be important for thorough suppression of VZV reactivation.
  • Hideki Nakasone, Michiko Kida, Seiko Iki, Kensuke Usuki
    Leukemia research 32 4 659 - 64 2008年04月 [査読有り][通常論文]
     
    We have reported a rare case of acute lymphoblastic leukemia (ALL) recurring 19 years after the first presentation. Since 1984, 36 relapse cases 10 years or more after the first diagnosis have been reported. All cases were childhood ALL with a low to standard risk. Twenty-six attained CR2, and 18 of them remained in sustained CR2. The sustained CR2 ratio was 80% without transplantation. Sustained CR2 ratio was significantly lower in patients with lower leukocytes (<10 x 10(9)l(-1)) at initial presentation. A very late relapse of ALL remains chemosensitive, and its prognosis is not unfavorable.
  • Yuki Asano-Mori, Yoshinobu Kanda, Kumi Oshima, Shinichi Kako, Akihito Shinohara, Hideki Nakasone, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
    International journal of hematology 87 3 310 - 8 2008年04月 [査読有り][通常論文]
     
    Late cytomegalovirus (CMV) disease beyond day 100 after hematopoietic stem cell transplantation (HSCT) has become an increasing problem after the introduction of preemptive ganciclovir (GCV) administration. To clarify the risk factors and outcome for late CMV reactivation and disease, we retrospectively analyzed the records of 101 Japanese adult patients who underwent allogeneic HSCT between 1998 and 2005 at our hospital. Fifty-one developed late positive CMV antigenemia, with a cumulative incidence of 53%. Recipient CMV seropositivity, the use of alemtuzumab, chronic GVHD, and high-dose steroids were significantly associated with late positive antigenemia. Eight patients developed late CMV disease, with a cumulative incidence of 8%, including retinitis and gastrointestinal disease. None progressed to a fatal disease. The use of alemtuzumab was identified as an independent significant risk factor for late CMV disease, although it was not associated with increased non-relapse mortality. Among the 51 patients with late positive antigenemia, 28 had consistently less than three positive cells, 25 of whom showed negative conversion without antiviral agents. In conclusion, late CMV antigenemia appeared to develop frequently, especially in patients with profound immune suppression; however, a fatal outcome could be prevented by optimal preemptive therapy. Low-level antigenemia may not require antiviral treatments.
  • Kumi Oshima, Yoshinobu Kanda, Hideki Nakasone, Shunya Arai, Nahoko Nishimoto, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
    American journal of hematology 83 3 226 - 32 2008年03月 [査読有り][通常論文]
     
    Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.
  • Yuki Asano-Mori, Yoshinobu Kanda, Kumi Oshima, Shinichi Kako, Akihito Shinohara, Hideki Nakasone, Makoto Kaneko, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
    The Journal of antimicrobial chemotherapy 61 2 411 - 6 2008年02月 [査読有り][通常論文]
     
    OBJECTIVES: Although Aspergillus galactomannan (GM) antigen detection is widely applied in the diagnosis of invasive aspergillosis (IA), false-positive reactions with fungus-derived antibiotics, other fungal genera or the passage of dietary GM through injured mucosa are a matter of concern. The aim of this study was to investigate the cumulative incidence and risk factors for false-positive GM antigenaemia. PATIENTS AND METHODS: The records of 157 adult allogeneic haematopoietic stem cell transplantation (HSCT) recipients were retrospectively analysed. Episodes of positive GM antigenaemia, defined as two consecutive GM results with an optical density index above 0.6, were classified into true, false and inconclusive GM antigenaemia by reviewing the clinical course. RESULTS: Twenty-five patients developed proven or probable IA with a 1 year cumulative incidence of 12.9%, whereas 50 experienced positive GM antigenaemia with an incidence of 32.2%. Among the total 58 positive episodes of the 50 patients, 29 were considered false-positive. The positive predictive value (PPV) was lower during the first 100 days than beyond 100 days after HSCT (37.5% versus 58.8%). Gastrointestinal chronic graft-versus-host disease (GVHD) was identified as the only independent significant factor for the increased incidence of false-positive GM antigenaemia (PPV 0% versus 66.7%, P = 0.02). CONCLUSIONS: GM antigen results must be considered cautiously in conjunction with other diagnostic procedures including computed tomography scans, especially during the first 100 days after HSCT and in patients with gastrointestinal chronic GVHD.
  • Kensuke Usuki, Hideki Nakasone, Kazuki Taoka, Michiko Kida, Seiko Iki, Akio Urabe
    [Rinsho ketsueki] The Japanese journal of clinical hematology 48 8 618 - 23 2007年08月 [査読有り][通常論文]
     
