神田 善伸

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49-0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68-1.16], P = 0.40; NRM 0.98 [95% CI: 0.68-1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens.

Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD.

BACKGROUND: A change in empirical antibiotics or the addition of glycopeptide antibiotics is often applied in cases of persistent febrile neutropenia (FN) despite the administration of broad-spectrum antibiotics. However, the clinical benefit of these approaches remains unclear. METHODS: We conducted a retrospective study to evaluate the effectiveness of a change in antibiotics or the addition of glycopeptide antibiotics for persistent FN after autologous hematopoietic cell transplantation (auto-HCT). We retrospectively reviewed the records of 208 patients who received auto-HCT at our institution between 2007 and 2019. FN that lasted for 4 days or longer was defined as persistent FN. We compared the time to defervescence between patients whose initial antibiotics were changed and/or who additionally received glycopeptide antibiotics, and those without these antibiotic modifications. RESULTS: Among patients who fulfilled the criteria of persistent FN (n = 125), changes in antibiotics were not significantly associated with the time to defervescence in a multivariate analysis (hazard ratio [HR] 0.72, p = 0.27). On the other hand, the addition of glycopeptide antibiotics was paradoxically associated with a delay in defervescence (HR 0.56, p = 0.033). CONCLUSIONS: Although there may be differences in patient backgrounds, no significant differences were observed in either a univariate or multivariate analysis. Since neither a change in antibiotics nor the addition of glycopeptide antibiotics was associated with earlier defervescence in persistent FN after auto-HCT, routine antibiotic modifications might not be necessary in this setting.

BACKGROUND AIMS: Pre-transplant lung dysfunction is known to be a risk factor for non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). It is unclear which cell source gives better outcomes for patients with pulmonary dysfunction. METHODS: We analyzed 3289 adult patients with standard-risk disease who had received HLA-matched allo-HCT, and compared outcomes between those who received peripheral blood stem cell (PBSC) vs. bone marrow (BM) in two cohorts based on the presence of a lung score by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI): the Lung-scored (LS) and non-LS cohorts. RESULTS: In the LS cohort, the 2-year overall survival (OS) in the BM group tended to be higher than that in the PBSC group (72.4% vs. 61.4%; P = 0.044). In the non-LS cohort, there was no significant difference between the two groups (71.7% vs. 73.2%; P = 0.13). Multivariate analyses confirmed that PBSC was significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54; P = 0.019). On the other hand, the cell source did not affect OS in the non-LS cohort (HR, 0.92; 95% CI, 0.76-1.12; P = 0.41). We found that PBSC was associated with an increased risk of NRM in the LS cohort (HR, 2.17; 95% CI, 1.16-4.05; P = 0.016), while the cell source did not significantly affect NRM in the non-LS cohort. PBSC was not identified as a risk factor for relapse in either cohort. CONCLUSIONS: Our results suggest that BM might be beneficial for recipients with lung dysfunction in HLA-matched allo-HCT.

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.

BACKGROUND: Human T-cell leukemia virus type I (HTLV-1) is a retrovirus known to cause adult T-cell leukemia/lymphoma (ATL). There are few reports on hematopoietic stem cell transplantation (HSCT) for HTLV-1 carriers with diseases other than ATL. METHODS: A total of 25,839 patients (24,399 adults and 1440 children) with pre-transplant HTLV-1 serostatus information recorded in the Japanese National Survey Database who had undergone their first HSCT were analyzed. We investigated the overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT in relation to HTLV-1 serologic status. FINDINGS: Three hundred and forty-eight patients were HTLV-1 antibody carriers. The number of HTLV-1 carriers and noncarriers among adult patients who received allogeneic HSCT (allo-HSCT) or autologous HSCT (auto-HSCT) was 237/15,777 and 95/8920, respectively, and was 16/1424 among pediatric patients who received allo-HSCT. No pediatric HTLV-1 carrier recipients undergoing auto-HSCT were identified. There were no significant differences between HTLV-1 carriers and non-carriers regarding stem cell source, disease risk, or HCT-CI score prior to allo-HSCT. Multivariate analysis of OS (P = 0.020) and TRM (P = 0.017) in adult patients showed that HTLV-1 positive status was a significant prognostic factor. In children, TRM was significantly higher (P = 0.019), but OS was not significantly different. In adult patients who underwent auto-HSCT, HTLV-1 positive status was not a significant prognostic factor. In adult allo-HSCT patients, cytomegalovirus reactivation was significantly more common in HTLV-1 carriers (P = 0.001). INTERPRETATION: HTLV-1 antibody positivity was shown to have a poor prognosis in OS and TRM after allo-HSCT in adult patients and in TRM after allo-HSCT in pediatric patients. FUNDING: This work was supported in part by the practical research programs of the Japan Agency for Medical Research and Development (AMED) under grant number 17ck0106342h0001.

