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The medium-dose etoposide (VP16) added on cyclophosphamide (CY)/total body irradiation (TBI) is one of the intensified myeloablative conditioning regimens used in allogenic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL). However, the patient subgroups who can actually benefit from VP16/CY/TBI compared to CY/TBI have not been precisely defined. Therefore, we conducted a multi-center retrospective study using the Japanese nationwide registry database to elucidate the efficacy of VP16/CY/TBI on post-transplant prognosis. Biological and clinical distinct subtypes (i.e., Philadelphia chromosome-positive (Ph+) and -negative (Ph-) ALL) were evaluated separately, which included 820 Ph+ and 1463 patients with Ph- ALL, respectively. Compared with the CY/TBI group, the VP16/CY/TBI group showed superior progression-free survival (PFS) in patients with Ph+ ALL (65% vs. 57% at 3 years after HSCT; adjusted hazard ratio (HR), 0.73; 95% confidence interval (CI), 0.55-0.98; p = 0.03), along with significantly reduced incidence of relapse (adjusted HR, 0.58; 95% CI, 0.37-0.90; p = 0.02) without the increase of non-relapse mortality (NRM). By contrast, in patients with Ph- ALL, VP16/CY/TBI did not improve PFS nor incidence of relapse; addition of VP16 reduced relapse (HR, 0.65; p = 0.06) in patients with Ph- ALL transplanted at CR1, while improved PFS was not observed (HR, 0.90; p = 0.52) due to increased NRM. This study demonstrated that VP16/CY/TBI is a more effective and well-tolerated regimen in comparison with CY/TBI in patients with myeloablative allo-HSCT for adult Ph+ ALL. Our findings can provide a novel algorithm for conditioning regimen selection in patients with adult ALL.

Although several studies have reported significant effects of patient age on outcomes of allogeneic hematopoietic cell transplantation (HCT), the prognostic relevance of age must be determined separately for myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). We analyzed Japanese nationwide transplantation registry data of patients aged 20-79 years with acute myeloid leukemia who underwent allogeneic HCT using MAC (n = 7525) or RIC (n = 3154) between 2008 and 2019. Patient were divided into six groups by age, with each group representing a decade, and overall survival (OS), relapse, and non-relapse mortality (NRM) were compared between adjacent age groups. The adverse impact of age on OS increased each decade starting at age 40 among patients receiving MAC, but only differed significantly between patients in their 50s and 60s among those receiving RIC. In patients receiving both MAC and RIC, the detrimental effect of advanced age on OS was accompanied by an increased risk of NRM. These findings show that age affects NRM and OS significantly, but differs depending on conditioning intensity. RIC mitigates the adverse prognostic impact of older age and is thus considered a reasonable option for older patients.

The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease-free survival (DFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host disease for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60 years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8526 patients who received first allogeneic transplantation from 6/6 antigen-matched sibling donor (MSD, n = 2768), 8/8 allele-matched unrelated donor (MUD, n = 2357), and unrelated single-cord blood (UCB, n = 3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12 Gy or busulfan 12.8 mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P 0.001) and relapse rate (HR, 0.70, P 0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR, 1.39, P = 0.008) and MUD (HR, 1.47, P = 0.002) transplants but not UCB transplants (HR, 1.12, P = 0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR, 1.24, P 0.001), whereas it was significantly lower after reduced-intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR, 0.82, P 0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment.

We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising treatment for adult acute lymphoblastic leukemia (ALL), an intractable hematological malignancy. The trends in allo-HCT outcomes over the past 30 years were examined to verify the efficacy of evolving treatment methods and to identify further challenges. We analyzed data from a registry database that included 8467 adult ALL patients who underwent their first allo-HCT between 1990 and 2019. The period was divided into three 10-year intervals for analysis. Five-year overall survival improved from 48.2% to 70.2% in the first complete remission (CR1), from 25.6% to 44.1% in subsequent CR, and from 10.0% to 22.7% in non-CR. Nonrelapse mortality improved over the 3 decades in each disease stage. However, the relapse rate only improved in CR1 every decade (26.3% to 15.9% in CR1, 33.4% to 32.8% in subsequent CR, and 53.6% to 54.8% in non-CR). Although there were continual improvements in adjusted survival for Philadelphia chromosome (Ph)-positive patients, the improvement was inadequate for Ph− patients with t(4;11), t(8;14), t(14;18), or hypodiploidy. Allo-HCT outcomes for adults with ALL have improved over the past 30 years. Improved outcomes in the future will require more effective prevention of relapse in patients with ALL not in CR1 and in those with high-risk chromosomal abnormalities.