    Twenty-three patients with acute myelogenous leukemia (AML) have received autologous hematopoietic stem cell transplantation (autoHSCT) in our institute from 1997 to 2005. Among them, 3 patients relapsed, and the other 4 patients (17%) showed cytogenetic abnormalities after the autoHSCT. In these 4 patients with AML1/MTG8 or CBFbeta/MYH11 AML, RT-PCR findings using bone marrow cells were all negative when a cytogenetic abnormality was detected. Myelodysplasia was not detected in the bone marrow and no abnormal findings were seen in the peripheral blood. Cytogenetic abnormalities were detected 12-48 months after AutoHSCT, which disappeared in three patients and decreased in the remaining one patient with a median follow up time of 51 months (30-72 months) after their detection. We present our finding together with a review of the literature on post-autoHSCT cytogenetic abnormalities not related to relapse or secondary leukemia/myelodysplastic syndrome.
  • Usukine K, Shinhori H, Idetsuki T, Taoka K, Nakasone H, Kida M, Iki S, Urabe M, Oseto K, Igarashi A
    [Rinsho ketsueki] The Japanese journal of clinical hematology 48 5 351 - 352 2007年05月 [査読有り][通常論文]
  • Akihide Yoshimi, Kazuki Taoka, Hideki Nakasone, Kimiko Iijima, Michiko Kida, Seiko Iki, Akio Urabe, Kensuke Usuki
    [Rinsho ketsueki] The Japanese journal of clinical hematology 47 12 1533 - 8 2006年12月 [査読有り][通常論文]
     
    Superior sagittal sinus thrombosis (SSST) has been reported to be caused by coagulopathy following oral contraceptive therapy, DIC, infection around the sinus, compression from a tumor, infiltration of tumor, and an inherited deficiency of proteins C and S, but SSST associated with hematological malignancies and L-asparaginase (L-Asp) therapy is rare. We report a case of an adult patient with acute lymphoblastic leukemia (ALL) who developed SSST during the remission induction therapy. A 25-year-old man was admitted with left facial nerve palsy and, following bone marrow aspiration and lumbar puncture, he was diagnosed as having T-ALL with CNS involvement. He received a 1-AdVP regimen as remission induction therapy and intrathecal administration of methotrexate and cytarabine. On day 29, he had a generalized convulsion and SSST was demonstrated by imaging tests. Lymphoid malignancy (ALL in particular), the use of L-Asp, CNS involvement, and intrathecal chemotherapy might be risk factors for the occurrence SSST. When a patient with those factors develops any neurological symptoms, we should pay attention to the occurrence of SSST, as well as stroke or CNS involvement, though SSST is rare.
  • N Takeda, T Takahashi, Y Seko, K Maemura, H Nakasone, K Sakamoto, Y Hirata, R Nagai
    INTERNAL MEDICINE 44 3 256 - 260 2005年03月 [査読有り][通常論文]
     
    A 15-year-old Japanese man was referred for evaluation of heart failure. Conventional heart failure therapy had little effect, and severe left ventricular dysfunction as well as elevated erythrocyte sedimentation rate persisted. Magnetic resonance angiography showed aortic dilatation with wall thickening characteristic of Takayasu's arteritis. An endomyocardial biopsy specimen revealed infiltration of natural killer cells and gamma delta T lymphocytes, which play major roles in vascular injury of Takayasu's arteritis. Prednisolone administration provided great benefits to cardiac function. These findings suggest that autoimmune cytotoxic mechanisms similar to those in arterial tissue may contribute to cardiac impairment in Takayasu's arteritis.
  • Hiroshi Sakugawa, Tomofumi Nakayoshi, Kasen Kobashigawa, Hiroki Nakasone, Yuko Kawakami, Tsuyoshi Yamashiro, Tatsuji Maeshiro, Ko Tomimori, Satoru Miyagi, Fukunori Kinjo, Atsushi Saito
    WORLD JOURNAL OF GASTROENTEROLOGY 10 7 1052 - 1055 2004年04月 [査読有り][通常論文]
     