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

Combination of calcineurin inhibitors (CIs) with short-term methotrexate is a standard prophylactic regimen for graft-versus-host disease (GVHD). However, it is sometimes difficult to continue CIs due to adverse effects, such as renal impairment and fluid overload. In such cases, we replace CIs with corticosteroids, considering that full dose of CIs is equivalent to prednisolone (PSL) at 1 mg/kg. We retrospectively evaluated the clinical significance of replacement of CIs with corticosteroids after allogeneic hematopoietic cell transplantation (HCT). We evaluated 42 patients switched from CIs to corticosteroids within 90 days among the 479 patients who underwent allogeneic HCT at our center between 2007 and 2019. Renal impairment (n = 33), fluid overload (n = 13), and thrombotic microangiopathy (n = 3) were the main reasons for switching. Although creatinine and body weight returned to baseline at 4 weeks after switching, 100-day non-relapse mortality was high (57.1%). Grade II-IV acute GVHD was seen in 10 (24.4%) patients who did not have it before switching treatment (n = 41). In conclusion, CIs were switched to corticosteroids in patients with severe clinical conditions. The incidence of acute GVHD was acceptable. Although the short-term mortality rate was high, improvement of renal function or fluid overload was observed in a certain proportion of the patients.

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, since H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified according to donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD following transplantation from HLA-identical female siblings [HLA-DRB1*15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = 0.025]. Co-expression of HLA-DRB1*15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD [68.8% vs. 31.7% at 1 year, P = 0.002]. Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD, and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.

Abstract Allogeneic hematopoietic cell transplantation between female donors and male recipients (female-to-male allo-HCT) is a well-established risk factor for inferior survival outcomes due to a higher incidence of graft-versus-host disease (GVHD). However, a clinical significance of anti-thymocyte globulin (ATG) in the female-to-male allo-HCT has not been elucidated. In this study, we retrospectively evaluated male patients who underwent allo-HCT between 2012 and 2019 in Japan. In the female-to-male allo-HCT cohort (n = 828), the use of ATG was not associated with a decreased risk of GVHD (HR of acute GVHD 0.691 [95% CI: 0.461–1.04], P = 0.074; HR of chronic GVHD 1.06 [95% CI: 0.738–1.52], P = 0.76), but was associated with favorable overall survival (OS) and a decreased risk of non-relapse mortality (NRM) (HR of OS 0.603 [95% CI: 0.400–0.909], P = 0.016; HR of NRM 0.506 [95% CI: 0.300–0.856], P = 0.011). The use of ATG in female-to-male allo-HCT resulted in survival outcomes that were almost equivalent to those in the male-to-male allo-HCT group. Therefore, GVHD prophylaxis with ATG might overcome the inferiority of survival outcomes in female-to-male allo-HCT.

34歳男性。KMT2A-MLLT1陽性急性骨髄性白血病の第1寛解期で,busulfan/高用量cyclophosphamideを前処置としてHLA適合の妹より同種末梢血幹細胞移植を施行した。Day14に生着し以降は寛解を維持した。重篤な移植片対宿主病も認めなかったが,経口cyclosporin(CsA)10mg/dayまで減量した移植後6ヶ月の時点で間質性肺炎を発症した。間質性肺炎に対して投与したprednisolone(PSL)の効果は一時的で,間質性肺炎は急速に増悪した。追加精査にて抗MDA5抗体陽性が判明したためcyclophosphamide+PSL+CsAによる3剤併用療法を開始して奏効が得られた。しかし,後遺症の呼吸不全で人工呼吸器管理を要したため,弟と妹より生体肺移植を施行した。3剤併用療法と生体肺移植により呼吸状態の改善を得た抗MDA5抗体陽性急速進行性間質性肺疾患の症例を経験したため,ここに報告する。(著者抄録)

