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The fludarabine/intravenous busulfan 12.8 mg/kg (FB4) regimen is an effective conditioning regimen in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome (MDS); however, limited data is available on the prognostic impact of FB4 with low-dose anti-thymoglobulin (ATG ≤ 5 mg/kg) or low-dose total body irradiation (TBI ≤ 4 Gy). Therefore, we retrospectively evaluated the outcomes in 280 adults with de novo MDS who underwent their first transplantation from an unrelated donor between 2009 and 2018. Median age was 61 years (range, 16 to 70 years). In the FB4 alone (FB4), FB4 plus ATG (FB4-ATG), and FB4 plus TBI (FB4-TBI) groups, 3-years overall survival (OS) rates were 39.9%, 64.8%, and 43.7%; 3-years nonrelapse mortality (NRM) were 32.1%, 22.1%, and 27.1%; and 3-years relapse incidences were 34.7%, 21.2%, and 28.9%, respectively. The multivariate analyses showed that FB4-ATG group significantly correlated with better OS (hazard Ratio [HR], 0.51; 95% confidence interval [CI], 0.27 to 0.95; P = .032) than FB4 group. FB4-ATG group tended to correlate with lower NRM (HR, 0.36; 95% CI, 0.13 to 1.06; P = .063) than FB4 group. In comparison with FB4-TBI group, FB4-ATG group showed better OS (HR 0.52, 95% CI 0.27 to 0.99, P = .049) and NRM (HR 0.034, 95% CI 0.11 to 0.92, P = .034). No significant differences were observed in OS and NRM between the FB4-TBI and FB4 groups. The present study demonstrated that the FB4 plus low-dose ATG regimen improved OS and NRM, but FB4 plus low-dose TBI regimen had no clear benefit over FB4 alone, in MDS patients who used unrelated donors., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Cytomegalovirus (CMV) reactivation is a prominent complication associated with adverse outcomes in allogeneic hematopoietic stem cell transplantation (HSCT). However, CMV reactivation after allogeneic HSCT may be associated with a lower incidence of relapse in some hematological malignancies. This study analyzed the Japanese registry data from 1082 patients with myelodysplastic syndrome (MDS) who underwent their first allogeneic HSCT and survived for 100 days after transplantation without graft failure or disease relapse to investigate this association. Patients who received cord blood transplants, demonstrated in vivo T cell depletion, underwent prophylactic anti-CMV treatment, or diagnosed with secondary MDS were excluded. CMV reactivation measured by pp65 antigenemia within 100 days after allogeneic HSCT was observed in 57.5% of patients, with a median time of 46 days from transplant. The 5-yr overall survival and cumulative incidence of relapse (CIR) in the cohort were 60.5% and 15.6%, respectively. The 5-yr CIR showed no significant difference between patients with and without CMV reactivation (14.4% versus 17.2%; P = .185). Interestingly, CMV reactivation within 100 days was significantly associated with a lower 5-yr CIR (7.6% versus 16.4%; P = .002) in patients with <5% myeloblasts in the bone marrow (BM) just before HSCT. Furthermore, this relevancy confirmed even when excluding patients with Grade II to IV acute GVHD (Hazard ratio: 0.38; 95% confidential intervals: 0.18-0.801; P = .011). Our findings indicate a correlation between early CMV reactivation and MDS relapse, based on the proportion of myeloblasts in the BM. These results may contribute to the development of effective CMV prophylaxis post-HSCT., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder characterized by systemic hyperinflammation. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative treatment for primary and relapsed/refractory HLH, the optimal strategy has not been established. We retrospectively analyzed 56 adult patients (≥18 years) with primary and secondary HLH (mainly consisting of Epstein-Barr virus-associated HLH) who underwent allo-HSCT using the registry database of the Japanese Society for Transplantation and Cellular Therapy, including 26 patients who underwent cord blood transplantation (CBT). One-fourth of patients received myeloablative conditioning (MAC), mainly consisting of total body irradiation-based regimens. The 3-year overall survival (OS) was 40.6%, while the 3-year cumulative incidences of relapse and non-relapse mortality (NRM) were 19.8% and 39.6%, respectively. In univariable analysis, age at allo-HSCT (the 3-year OS: 27.5% for ≥ 25 years old vs 58.0% for < 25 years old, P = .025), conditioning intensity (7.1% for MAC vs 51.8% for reduced-intensity conditioning (RIC), P = .002), and donor source (26.0% for CBT vs 52.9% for bone marrow or peripheral blood stem cell transplantation (BMT/PBSCT), P = .030) were associated with significantly inferior OS. In multivariable analysis, older age at allo-HSCT (≥ 25 years old) (Hazard ratio [HR], 2.37; 95% CI, 1.01 to 5.58; P = .048), MAC (HR, 2.45; 95% CI, 1.09 to 5.53; P = .031), and CBT (HR, 2.21; 95% CI, 1.04 to 4.71; P = .040) were independently associated with worse OS. In addition, only conditioning intensity predicted higher NRM (the 3-year NRM: 