Human leukocyte antigen (HLA)-matched sibling donors (MSDs) are the preferred choice for allogeneic hematopoietic cell transplantation (HCT). However, as myelodysplastic syndrome (MDS) is most frequently diagnosed in the elderly, MSDs are also likely to be of advanced age. It is unclear whether an MSD should be considered the primary choice for allogeneic HCT in elderly patients with MDS. We retrospectively compared survival and other outcomes in 1787 patients with MDS over 50 years of age and receiving allogeneic HCT between 2014 and 2020, using either MSD (n = 214), 8/8 allele-matched unrelated donor (MUD) (n = 562), 7/8 allele-MUD (n = 334), or unrelated cord blood (UCB) (n = 677) in Japan. In multivariate analysis, compared to MSD transplants, the risk of relapse was significantly lower following 8/8MUD transplants (hazard ratio [HR], 0.74; P = 0.047), whereas non-relapse mortality was significantly higher following UCB transplants (HR, 1.43; P = 0.041). However, donor type did not determine overall survival, disease-free survival, or graft-versus-host disease (GVHD)-free, relapse-free survival, but chronic GVHD-free, relapse-free survival was better after UCB (HR, 0.80; P = 0.025) and 8/8MUD (HR, 0.81; P = 0.032) compared to MSD transplants. Our study demonstrated that MSDs are not superior to alternative HCT methods, such as 8/8MUD, 7/8MUD, or UCB, in this population.

The introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment has dramatically improved the prognosis of CML patients and reduced the number of patients receiving allogeneic stem cell transplantation (allo-SCT). However, the impact of the newest-generation TKIs on the overall survival (OS) after allo-SCT has not been well described. To investigate the beneficial effects of TKIs on the prognosis after allo-SCT, we conducted a retrospective observational study using the Transplant Registry Unified Management Program database in Japan. We analyzed 1188 patients (male/female: 738/450; median age: 44 years; range: 16-75) who underwent their first allo-SCT between January 2001 and December 2018. We divided the patients into two groups according to the TKI treatment used before allo-SCT: group 1 was treated with the first generation TKI imatinib; group 2 was treated with the second generation TKIs nilotinib, dasatinib, or bosutinib and/or the third generation TKI ponatinib. We compared the post allo-SCT OS between the two groups. The 3-year OS rates (95%CI) of groups 1 and 2 were 59.3% (54.8%-63.5%) and 65.8% (61.6%-69.6%), respectively (p = 0.017). Multivariate analysis confirmed that group 2 had superior OS after allo-SCT compared to group 1 (p = 0.002). Other factors associated with superior prognosis were age ≤65, performance status (PS) 0/1, a 6/6 HLA-matched donor and chronic-phase (CP) disease status at allo-SCT. A subgroup analysis showed poor prognoses for patients who could not obtain a molecular response before allo-SCT and patients with positive T315I mutation in the BCR/ABL gene. In group 2, early allo-SCT was correlated with superior OS in patients with a blast-crisis disease status at allo-SCT (p = 0.001). The cumulative incidence of non-relapse mortality rate significantly decreased in group 2 (p = 0.0005). The post allo-SCT OS was improved both by pre- and post-management of allo-SCT and by the introduction of newer TKIs.

Key Points Dasatinib-based 2-step induction resulted in a 100% CR rate with minimal toxicities and 53% MRD negativity.This protocol treatment increased the number of HSCTs in CR1, thereby improving 3-year EFS., Visual Abstract, The standard treatment for adults with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.

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.

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.

Myeloablative conditioning with fludarabine/busulfan (Flu/Bu4) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is effective for acute myeloid leukemia. However, the effectiveness of Flu/Bu4 for myelodysplastic syndrome (MDS) remains poorly understood. Therefore, we retrospectively analyzed nationwide registry data in Japan from 2006 to 2018 and compared transplant outcomes of adult MDS patients receiving Flu/Bu4 and busulfan/cyclophosphamide (Bu4/Cy) using propensity score (PS) matching. The primary endpoint was overall survival (OS). Among 2,482 MDS patients, 153 patients were assigned each to the Flu/Bu4 and Bu4/Cy groups. The 3-year OS rates were 52.7% (95% confidence interval [CI], 43.8-60.8%) and 49.5% (95% CI, 40.8-57.6%) in the Flu/Bu4 and Bu4/Cy group, respectively (P = 0.548). The 3-year progression-free survival (P = 0.858), the cumulative incidence of relapse (P = 0.536), and cumulative incidence of non-relapse mortality (P = 0.684) were not significantly different between the two groups. According to the findings of subgroup analyses, no patient had a favorable OS when using either of the two regimens. In conclusion, although our PS-matched cohort mainly comprised older patients who had a low hematopoietic cell transplantation-comorbidity index and low-risk disease status, Flu/Bu4 could be an alternative to Bu4/Cy for MDS patients prior to allo-HSCT.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