BACKGROUND: In autologous hematopoietic cell transplantation (HCT), myelosuppression and mucosal damage are more severe than those in conventional chemotherapy because of high-dose chemotherapy, but the duration of neutropenia is shorter due to stem cell rescue. METHODS: We retrospectively evaluated febrile neutropenia (FN) and bloodstream infection (BSI) in 208 patients who underwent their first autologous HCT at our institution between 2007 and 2019. They were compared to those in patients who underwent intensive chemotherapy for acute myeloid leukemia (AML) (130 induction/salvage and 191 consolidation). RESULTS: The median neutropenic period in autologous HCT, AML induction/salvage and consolidation was 9, 26.5, and 19 days, respectively. The incidence of FN was 93.8%, 92.3%, and 81.7%, and that of BSI in initial FN was 7.2%, 7.5% and 26.3%, respectively. The incidence of oral mucositis (≥ grade 2) was 63.1%, 9.2% and 12.2%, and that of diarrhea (≥ grade 2) was 53.3%, 9.2% and 6.4%, respectively. Although there were significant differences in the incidence of shaking chills, the degree of fever and the value of CRP between patients with and without BSI in initial FN of AML chemotherapy, no significant risk factors or predictive factors for BSI were identified in autologous HCT. CONCLUSIONS: The profile of infectious complications in autologous HCT was characterized by a high incidence of FN maybe due to mucosal damage. On the other hand, the incidence of BSI was lower compared to that in AML consolidation chemotherapy.

The prognosis of multiple myeloma (MM) has dramatically improved with the development of new drugs, and it has become important to determine the appropriate combinations of these novel agents. This study was a systematic review and network meta-analysis (NMA) of randomized trials in patients with relapsed and/or refractory (RR) MM. The PubMed, Cochrane, and Embase databases were searched for randomized trials from 1 January 2002 to 28 February 2022 of patients treated for MM. The primary end-point was progression-free survival (PFS), evaluated as a hazard ratio (HR) with a 95% confidence interval (95% CI) compared to dexamethasone (DEX). The p-score was used to rank treatments. Of a total of 1136 abstracts screened, 37 studies were selected, including 34 treatment options for RRMM. Daratumumab, lenalidomide and DEX was found to be the best treatment for RRMM, with the best HR compared to DEX (HR, 0.13; 95% CI, 0.08-0.20; p-score 0.9796). There was no evidence of significant heterogeneity (I2 , 41.3%; p = 0.146). The current NMA confirmed the excellent efficacy of three-drug regimens including anti-CD38 antibodies to treat RRMM and provides background data to evaluate the efficacy of chimeric antigen receptor T-cell treatments and bispecific T-cell engager therapies.

Anti-thymocyte globulin (ATG) is widely used to reduce acute and chronic graft-versus-host disease (a/cGVHD), one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). As the removal of alloreactive T cells by ATG may also reduce the graft-versus-leukemia effect, the question of whether ATG use affects relapse incidence and survival outcomes in acute leukemia patients with pre-transplant bone marrow residual blasts (PRB) remains controversial. Here, we evaluated the impact of ATG on transplant outcomes in acute leukemia patients with PRB (n = 994) who underwent HSCT from HLA 1-allele mismatched unrelated donors (MMUD) or HLA 1-antigen mismatched related donors (MMRD). In MMUD with PRB (n = 560), multivariate analysis demonstrated that ATG use significantly decreased grade II-IV aGVHD (hazard ratio [HR], 0.474; P = 0.007) and non-relapse mortality (HR, 0.414; P = 0.029) and marginally improved extensive cGVHD (HR, 0.321; P = 0.054) and GVHD-free/relapse-free survival (HR, 0.750; P = 0.069). We concluded that ATG had different effects on transplant outcomes using MMRD and MMUD, and its use would be beneficial to decrease a/cGVHD without increasing non-relapse mortality and relapse incidence in acute leukemia patients with PRB following HSCT from MMUD.

Cytomegalovirus reactivation (CMVR) after allogeneic hematopoietic cell transplantation (HCT) is a frequent complication related to survival outcomes, but the impact of CMVR on relapse is still unclear, especially in acute lymphoblastic leukemia (ALL). In this nationwide retrospective study, we included patients with acute myeloid leukemia (AML) and ALL in first or second complete remission who underwent their first HCT using pre-emptive strategy for CMVR. Because ninety percent of cases with CMVR had occurred by day 64 and ninety percent of cases with grades II to IV acute GVHD had occurred by day 58, a landmark point was set at day 65. In the landmark analyses, 3793 patients with AML and 2213 patients with ALL who survived without relapse for at least 65 days were analyzed. In the multivariate analyses, CMVR was associated with a lower incidence of relapse in both AML (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69-0.95; P = 0.009) and ALL (HR, 0.81; 95% CI, 0.66-0.99; P = 0.045). These findings were confirmed when we treated CMVR as a time-dependent covariate. Moreover, our study suggested that the protective effect of CMVR on relapse was independent of acute GVHD. A post-hoc subgroup analysis that combined AML and ALL showed that CMVR had a mild anti-leukemia effect without effect modification in contrast to the impact of CMVR on NRM. Our findings may provide important implications for the strategy used for CMV prophylaxis after HCT.