78.6% for MAC vs 26.6% for RIC), while no factors were associated with the relapse rate. This study includes the largest number of adult HLH patients undergoing CBT. Although the use of CBT is acceptable, BMT/PBSCT are more favorable strategies in allo-HSCT in adult HLH. Regarding conditioning intensity, RIC regimens are more beneficial in this setting., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Umbilical cord blood (UCB) is a valuable alternative donor source for allogeneic hematopoietic stem cell transplantation. Various conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens aimed at improving the outcomes of umbilical cord blood transplantation (UCBT) have been explored; however, the differences in their effects remain unclear. This study was conducted to elucidate the differences in the effects of conditioning and GVHD prophylaxis regimens on UCBT outcomes by disease type in a nationwide, retrospective study. We retrospectively analyzed the effects of conditioning and GVHD prophylaxis regimens on the outcomes of UCBT performed with cyclophosphamide (Cy)/total body irradiation (TBI)-based regimens in patients with acute myeloid leukemia (AML; n = 1126), acute lymphoblastic leukemia (ALL; n = 620), myelodysplastic syndrome (MDS; n = 170), and lymphoma (n = 128). Multivariate analysis for overall survival (OS) demonstrated the benefit of adding high-dose cytarabine to the Cy/TBI regimen for the AML group (relative risk [RR], .76; P = .003) and lymphoma group (RR, .54; P = .02), but not for the ALL and MDS groups. In the ALL group, adding etoposide to the Cy/TBI regimen was associated with a lower OS (RR, 1.45; P = .03). For GVHD prophylaxis, a tacrolimus/methotrexate regimen was associated with a lower OS compared with a cyclosporine/methotrexate regimen in the AML group (RR, 1.26; P = .01); this difference was not observed in the other groups. These differences in OS according to the conditioning and GVHD prophylaxis regimen were attributable mainly to differences in relapse risk. Our data show that the effects of conditioning regimens and GVHD prophylaxis on UCBT outcomes differed according to disease type. UCBT outcomes could be improved by selecting optimal conditioning regimens and GVHD prophylaxis for each disease type., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. This study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Our retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. The very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30 to 1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73 to 0.94), 0.69 (95% CI: 0.61 to 0.79), and 0.68 (95% CI: 0.60 to 0.76), respectively, compared with the very low-volume group. In conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic (allo-) hematopoietic cell transplantation (HCT) has evolved as a curative therapy for hematologic malignancies and diseases, with practice changes over the past 2 decades. This study aimed to evaluate the change in 5-year net survival (NS) of allo-HCT recipients in a population-based cohort over the past 2 decades, which allows the estimation of a more HCT-specific long-term survival rate by considering background mortality changes. This study included 42,064 patients with hematologic malignancies who underwent their first allo-HCT in Japan between 2000 and 2018 and were reported to the Transplant Registry Unified Management Program. We compared the 5-year NS after allo-HCT in 4 consecutive HCT periods (2000 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2018). The 5-year NS of the latest period was estimated using the period analysis method. Adjusted excess hazard ratios (EHRs) for 5-year NS over the HCT period were analyzed using an EHR model. In addition to the analysis of all hematologic malignancies, adjusted 5-year NS for each major hematologic malignancy, including acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, adult T cell leukemia/lymphoma, chronic myeloid leukemia (CML), and malignant lymphoma, was analyzed. The probability of adjusted 5-year NS after HCT improved significantly over time: 35% in 2000 to 2004, 39% in 2005 to 2008, 45% in 2009 to 2012, and 49% in 2013 to 2018. The adjusted EHRs were .90 (95% confidence interval [CI], .86 to .93) in the 2005 to 2008 period, .77 (95% CI, .74 to .80) in the 2009 to 2012 period, and .65 (95% CI, .63 to .68) in the 2013 to 2018 period, with the 2000 to 2004 period as the reference. The 5-year NS improved among all hematologic malignancies, with a significant improvement in CML and ALL. The changes in 5-year NS from the 2000 to 2004 period to the 2013 to 2018 period ranged from 46% to 66% in CML and from 41% to 59% in ALL. In addition to the large improvement of 1-year NS, smaller but continued improvement in NS between 1 and 5 years after transplantation was observed. NS at 5 years conditional on being alive at 1 year increased from 64% in 2000 to 2004 to 73% in 2013 to 2018. Even after subtracting the background mortality in the general population, we found a significant improvement