To evaluate whether outcomes following allogeneic hematopoietic cell transplantation differ according to disease type, a three-way comparison for patients with de novo acute myeloid leukemia (AML) (n = 3318), AML evolving from myelodysplastic syndromes (MDS) (n = 208), and MDS with excess blasts (MDS-EB) (n = 994) was performed. The 5-year probabilities of overall survival (OS) for de novo AML, AML evolving from MDS, and MDS-EB were 60%, 42%, and 41% (p < 0.001), respectively. Multivariate analysis revealed that, compared to de novo AML, AML evolving from MDS was associated with a higher risk of NRM (p = 0.030) and MDS-EB with a higher risk of relapse (p < 0.001), both leading to lower OS (p = 0.010 and p < 0.001, respectively). These findings demonstrate inter-disease differences in post-transplant outcomes and highlight the needs to reduce NRM for AML evolving from MDS and to reduce relapse for MDS-EB.

Background : Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) and/or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pre-transplant RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. Objective : The objective was to examine the significance of pre-transplant RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. Study Design : We retrospectively evaluated the effect of pre-transplant RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Results : Both higher pre-transplant RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pre-transplant RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. Conclusion : In summary, our study clearly demonstrated that a higher pre-transplant RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P

Chromosomal abnormalities in the role of prognostic factor for transplant patients with myelofibrosis (MF) are not fully investigated. Regarding complex karyotype (CK), we retrospectively analyzed 241 patients with primary and secondary MF who received a first allogeneic hematopoietic cell transplantation (HCT). Based on an unfavorable karyotype in the Dynamic International Prognostic Scoring System, we compared the outcomes in 3 groups: favorable karyotype, unfavorable karyotype including CK (unfavorable-CK(+)), and unfavorable karyotype not including CK (unfavorable-CK(-)). Overall survival was significantly shorter in the unfavorable-CK(+) group (hazard ratio (HR) 2.49, 95% CI: 1.46-4.24, P 0.001), whereas there was no difference between the unfavorable-CK(-) group and the favorable group (HR 0.57, 95% CI: 0.20-1.59, P = 0.28). In addition, a significantly higher proportion of patients in the unfavorable-CK(+) group did not achieve complete remission after HCT (P = 0.007). The cumulative incidence of disease progression was significantly higher in the unfavorable-CK(+) group (HR 2.5, 95% CI 1.6-3.92, P 0.001), whereas that in the unfavorable-CK(-) group was comparable to that in the favorable group (HR 0.49, 95% CI 0.12-1.94, P = 0.31). Further investigations will be needed to clarify the impact of CK on transplant outcomes in MF.

A conditioning regimen is an essential prerequisite of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome (MDS). However, the optimal conditioning intensity for a patient may be difficult to establish. This study aimed to identify optimal conditioning intensity (reduced-intensity conditioning regimen [RIC] or myeloablative conditioning regimen [MAC]) for patients with MDS. Overall, 2567 patients with MDS who received their first HCT between 2009 and 2019 were retrospectively analyzed. They were divided into a training cohort and a validation cohort. Using a machine learning-based model, we developed a benefit score for RIC in the training cohort. The validation cohort was divided into a high-score and a low-score group, based on the median benefit score. The endpoint was progression-free survival (PFS). The benefit score for RIC was developed from nine baseline variables in the training cohort. In the validation cohort, the hazard ratios of the PFS in the RIC group compared to the MAC group were 0.65 (95% confidence interval [CI]: 0.48-0.90, P = 0.009) in the high-score group and 1.36 (95% CI: 1.06-1.75, P = 0.017) in the low-score group (P for interaction 0.001). Machine-learning-based scoring can be useful for the identification of optimal conditioning regimens for patients with MDS.

Impact of donor age considering HLA disparity on hematopoietic cell transplantation (HCT) outcomes has not been fully evaluated. We evaluated 8486 patients who received unrelated bone marrow transplantation (UR-BMT) from 8/8 or 7/8 HLA-matched donors. Compared to 8/8 HLA-matched younger donors (

This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III-IV) aGVHD was associated with a higher risk of BSI (vs. grade 0-I aGVHD: hazard ratio [HR] 3.34 [95% confidence interval (CI), 2.85-3.92; P < 0.001]). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0-I aGVHD: HR 2.61 [95% CI 2.18-3.11; P < 0.001]). In addition, BSI (vs. no-BSI: HR 1.20 [95% CI, 1.12-1.29; P < 0.001]) and severe aGVHD (vs. grade 0-I aGVHD: HR 1.97 [95% CI, 1.83-2.12; P < 0.001]) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality.