Tandem autologous stem cell transplantation (ASCT) has been reconsidered for high-risk patients with myeloma, and the eligibility criteria for up-front ASCT have been updated to include more elderly patients. This study aimed to evaluate the efficacy and tolerability of tandem ASCT in elderly patients with myeloma compared to tandem ASCT in young patients and single ASCT in elderly patients. A retrospective study using the Transplant Registry Unified Management Program database of the Japanese Society for Transplantation and Cellular Therapy, which included 64 elderly and 613 young patients who received tandem ASCT, and 891 elderly patients who received single ASCT, was conducted. The median overall survival (OS) over 38.5 months in the elderly and young patients who received tandem ASCT, and elderly patients who received single ASCT was 78.9, 92.5, and 77.1 months, respectively; No significant difference in the median OS was observed. The cumulative incidence of transplantation-related mortality was similar in the elderly and young patients receiving tandem ASCT. High-risk cytogenetic abnormality was not identified as a poor prognostic factor for OS in elderly patients who received tandem ASCT but in those who received single ASCT. Thus, tandem ASCT was effective and tolerable in elderly patients with myeloma. This article is protected by copyright. All rights reserved.

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n = 1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P <.001, log-rank test) and limited chronic GVHD (P <.001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT,.73, 95% confidence interval [CI],.60 to.87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI,.70 to 1.64; P for interaction =.038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

A 34-year-old man with KMT2A-MLLT1 acute myeloid leukemia in first complete remission underwent allogeneic peripheral blood stem cell transplantation from his HLA-matched sister after conditioning with busulfan/cyclophosphamide. He did not have severe graft-versus-host disease, but he developed interstitial pneumonia six months after transplantation when his oral cyclosporine A (CsA) dose was reduced to 10 mg/day. He was given prednisolone (PSL), which temporarily improved his respiratory condition, but he quickly deteriorated when PSL was reduced. Anti-MDA5 antibody was found to be positive after additional testing, and a three-drug combination of intravenous cyclophosphamide+PSL+CsA was initiated for anti-MDA5 antibody positive rapidly progressive interstitial lung disease, which was effective for interstitial pneumonia. He received a successful living-donor lung transplant from his younger brother and sister. We present a case of rapidly progressive anti-MDA5 antibody positive interstitial lung disease in which the patient's respiratory condition improved after triple therapy and subsequent living-donor lung transplantation.

Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable to those with myeloablative conditioning (MAC) due to a lower risk of NRM but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the Risk assessment for the Intensity of Conditioning regimen in Elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50-69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥ 60 y), Hematopoietic Cell Transplantation-Specific Comorbidity Index (≥ 2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of nonrelapse mortality (NRM) between MAC and RIC - the RICE score, which is the sum of these three factors: 0 or 1, low RICE score; or 2 or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: HR, 0.73, 95%CI, 0.60-0.90, P = 0.003; validation cohort: HR, 0.57, 95%CI, 0.43-0.77, P < 0.001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99, 95%CI, 0.85-1.15, P = 0.860; validation cohort: HR, 0.81, 95%CI, 0.66-1.01, P = 0.061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and might improve transplant outcomes in elderly patients.

Fatal cardiac complications can occur from the early to late phases after hematopoietic cell transplantation (HCT). Herein, the Japanese transplant registry database was used to retrospectively analyze health records of 33,791 allogeneic HCT recipients to elucidate the pathogenesis and risk factors involved. Overall, 527 patients died of cardiac complications at a median of 130 (range 0-3924) days after HCT. The cumulative incidence of fatal cardiac complications was 1.2% (95% confidence interval [CI]: 1.0-1.3) and 1.6% (95% CI: 1.5-1.8) at 1 and 5 years after HCT, respectively. Fatal cardiovascular events were significantly associated with an HCT-specific comorbidity index (HCT-CI) score of ≥1 specific to the three cardiovascular items, lower performance status, conditioning regimen cyclophosphamide dose of >120 mg/kg, and female sex. Cardiovascular death risk within 60 days after HCT was associated with the type of conditioning regimen, presence of bacterial or fungal infections at HCT, and number of blood transfusions. Contrastingly, late cardiovascular death beyond 1 year after HCT was associated with female sex and older age. Lower performance status and positive cardiovascular disease-related HCT-CI were risk factors for cardiac complications in all phases after HCT. Systematic follow-up may be necessary according to the patients' risk factors and conditions.

Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.

