三﨑 柚季子

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.