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.

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

The impact of calcineurin inhibitor types and anti-thymocyte globulin (ATG) in conditioning on overall survival (OS) and GVHD-free, relapse-free survival (GRFS) has not yet been analyzed in detail for aplastic anemia. We herein examined 517 adult patients with aplastic anemia who underwent BMT from HLA-matched sibling donors (MSD, n = 255) and unrelated donors (UD, n = 262) and were treated with cyclosporine A (CSA) + methotrexate (MTX) (n = 258) and tacrolimus (TAC) + MTX (n = 259). In total, 330 patients received ATG in conditioning. CSA + MTX versus TAC + MTX did not have a significant impact on acute and chronic GVHD, OS, or GRFS in each donor type. The use of ATG in conditioning reduced the risk of grade II–IV acute GVHD in the MSD and UD cohorts (HR 0.42, P = 0.014, and HR 0.3, P

This study aimed to analyze the factors associated with outcomes of bone marrow transplantation (UR-BMT) or cord blood stem cell transplantation from unrelated donors (UR-CBT). We assessed the time from diagnosis to transplantation among acute myeloid leukemia (AML) patients with intermediate- or poor-risk cytogenetics to identify the potential clinical efficacy of transplantation. We retrospectively analyzed 5331 patients who received UR-BMT or UR-CBT between 2008 and 2017. Patients were divided into four groups according to time from diagnosis to transplantation: (1) UR-BMT and 5 months (n = 2353), (2) UR-BMT and ≤ 5 months (n = 379), (3) UR-CBT and 5 months (n = 1494), and (4) UR-CBT and ≤ 5 months (n = 1106). There was no difference in overall survival (OS) for transplantation at ≤5 months and 5 months in patients with first complete remission for both UR-BMT and UR-CBT, but OS in patients with primary induction failure (PIF) and transplantation at ≤ 5 months was significantly higher in the UR-CBT group compared with that at5 months (P 0.001). Multivariate Cox regression analysis also showed that transplantation at5 months in patients with PIF was an independent predictor of poorer OS. Therefore, UR-CBT at ≤ 5 months after diagnosis is an alternative option for AML patients with PIF.

Philadelphia chromosome-positive acute myeloid leukemia (Ph+ AML) confers a dismal prognosis when treated with chemotherapy alone. Data on allogeneic hematopoietic cell transplantation (allo-HCT) outcomes are limited. We retrospectively analyzed 4649 AML patients who received allo-HCT and were in complete remission. Outcomes of Ph+ AML (n = 30), intermediate-risk, and poor-risk AML patients were compared. The 3-year overall survival after allo-HCT was similar in intermediate-risk (62.7%; 95% CI: 61.0-64.3%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.42); however, it differed significantly between the poor-risk (49.7%; 95% CI: 45.9-53.4%) and Ph+ AML (73.3%; 95% CI: 51.5-86.4%) groups (P = 0.049). Disease-free survival in Ph+ AML patients was comparable to that in intermediate-risk patients but better than that in poor-risk patients. Relapse rates were significantly lower in Ph+ AML patients than in other groups. Non-relapse mortality (NRM) rates were similar among groups. Multivariate analysis showed that Ph+ AML was not a significant predictor of poor prognosis in terms of overall survival, disease-free survival, relapse, and NRM. Our data showed better post-transplant outcomes for Ph+ AML patients than for those with poor-risk AML. Hence, allo-HCT could be a feasible treatment option for Ph+ AML patients.

The long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) with reduced-intensity conditioning (RIC) remain inconclusive. To address this issue, we conducted a nationwide registry-based study of patients with acute myeloid leukemia (AML) age 50 years or older who underwent allogeneic HCT in complete remission using RIC (n = 284) or myeloablative conditioning (MAC, n = 190) between 2002 and 2007. The median follow-up period for surviving patients was 10.1 years for RIC recipients and 10.4 years for MAC recipients. The 10-year probabilities of overall survival, relapse, and non-relapse mortality were 36.4%, 30.0%, and 35.7% for RIC recipients, and 39.8%, 26.3%, and 35.5% for MAC recipients, respectively. Multivariate analysis revealed that the conditioning intensity did not affect overall mortality (P = 0.184), relapse (P = 0.904), or non-relapse mortality (P = 0.387). For the 218 patients qualifying for propensity score-matched pairing (109 pairs), RIC was found to be associated with similar survival (P = 0.095) and relapse (P = 0.467), and significantly lower non-relapse mortality (P = 0.046) compared with MAC. Our results confirm the long-term efficacy of RIC allogeneic HCT for older patients with AML and mitigate concerns over an increase in late relapse.