Acute myeloid leukemia (AML) is a malignancy that requires immediate treatment. However, the factors that predict very early mortality are not well known. We retrospectively analyzed 70 patients who were newly diagnosed with AML at our institution between 2014 and 2020. Very early death within 30 days after the initial consultation with a hematologist occurred in eight patients, including seven men. They were older than 30-day survivors (70.5 vs. 47 years, P < 0.01). In addition, four patients with a low score on the Glasgow Coma Scale (GCS) at diagnosis died within 30 days, and half of the early death group died due to cerebral hemorrhage. We next tried to predict early death using a ROC curve. Age, hemoglobin (Hb), estimated glomerular filtration rate (eGFR) and the international normalized ratio of prothrombin time (PT-INR) all had an area under the curve of greater than 0.8 for predicting very early death. A multivariate analysis revealed that older age (OR = 1.14, P = 0.033), Hb (OR = 0.48, P = 0.05), and low GCS (OR = 140.0, P = 0.0073) were significantly associated with very early death. Further studies will be needed to confirm which patients are at high risk for early death and to improve the treatment strategy for such patients.

Chronic active Epstein-Bar virus infection (CAEBV) is known to cause various symptoms. Although pulmonary artery hypertension (PAH) has been reported as a cardiovascular complication of CAEBV, the mechanisms of PAH and the effects of treatment have not been fully elucidated. We experienced 4 adult patients with CAEBV complicated by PAH. All of them received treatment for PAH with a vasodilator followed by chemotherapy with or without allogeneic hematopoietic cell transplantation for CAEBV. In all of these patients, the transtricuspid pressure gradient improved under treatment with vasodilator, and further improvement was observed under treatment for CAEBV in 3 patients. Autopsy was performed in 2 patients, which revealed EBER-positive cells and a change in the pulmonary artery at each stage in the pathology. In conclusion, EBV-infected cells can cause vasculitis and finally PAH. However, PAH complicated with CAEBV can be improved by PAH medication and treatment of CAEBV.

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m2/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m2 (range, 0-950 mg/m2), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m2). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m2 was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.

In general, the recipient's ABO blood type changes to the donor's ABO blood type after ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). However, we experienced a 26-year-old male with acute myelogenous leukemia (AML) who underwent ABO-incompatible HSCT twice and persistently showed his original blood type even after demonstrating complete donor-type chimerism. Based on the results of various examinations, we considered that the antigen of the recipient's original blood type persistently synthesized in the recipient's non-hematopoietic organs was secreted and adsorbed on the surface of donor-derived RBCs. We should therefore perform detailed examinations to determine the precise blood type after ABO-incompatible HSCT.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody is one of auto-immune antibodies which is associated with a rare subtype of dermatomyositis (DM), and MDA5-DM is well-characterized by rapid progressive interstitial lung disease (ILD) which in part resembles pulmonary complications after allogeneic hematopoietic cell transplantation (allo-HCT). However, previous studies about anti-MDA5 antibody after allo-HCT were extremely limited. Here, we present 4 cases of ILD with anti-MDA5 antibody after allo-HCT. All of the cases showed rapidly progressive clinical course and 3 of 4 cases died despite intensive immunosuppressive therapies which included prednisolone, cyclophosphamide and calcineurin inhibitor. Additionally, 3 of 4 cases had tested positive for anti-MDA5 antibody by using cryopreserved plasma which were collected about 2-3 months before the diagnosis of MDA5-DM-ILD. It suggests that an inflammatory condition due to MDA5-DM-ILD might have sub-clinically occurred before the development of respiratory failure. The current cases suggest that the clinical feature was relatively similar to classical MDA5-DM-ILD, although it is difficult to distinguish MDA5-DM-ILD from chronic GVHD and other pulmonary complications after allo-HCT. Since clinical courses of MDA5-DM-ILD is considerably aggressive, it is important to discriminate MDA5-DM-ILD from other complications after allo-HCT.

BACKGROUND: Pancreatic atrophy after allogeneic hematopoietic cell transplantation (HCT) is one of the symptoms associated with chronic graft-versus-host disease (GVHD). Although pancreatic atrophy has been considered to cause exocrine insufficiency and weight loss, it is not yet clear what kinds of recipients can be expected to recover their body weight (BW) or pancreatic thickness. In addition, the effect of pancreatic atrophy on the prognosis has not been clarified. METHODS: We retrospectively analyzed 170 recipients who received allogeneic bone marrow transplantation or peripheral blood stem cell transplantation, and evaluated them using the CT scan images obtained closest to 1, 2, 3, and 4 years after HCT. RESULTS: Fifty-five recipients (32.4%) demonstrated pancreatic atrophy, and 11 (20%) of them recovered their pancreatic thickness. While recipients without pancreatic atrophy gradually recovered their BW (P < 0.001), those with atrophy did not (P = 0.12). Moderate and severe chronic GVHD tended to be slightly more common in the atrophy group (47.3% vs 38.3%), whereas the pancreatic thickness tended to recover in these recipients (30.8% vs 10.3%). HCT from a female donor to a male recipient showed superior pancreatic recovery compared to other donor and recipient sex combinations. Pancreatic atrophy treated as a significantly associated with inferior survival (HR 4.91, P < 0.001) and an increased risk of non-relapse mortality (HR 8.75, P < 0.001). CONCLUSIONS: These results suggest that it is important to monitor pancreatic thickness after HCT. Further prospective investigations are warranted to clarify the significance of pancreatic atrophy on clinical outcomes.