    AIM: This study aimed to determine whether metabolic syndrome is directly or indirectly, through fatty liver, associated with elevated gamma-glutamyl transpeptidase (GGT) levels in Japanese women. METHODS: From 4 366 women who received their annual health check-up, 4 211 women were selected for analysis. All 4 211 women were negative for both hepatitis B surface antigen and antibody to hepatitis C virus. Clinical and biochemical variables were examined by using univariate and multivariate analysis. RESULTS: A raised GGT level (>68 IU/L) was seen in 258 (6.1%) of the 4 211 women. In univariate analysis, all variables examined (age, body mass index, blood pressure, hemoglobin concentration, fasting blood glucose, glycosylated hemoglobin A1c, cholesterol, triglyceride, and uric acid) were associated with the elevated GGT level, whereas in multivariate analysis, four variables (age >= 50 yr, hemoglobin >= 14 g/dL, triglyceride >= 150 mg/dL, and presence of diabetes) were significantly and independently associated with raised GGT level. Clinical variables predicting the presence of ultrasonographic evidence of fatty liver were also examined by multivariate analysis; four variables were associated with the presence of fatty liver: BMI >= 25 kg/m(2), hemoglobin >= 14 g/dL, triglyceride >= 150 mg/dL, and uric acid >= 7 mg/dL. There was no significant association between the raised GGT level and the presence of fatty liver. Hypertriglyceridemia was significantly and independently associated with both the raised GGT level and the presence of fatty liver. CONCLUSION: Metabolic syndrome seemed to be directly, not indirectly through fatty liver, associated with the raised GGT level in Japanese women.
  • Tomokuni Nakayoshi, Tatsuji Maeshiro, Tomofumi Nakayoshi, Hiroki Nakasone, Hiroshi Sakugawa, Fukunori Kinjo, Etsuro Orito, Masashi Mizokami
    Journal of Medical Virology 70 3 350 - 354 2003年07月 [査読有り][通常論文]
     
    The factors contributing to the prognosis of hepatitis B virus (HBV)- related chronic liver disease were assessed prospectively in 72 patients with chronic hepatitis B confirmed clinically and pathologically. A comparative study was undertaken between patients infected with genotype B and those with genotype C. During the follow-up period, 13 (81.3%) of 16 patients with genotype B who were initially hepatitis B e antigen (HBeAg) positive became HBeAg negative and 14 (51.9%) of 27 with genotype C became HBeAg negative. HBeAg had been cleared in 8 (61.5%) of 13 patients with genotype B within the first 2 years of the follow-up, but in only one (7.1%) of 14 with genotype C (P< 0.05). Four (11.4%) of 35 patients with genotype B had progressed to cirrhosis, whereas, 12 (32.4%) of 37 patients with genotype C progressed to cirrhosis, including two patients with hepatocellular carcinoma. Multivariate analysis showed that difference in HBV genotype influenced significantly either the clearance of HBeAg or the development of cirrhosis. In conclusion, HBeAg was cleared from sera more frequently and earlier in patients with genotype B compared with those with genotype C, and development of cirrhosis occurred less frequently in patients with genotype B compared with those with genotype C. Thus, HBV genotypes may influence the prognosis of HBV-related chronic liver disease. © 2003 Wiley-Liss, Inc.
  • Hiroshi Sakugawa, Hiroki Nakasone, Tomofumi Nakayoshi, Etsuro Orito, Masashi Mizokami, Tsuyoshi Yamashiro, Tatsuji Maeshiro, Fukunori Kinjo, Atsushi Saito, Yasuhiro Miyagi
    Journal of Medical Virology 67 4 484 - 489 2002年 [査読有り][通常論文]
     
    The present study was designed to examine the distribution of hepatitis B virus (HBV) genotypes among patients at various stages of chronic liver disease type B in Okinawa Prefecture, Japan, where the prevalence of hepatitis B surface antigen is the highest in Japan despite the lowest mortality rate from primary liver cancer. Serum samples from 227 HBV carriers were determined for HBV genotype by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Five of 227 sera were negative for HBV DNA by nested PCR and were excluded from the genotype analysis. Genotype B was predominant in asymptomatic carriers (45/67, 67%), whereas genotype C was predominant in chronic liver disease: 49% (50/103) in patients with chronic hepatitis, 63% (20/32) in patients with cirrhosis, and 60% (12/20) in patients with hepatocellular carcinoma. The distribution of genotype B decreased with increasing liver disease severity. However, this tendency was seen among patients aged less than 50 years old, whereas the prevalence of genotype B was similar among carriers with various liver diseases who were older than age 50. In conclusion, HBV genotype B was prevalent and less frequent among patients with advanced liver disease, particularly in patients aged less than 50 years. These findings suggest that the preponderance of genotype B is responsible for the low mortality rate of primary liver cancer associated with HBV seen in Okinawa Prefecture, despite having the highest HBV carrier rate in Japanese. © 2002 Wiley-Liss, Inc.
  • An autopsy case report of T-cell lymphoma accompanied by hemophagocytic syndrome and acute hepatic failure.
    Sunagawa T, Nakasone H, Kochi A, Sakugawa H, Kinjo F, Saito A, Morioka T, Arakaki Y, Ito E
    17 57 - 60 1997年 [査読有り][通常論文]

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