A prospectively registered observational study was conducted to assess the significance of allogeneic hematopoietic stem cell transplantation from highly HLA-matched unrelated donors (UD) and cord blood (CB) on outcomes in adult acute leukemia (AL) and myelodysplastic syndrome (MDS). Between 2007 and 2015, 231 transplant-eligible patients were registered for a phase 2 study of alternative donor transplantation. After registration, a sufficient time period was given to find appropriate UD. Patients received CB transplantation (CBT) if an appropriate UD was unavailable. In total, 119 patients received CBT (106 AL and 13 MDS) and 91 patients received UD transplantation (UDT) (86 AL and 5 MDS). The median age was 39 years in both groups. The primary objective was overall survival (OS); secondary objectives included cumulative incidences of non-relapse mortality (NRM) and relapse, and disease-free survival. Diagnosis, disease status at transplantation, refined disease risk index, and hematopoietic cell transplant-specific comorbidity index did not differ between UDT and CBT. In multivariate analyses, graft source was not a significant risk factor for all objectives. In adjusted analyses, UDT and CBT showed similar OS, NRM, and relapse in this prospective study. CB can be a comparable alternative stem cell source to UD by achieving a timely transplant.

Mixed chimerism (MC) and/or secondary graft failure (SGF) with recipient- or donor-type chimerism is a major obstacle in allogeneic transplantation for aplastic anemia (AA). From a registry database in Japan, patients with AA age >15 years who underwent a first allogeneic bone marrow or peripheral blood stem cell transplantation between 2000 and 2014 and achieved engraftment were included in this study. MC that did not require either granulocyte-colony stimulating factor (G-CSF) or transfusion support (group 1), MC (not SGF) that required G-CSF and/or transfusion support (group 2), SGF with MC or complete recipient-type chimerism (group 3), and SGF with complete donor-type chimerism (group 4) developed in 26, 16, 19, and 17 patients, respectively. The overall median duration of follow-up for survivors was 1727 days. The overall survival (OS) was 90.4% at 1 year and 83.5% at 5 years in patients without MC or SGF (n = 340), which was not different from the OS in groups 1 and 2. However, inferior OS was observed in group 3 (1 year, 52.1%; 5 years, 52.1%) and group 4 (1 year, 82.4%; 5 years, 56.3%). In multivariate analyses, the use of fludarabine (Flu) and the absence of irradiation in conditioning were associated with the development of SGF with MC or complete recipient-type chimerism, and the use of Flu in conditioning was associated with SGF with complete donor-type chimerism. In conclusion, the use of Flu may affect the occurrence of SGF with both recipient-type and donor-type chimerism.

There are few reports on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia (B-ALL) harboring t(1;19)(q23;p13.3). We used nationwide registry data of Japan for 2003–2016 to evaluate transplant outcomes and clarified prognostic factors among adult allo-HSCT recipients with B-ALL harboring t(1;19)(q23;p13.3) (n = 125). Compared with cytogenetically normal (CN) B-ALL patients (n = 1057), their 3-year overall survival (OS) rates were comparable (55.4% for t(1;19) and 54.4% for CN; P = 0.76). Considering only patients in first complete hematological remission (CR1), the 3-year OS rates remained comparable (70.5% for t(1;19) and 67.8% for CN; P = 0.86). For t(1;19) patients in CR1, minimal residual disease (MRD) at transplantation was associated with relatively worse outcomes. The 3-year OS rates were 43.6% for patients with MRD and 77.4% for those without it (P = 0.016). The 3-year relapse rates were 54.5% for patients with MRD and 12.8% for those without it (P

This study aimed to investigate time-varying effects of graft type on outcomes for patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant. For this purpose we analyzed 3952 patients, 720 of whom underwent matched related bone marrow transplantation (BMT), 1004 matched related peripheral blood stem cell transplantation (PBSCT), 856 matched unrelated BMT, and 1372 umbilical cord blood transplantation (UCBT) during complete remission. The 4-year relapse-free survival (RFS) rates were 59.1%, 52.8%, 59.5%, and 50.6%, respectively. Compared with related BMT, related PBSCT, unrelated BMT, and UCBT were associated with higher risk of nonrelapse mortality and unrelated BMT and UCBT with lower risk of relapse. As a result, both RFS and overall survival were comparable between related BMT and unrelated BMT but were worse for related PBSCT and UCBT than for related BMT. Adverse impact of UCBT was observed only during the early phase of transplant, whereas that of related PBSCT continued even after 2 years post-transplant. Our findings raise concerns about the increased risk of late nonrelapse mortality with the use of PBSC grafts and suggest that related BMT is preferable to related PBSCT; matched unrelated BMT is the next choice in the absence of a matched related donor.

Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P.001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.

Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) is an enzyme that converts cholesterol to cholesteryl esters. A recent in vivo study reported that inhibiting ACAT1 enzyme activity upregulates the membrane cholesterol levels of T cells, enhancing their cytotoxic function. In the present study, we investigated whether the presence of the ACAT1 single nucleotide polymorphism rs11545566 in transplant donors affected the risk of graft-versus-host disease (GVHD) in 116 adult patients who underwent bone marrow transplantation from human leukocyte antigen-identical sibling donors, and who received GVHD prophylaxis with short-term methotrexate and cyclosporine. The frequencies of the AA, AG, and GG genotypes in the donors were 31%, 45%, and 24%, respectively. The cumulative incidences of grade II–IV acute GVHD on day 100 in patients whose donors had AA vs. non-AA genotypes were 6% and 18%, respectively, and those of extensive chronic GVHD at 2 years were 7% and 32%, respectively. Multivariate analyses demonstrated that donor rs11545566 non-AA genotypes showed a trend toward a higher incidence of grade II–IV acute GVHD (P = 0.079), and were significantly associated with a higher incidence of extensive chronic GVHD (P = 0.021). These results suggest that donor ACAT1 rs11545566 genotype may be predictive of GVHD., ファイル公開：2021/01/01

Therapy-related myelodysplastic syndromes (t-MDS) are generally progressive and associated with poorer outcomes than de novo MDS (d-MDS). To evaluate the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for t-MDS, we conducted a propensity score matched-pair analysis of patients with t-MDS and d-MDS using a nationwide database. A total of 178 patients with t-MDS underwent allo-HSCT between 2001 and 2018, and 178 out of 3123 patients with d-MDS were selected. The probability of 3-year overall survival rate was 40.0% and 50.0% in the t-MDS and d-MDS groups, respectively (p = 0.032). The 3-year transplant-related mortality was 30.9% and 19.0% in the t-MDS and d-MDS groups, respectively (p = 0.005). The 3-year cumulative incidence of relapse was 32.8% and 33.0% in the t-MDS and d-MDS groups, respectively (p = 0.983). A multivariate analysis identified four adverse factors for overall survival in the t-MDS group: age ≥ 55 years (hazard ratio [HR], 2.09; 95% CI, 1.11-3.94; p = 0.023), the poor cytogenetic risk group (HR, 2.19; 95% CI, 1.40-4.19; p = 0.019), performance status at allo-HSCT 2-4 (HR, 2.14; 95% CI, 1.19-3.86; p = 0.011), and a shorter interval from diagnosis to transplantation (8 months; HR, 1.61; 95% CI, 1.00-2.57; p = 0.048). The most frequent cause of transplant-related death was the infectious complications (21.6%) in t-MDS group and organ failure (12.5%) in d-MDS group. In conclusion, allo-HSCT potentially provides long-term remission in patients with t-MDS; however, further efforts to reduce transplant-related death are needed.

The impact of the killer immunoglobulin-like receptor (KIR)-ligand mismatch between donor and recipient in hematopoietic stem cell transplantation is controversial. Recently, it has been suggested that their effect on cord blood transplantation (CBT) differs among types of mismatched KIR-ligand and graft-versus-host disease (GVHD) prophylaxis. To investigate their role in acute myeloid leukemia (AML), mismatch of KIR2DL1, KIR3DL1, and KIR3DL2-ligand (HLA-C2, Bw4, and A3/11) were retrospectively assessed in patients undergoing CBT with GVHD prophylaxis comprising a calcineurin inhibitor plus methotrexate (CNI/MTX) or mycophenolate mofetil (CNI/MMF). In patients who received CNI/MTX, a favorable effect of KIR-ligand mismatch on relapse was noted in HLA-C2 mismatched cases (24.8% at 3 years post-CBT [no HLA-C2 mismatch, n = 1602] vs. 15.4% [HLA-C2 mismatch, n = 161], P = 0.0116). In this group, overall survival (OS) was also superior (68.2%, P = 0.0083) compared to the other group (55.0%). Multivariate analysis results supported these findings (hazard ratio [HR] 0.61 for relapse, P = 0.017 and HR 0.72 for OS, P = 0.016). However, the KIR-ligand mismatch effect was not observed in patients with KIR-ligand mismatch types other than HLA-C2 and those using CNI/MMF for GVHD prophylaxis. These results suggest that HLA-C2 mismatch in CBT using CNI/MTX as GVHD prophylaxis may improve the outcomes of patients with AML.