TEMPI syndrome is a rare disease associated with plasma cell neoplasms. Although previous studies have reported that bortezomib is effective as a 1st-line treatment for TEMPI syndrome, some cases are refractory to this treatment. Pomalidomide, a kind of immunomodulatory drugs, is widely used for the treatment of relapsed or refractory multiple myeloma and could be administered without dose modification in patients with renal dysfunction. We present a case of bortezomib-refractory TEMPI syndrome with renal insufficiency that was successfully treated with a combination of pomalidomide and low-dose dexamethasone with minimal adverse effects, followed by autologous hematopoietic stem cell transplantation. To the best of our knowledge, this is the first case of TEMPI syndrome that was successfully treated with pomalidomide. Pomalidomide may be suitable for patients who do not respond to a proteasome inhibitor-based treatment. In addition, a subsequent ASCT could also be effective for achieving a further treatment response.

Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) and the mechanisms of relapse remain unclear. We encountered a 58-year-old man with chronic myelomonocytic leukemia (CMML) that relapsed after haploidentical HCT from his daughter. Peripheral blood samples collected at HCT and at relapse were analyzed, and CD14+/CD16- monocytes that typically accumulate in CMML were isolated by flow cytometry. Whole-exome sequencing of the monocytes revealed 8 common mutations in CMML at HCT. In addition, a PHF6 nonsense mutation not detected at HCT was detected at relapse. RNA sequencing could not detect changes in expression of HLA or immune-checkpoint molecules, which are important mechanisms of immune evasion. However, gene set enrichment analysis (GSEA) revealed that a TNF-α signaling pathway was downregulated at relapse. Ubiquitination of histone H2B at lysine residue 120 (H2BK120ub) at relapse was significantly decreased at the protein level, indicating that PHF6 loss might downregulate a TNF-α signaling pathway by reduction of H2BK120ub. This case illustrates that PHF6 loss contributes to a competitive advantage for the clone under stress conditions and leads to relapse after HCT.

Chromosome analysis is a powerful prognostic tool in myeloid malignancies. Recipients who experience relapse after allogeneic hematopoietic cell transplantation (allo-HCT) often show chromosomal changes between diagnosis and relapse. However, the clinical impact of chromosomal changes and the efficacy of post-relapse treatment according to chromosomal changes have not been fully investigated. We retrospectively analyzed 72 recipients who had experienced relapse after allo-HCT for acute myeloid leukemia or myelodysplastic syndrome. We categorized them into two groups: with or without clonal chromosomal changes at relapse after allo-HCT. Post-relapse survival was shorter in the clonal chromosomal change group (median 117 days vs 275 days, P = 0.019). Moreover, acquisition of chromosome 7 abnormality or complex changes tended to be associated with inferior survival in a univariate analysis (median 92 days vs median 173 days, P = 0.043), and this adverse impact was confirmed in a multivariate analysis (hazard ratio 2.07, P = 0.024). The patterns of chromosomal changes from diagnosis to relapse after allo-HCT were heterogenous, and further investigations are required to clarify the effect of individual chromosomal changes.

High-dose cytarabine (HD-AraC) or anthracycline-containing chemotherapies are used as post-remission therapy for acute myeloid leukemia (AML) patients. However, it remains unclear which regimen would be better as post-remission therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, we compared the incidence of cardiac events and event-free survival (EFS) after allo-HSCT at two Japanese hospitals between HD-AraC and anthracycline-containing post-remission therapy to clarify the safety of post-remission therapy. Of a total of 132 patients, 68 received HD-AraC (HD-AraC group) and 64 received anthracycline-containing chemotherapy (ANT group). HD-AraC was preferentially selected for core-binding factor AML patients (p = 0.008). The median cumulative anthracycline dose was 115.2 mg/m2 in the HD-AraC group and 318.7 mg/m2 in the ANT group (p < 0.0001). Cardiac events were observed in 18 (13.6%) patients during the follow-up period. The 3-year cumulative incidence of cardiac events was 9.1% in the HD-AraC group and 11.0% in the ANT group (p = 0.70). EFS at 3 years after allo-HSCT was 40.9% in the HD-AraC group and 39.6% in the ANT group (p = 0.51). In conclusion, incidence of cardiac events did not differ significantly between post-remission therapy regimens in AML patients who underwent allo-HSCT.

Idiopathic pneumonia syndrome (IPS) is a fatal pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HCT). However, it is often difficult to diagnose IPS, since a considerable number of IPS patients are critically ill, which makes it difficult for them to undergo bronchoscopy. In this study, we explored the risk factors of IPS based on two definitions. Definite IPS was diagnosed based on the results of bronchoscopy, whereas clinical IPS was diagnosed based on the clinical condition and bronchoscopy was not mandatory. Among 444 allo-HCT recipients at our center, 30 definite IPS and 54 clinical IPS were identified. In a multivariable analysis, a high ferritin level was associated with a higher incidence of definite IPS, whereas clinical IPS was frequently associated with older age, MAC, high ferritin level, low %DLCO and second allo-HCT due to graft failure. These risk factors may contribute to the accurate and early diagnosis of IPS.

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.

The graft-versus-leukemia (GVL) effect is one of the curative mechanisms of allogeneic hematopoietic stem cell transplantation (allo-HCT). H-Y antigens, which are encoded by Y chromosome, are important targets of the GVL effect. Thus, deletion of the Y chromosome (del[Y]) might cause the GVL effect to deteriorate in a transplantation involving a female donor and male recipient, although the clinical significance of the del(Y) group remains to be elucidated. In this study, we evaluated adult male patients who underwent allo-HCT between 2010 and 2019 in Japan. There were 155 cases in the del(Y) group and 4149 cases without del(Y) who underwent female-to-male allo-HCT. Del(Y) was significantly associated with inferior overall survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.00-1.53; P = .049) and an increased risk of relapse (HR, 1.40; 95% CI, 1.08-1.80; P = .0098) in multivariate analyses. There was no significant difference in nonrelapse mortality between recipients with and without del(Y) (HR, 1.08; 95% CI, 0.769-1.51; P = .67). In contrast, del(Y) was not significantly associated with any clinical outcomes in the cohort of male-to-male allo-HCT. A higher incidence of relapse might have been caused by attenuation of the GVL effect resulting from a lack of H-Y antigens. Because a GVL effect resulting from sex mismatch may not be expected in men with del(Y) who undergo allo-HCT with a female donor, additional post-allo-HCT strategies might be required to prevent disease relapse.

There are limited data comparing myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) and reduced-intensity conditioning with fludarabine/busulfan (Flu/Bu2) in patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data and compared the outcomes of adult patients with MDS receiving Flu/Bu4 and Flu/Bu2 by propensity score (PS) matching. Patients who met the following criteria were eligible for enrollment: (1) age ≥16 years; (2) diagnosis of de novo MDS; (3) first allo-HSCT between 2006 and 2018; (4) related bone marrow transplantation (BMT) or peripheral blood stem cell transplantation from an HLA-matched donor, unrelated BMT from an HLA-matched or HLA-1 allele-mismatched donor, or unrelated cord blood transplantation; and (5) receiving Flu/Bu4 or Flu/Bu2 as a conditioning regimen. Flu/Bu4 comprised intravenous busulfan (total dose, 12.8 mg/kg) combined with fludarabine (total dose, 125-180 mg/m2). Flu/Bu2 comprised intravenous busulfan (total dose, 6.4 mg/kg) combined with the same dose of fludarabine. To minimize selection bias and confounding factors, we performed a propensity score (PS)-matched analysis. The primary endpoint was overall survival (OS) after allo-HSCT. A total of 3386 patients with de novo MDS underwent their first allo-HSCT between 2006 and 2018. Among them, 202 patients were assigned each to the Flu/Bu4 and Flu/Bu2 groups after PS-matched analysis. The median age was 61 (interquartile, 57-65) years. The 3-year OS rates were 44.8% (95% confidence interval [CI], 37.1-52.1%) and 46.9% (95% CI, 39.2-54.2%) in the Flu/Bu4 and Flu/Bu2 groups, respectively (P = .67). The 3-year rates of graft-versus-host disease (GVHD)-free survival, relapse-free survival (GRFS) were 28.8% (95% CI, 22.2-35.7%) and 33.0% (95% CI, 26.2-40.0%), respectively (P = .36). The 3-year cumulative incidence rates of relapse were 28.9% (95% CI, 22.6-35.6%) and 30.0% (95% CI, 23.6-36.6%), respectively (P = .47). The 3-year cumulative incidence rates of non-relapse mortality (NRM) were 28.2% (95% CI, 21.7-35.0%) and 27.1% (95% CI, 20.6-33.9%), respectively (P = .60). The 100-day cumulative incidence rate of grade II-IV acute GVHD was significantly higher in the Flu/Bu4 group than in the Flu/Bu2 group (41.7% [95% CI, 34.8%-48.4%] versus 29.3% [95% CI, 23.2%-35.7%], P = 0.012). To identify patients who had more favorable outcomes with 1 of the 2 regimens, we compared the outcomes between the 2 groups after stratifying by age, hematopoietic cell transplantation-comorbidity index, cytogenetic risk, disease status at allo-HSCT, stem cell source, and donor type. OS, GRFS, relapse, and NRM did not differ between the 2 groups in any subgroup analyses. There were no significant interactions between the choice of conditioning regimens and any other factors. There are no differences in survival between Flu/Bu4 and Flu/Bu2, although our study population was highly selected by PS matching. Data from more patients and prospective studies are needed to determine the optimal intensity of conditioning regimens in patients with MDS.