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n = 382) was significantly lower than that in first complete remission (n = 1375) (51.8% versus 68.1%; P.001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P.001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P.001) and relapse (HR = 1.88; P.001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR = 2.10, P.001) and nonrelapse mortality (HR = 2.68; P.001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P.001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Some studies support the hypothesis that HLA genes and haplotypes evolved by natural selection through their protective abilities against specific infectious pathogens. However, very little is known regarding the impact of high-frequency HLA haplotypes on the risk of relevant infectious diseases among a given ethnic group. We evaluated the impact of high-frequency HLA haplotypes on cytomegalovirus (CMV) reactivation and infection in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a Japanese population as a model of infectious disease that has coexisted with humans. A total of 21,127 donor-patient pairs were analyzed. HLA-A-B-DRB1 haplotypes were estimated using the maximum probability algorithm. Seven haplotypes with1% frequency were defined as high-frequency haplotypes (HfHPs). Homozygotes of HfHP and heterozygotes had significantly lower risk of CMV reactivation and infection (hazard ratio [HR] = 0.88, P = .009 and HR = 0.93, P = .003, respectively) than homozygotes of low-frequency HLA haplotypes (LfHPs). In subgroup analyses of a different donor source, these associations were statistically significant in unrelated donor transplants. Finally, CMV risk for homozygotes and heterozygotes of each HfHP was compared with that of homozygotes of LfHPs. The 2 most predominant HfHP groups (A*24:02-B*52:01-DRB1*15:02 group and A*24:02-B*07:02-DRB1*01:01 group) had a significantly lower risk of CMV reactivation and infection (HR = 0.86, P.001 and HR = 0.91, P = .033, respectively). Our findings suggest that HfHPs may be protective against CMV reactivation and infection and that increased care regarding CMV reactivation and infection may be necessary for patients with LfHP after allo-HSCT.

The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2-33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases.

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.

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.

Cord blood transplantation (CBT) is a curative therapeutic option for patients with acute myeloid leukemia (AML) who do not have an HLA-matched donor. The decline in early nonrelapse mortality (NRM) after CBT has significantly improved overall survival (OS) during the past 20 years because of advances in CBT practices, including more careful patient selection, use of safer conditioning regimens, better cord blood unit selection, and improved supportive care. A previous study reported a conditioning regimen comprising fludarabine, busulfan, and melphalan (Flu/Bu4/Mel) developed for patients undergoing CBT in non-complete remission (CR) myeloid malignancies that showed durable engraftment and remission with acceptable nonrelapse mortality (NRM), leading to excellent survival outcomes. However, no prior study has focused on the role of Flu/Bu4/Mel in CBT conditioning and compared it with conventional myeloablative conditioning (MAC) for AML patients in CR. We aimed to investigate the efficacy and safety of Flu/Bu4/Mel compared with cyclophosphamide and total body irradiation (CY/TBI)-based MAC for AML patients in CR who underwent CBT. Patients were selected from the Japanese nationwide transplantation registry according to the following inclusion criteria: (1) patients with AML aged ≥16 years, (2) first single-unit CBT, and (3) CR at the time of transplantation. Of 477 eligible patients, 148 (31.0%) received CY/TBI, 223 (46.8%) received high-dose cytarabine (HDCA)/CY/TBI, and 106 (22.2%) received Flu/Bu4/Mel. The probability of OS at 3 years was 64.8% (95% confidence interval [CI], 56.0% to 72.3%) in the CY/TBI group, 65.1% (95% CI, 57.8% to 71.4%) in the HDCA/CY/TBI group, and 65.5% (95% CI, 53.7% to 74.9%) in the Flu/Bu4/Mel group (P = .71); the cumulative incidence of relapse at 3 years was 22.0% (95% CI, 15.2% to 29.5%), 17.2% (95% CI, 12.2% to 22.9%), and 18.0% (95% CI, 11.2% to 26.2%), respectively (P = .40); and the cumulative incidence of NRM at 3 years was 17.2% (95% CI, 11.5% to 24.0%), 20.7% (95% CI, 15.4% to 26.7%), and 18.6% (95% CI, 11.4% to 27.2%), respectively (P = .95). Multivariate analysis identified Flu/Bu4/Mel as a favorable factor for OS; however, it was not significantly favorable for relapse and NRM in the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups (hazard ratio [HR], .50 [95% CI, .29-.88], P = .015; .67 [95% CI, .31-1.46], P = .31; and .55 [95% CI, .26-1.18], respectively; P = .12). Flu/Bu4/Mel was a favorable factor for neutrophil engraftment (HR, 1.51; 95% CI, 1.08 to 2.12; P = .016). Multivariate analysis showed that Flu/Bu4/Mel had a favorable prognostic impact on OS and neutrophil engraftment despite the non-TBI regimen. Our findings suggest that Flu/Bu4/Mel may sustain the antileukemia effect with decreasing NRM and could be a favorable CBT conditioning regimen for patients with AML in CR.