The significance of antibody-identified epitopes stimulating humoral alloimmunity is not well understood in the identification of non-permissive human leukocyte antigen (HLA) mismatching patterns in hematopoietic stem cell transplantation (HSCT). This was a retrospective study in a cohort of 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA eplet mismatches (EMM) were quantified using HLAMatchmaker (HLAMM). The median age of patients was 48 years (range, 16 to 77). The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). In addition to the known high-risk mismatch patterns in the Japanese cohort, HLA-C EMM in the GVH direction was associated with a significantly higher risk for grade III-IV aGVHD, leading to a higher risk of non-relapse mortality and lower overall survival (compared with HLA-C matched patients, HR 1.67, 95% CI 1.44–1.95; HR 1.39, 95% CI 1.25–1.54; HR 1.20, 95% CI 1.10–1.30, respectively). HLAMM-based epitope matching might be useful for identifying patients who are at high risk for serious complications after HSCT from HLA mismatched unrelated donors.

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

BACKGROUND: It has been reported that prolonged neutropenia during post-remission chemotherapy is associated with a reduced risk of disease relapse in pediatric acute myeloid leukemia (AML) patients. METHODS: We retrospectively reviewed the charts of adult AML patients in first complete remission (CR1) who underwent consolidation chemotherapy with high-dose cytarabine. Those receiving allogeneic hematopoietic cell transplantation in CR1 were excluded. We calculated the D-index, which is an area-based neutropenia index. The patients were divided into 2 groups using the median value of the D-index during the first cycle of consolidation chemotherapy (C#1). RESULTS: Fifty-six patients were included. The 2-year cumulative incidence of relapse was 54.8% (95% confidence interval (CI): 37.5-73.8) in patients with a D-index < 5,118 and 62.0% (95%CI: 42.7-81.4) in those with a D-index ≥ 5,118 (P = 0.56). In a multivariate analysis, intermediate / adverse cytogenetic risk (HR 2.76), performance status ≥ 2 (HR 5.55) and 2 cycles of induction chemotherapy required to achieve CR1 (HR 4.29) were identified as significant factors associated with relapse. The D-index at C#1 did not have a significant impact. CONCLUSIONS: In contrast to pediatric patients, the severity of neutropenia is not associated with a risk of disease relapse in adult AML patients.

Cytomegalovirus reactivation is still a critical concern following allogeneic hematopoietic cell transplantation, and cellular immune reconstitution of cytomegalovirus-specific cytotoxic T-cells is necessary for the long-term control of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation. Here we show the features of repertoire diversity and the gene expression profile of HLA-A24 cytomegalovirus-specific cytotoxic T-cells in actual recipients according to the cytomegalovirus reactivation pattern. A skewed preference for BV7 genes and sequential "G" amino acids motif is observed in complementarity-determining region-3 of T cell receptor-β. Increased binding scores are observed in T-cell clones with complementarity-determining region-3 of T cell receptor-β with a "(G)GG" motif. Single-cell RNA-sequence analyses demonstrate the homogenous distribution of the gene expression profile in individual cytomegalovirus-specific cytotoxic T-cells within each recipient. On the other hand, bulk RNA-sequence analyses reveal that gene expression profiles among patients are different according to the cytomegalovirus reactivation pattern, and are associated with cytokine production or cell division. These methods and results can help us to better understand immune reconstitution following hematopoietic cell transplantation, leading to future studies on the clinical application of adoptive T-cell therapies.