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.

The optimal treatment for Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) has not been established in the high-intensity chemotherapy era. The outcomes of patients with Ph-negative ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen-matched related or unrelated donor in CR1 (HSCT-MRD group and HSCT-MUD group) were obtained from a Japanese registry database. Patients aged 16–24 years and 25–65 years were analyzed separately, and their outcomes were compared to those of patients who continued high-intensity chemotherapy in CR1 in studies (202U group and 202O group) by the Japan Adult Leukemia Study Group (JALSG). In the HSCT-MRD group, patients younger than 25 years had lower overall survival (OS) than the 202U group, presumably due to the higher non-relapse mortality (NRM) in the HSCT-MRD group. Patients 25 years and older had similar OS to the 202O group. The lower relapse rate was counterbalanced by higher NRM in the HSCT-MRD group. In the HSCT-MUD group, patients in both age groups had similar OS to their corresponding groups in the JALSG studies. In conclusion, high-intensity chemotherapy may change the role of HSCT for Ph-negative ALL.

Acute graft-versus-host disease (aGVHD) is 1 of the critical complications that often occurs following allogeneic hematopoietic stem cell transplantation (HSCT). Thus far, various types of prediction scores have been created using statistical calculations. The primary objective of this study was to establish and validate the machine learning–dependent index for predicting aGVHD. This was a retrospective cohort study that involved analyzing databases of adult HSCT patients in Japan. The alternating decision tree (ADTree) machine learning algorithm was applied to develop models using the training cohort (70%). The ADTree algorithm was confirmed using the hazard model on data from the validation cohort (30%). Data from 26 695 HSCT patients transplanted from allogeneic donors between 1992 and 2016 were included in this study. The cumulative incidence of aGVHD was 42.8%. Of >40 variables considered, 15 were adapted into a model for aGVHD prediction. The model was tested in the validation cohort, and the incidence of aGVHD was clearly stratified according to the categorized ADTree scores; the cumulative incidence of aGVHD was 29.0% for low risk and 58.7% for high risk (hazard ratio, 2.57). Predicting scores for aGVHD also demonstrated the link between the risk of development aGVHD and overall survival after HSCT. The machine learning algorithms produced clinically reasonable and robust risk stratification scores. The relatively high reproducibility and low impacts from the interactions among the variables indicate that the ADTree algorithm, along with the other data-mining approaches, may provide tools for establishing risk score.

Although the prognosis of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is worse than that of AML not otherwise specified (AML-NOS), transplantation outcomes and prognosticators of AML-MRC patients undergoing allogeneic stem cell transplantation (allo-SCT) remain unclear. Transplantation outcomes of AML-MRC (n = 4091) were compared with those of AML-NOS (n = 3964) in patients who underwent allo-SCT between 2003 and 2016 using a nationwide registration database. The 3-year overall survival (OS; 35.5% versus 50.6%) was lower and the relapse (42.3% versus 32.1%) and nonrelapse mortality (26.3% versus 22.0%) rates were higher in the AML-MRC group than in the AML-NOS group. Based on the hierarchical AML-MRC classification, myelodysplasia as the sole criterion was associated with better OS compared with AML-NOS, whereas monosomal or complex karyotype and -5/del(5q) were associated with poor OS. A history of myelodysplastic syndrome and -7/del(7q) did not affect OS. Accordingly, AML-MRC with complex karyotype or -5/del(5q) and that with monosomal karyotype were classified as intermediate and high risks, respectively, whereas the remaining cases were classified as low risk. The 3-year OS rates were 50.7%, 36.9%, and 13.8% in the low-, intermediate-, and high-risk groups, respectively (P.001). Risk classification, older age, and low performance status score were significant risk factors for survival in AML-MRC, independently of the disease status. Grades I to II acute graft-versus-host disease significantly reduced the 3-year relapse (24.7% versus 31.6%), leading to better survival (hazard ratio, .64). Our prognostic risk stratification can potentially aid in elucidating the diverse transplantation outcomes in patients with AML-MRC.