in long-term allo-HCT-specific survival rates for patients with hematologic malignancies over the past 2 decades in Japan., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aplastic anemia patients who are refractory to immunosuppressive therapy or with very low neutrophil counts require allogeneic hematopoietic stem cell transplantation (HSCT). Umbilical cord blood transplantation (UCBT) has been a treatment option when an HLA-matched donor is not available, and HSCT from a related haploidentical donor using post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis (PTCy-haplo) recently became another important approach. We aimed to compare the outcomes of PTCy-haplo and UCBT in adult patients with aplastic anemia to identify more effective and safer approaches for alternative donor transplantation. Data in a nationwide registry were analyzed retrospectively to assess the outcomes of aplastic anemia patients age ≥16 years who underwent PTCy-haplo or UCBT as their first HSCT between 2016 and 2020. The primary endpoint was 1-year overall survival (OS) after HSCT. Secondary endpoints included 1-year failure-free survival (FFS), neutrophil and platelet engraftment, and acute and chronic GVHD. Eighty-three patients who underwent PTCy-haplo (n = 24) or UCBT (n = 59) were eligible. The 1-year OS rate was 78.5% (95% confidence interval [CI], 55.7% to 90.5%) in the PTCy-haplo group and 77.5% (95% CI, 64.5% to 86.3%; P = .895) in the UCBT group. The 1-year FFS rate was 78.7% (95% CI, 56.1% to 90.6%) in the PTCy-haplo group and 62.2% (95% CI, 48.5% to 73.3%; P = .212) in the UCBT group. Among patients age <40 years, the PTCy-haplo group had a significantly higher FFS rate (92.9% [95% CI, 59.1% to 99.0%]) vs 63.9% [95% CI, 43.2% to 78.7%]; P = .047). Neutrophil engraftment and platelet engraftment rates were significantly higher in the PTCy-haplo group compared with the UCBT group: 95.8% (95% CI, 73.9% to 99.4%) vs 78.0% (95% CI, 65.1% to 86.6%, P < .001) and 83.3% (95% CI, 61.5% to 93.4%) vs 72.9% (95% CI, 59.6% to 82.4%; P = .025). No significant difference was observed in the cumulative incidence of grade II-IV acute GVHD and chronic GVHD between the 2 groups. Aplastic anemia patients achieved significantly higher neutrophil and platelet engraftment rates with PTCy-haplo than with UCBT. OS and the incidences of acute and chronic GVHD were similar between the 2 groups. In patients age <40 years, the FFS rate was higher in the PTCy-haplo group. PTCy-haplo is promising for alternative donor transplantation in adult patients with aplastic anemia., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Autologous stem cell transplantation (ASCT) is the standard of care for myeloma patients who achieve partial response (PR) or better after induction therapy. However, its clinical significance in patients with suboptimal response (SR) before ASCT, including stable disease (SD) and progressive disease (PD), has not been established. Additionally, functional high-risk, including SR and early PD within 12 months, was a poor prognostic factor up to now. This study aimed to evaluate the efficacy of ASCT in myeloma patients with SR in the novel agent era. This multicenter retrospective study was conducted using the Transplant Registry Unified Management Program database of the Japanese Society of Transplantation and Cellular Therapy and included 3898 transplantation-eligible patients with newly diagnosed multiple myeloma who underwent ASCT between 2007 and 2020 and were followed up until 2021. The SR rate was 4.7%, including 1.7% with PD. In survival time analysis for overall cases, a significant difference in PFS between the very good partial response (VGPR) and PR groups was observed, whereas there was no significant difference in overall survival (OS) between the VGPR and PR groups. Additionally, there was no significant difference in OS or PFS between the PR and SD groups. Therefore, we focused on the PR, SD, and PD groups, as the purpose of this retrospective study was to investigate the clinical significance of ASCT in patients with SR compared with those with PR. The median patient age was 60 years (range, 30 to 77 years). In total, 1605 (97.4%) patients received bortezomib, 561 (38.2%) received an immunomodulatory drug (ImiD), and 512 (34.9%) received both bortezomib and an ImiD. A total of 558 patients (38.0%) received reinduction therapy. There were 229 patients (37.7%) with high-risk cytogenetics (HRCA). With a median follow-up of 31.7 months, there was a significant difference in 30-month OS rates among the PR, SD, and PD groups (86.3%, 78.5%, and 39.4%, respectively; P <.001). OS was significantly shorter in the SD group compared to the PR group among the patients with HRCA (P < .001) and patients treated with reinduction therapy (P = .013). In the PD group, the 30-month OS and PFS rates were 39.4% and 17.9%, respectively. Finally, early PD within 12 months after ASCT was predictive of short OS, whereas OS without early PD even in the PD group was similar to that in the SD and PR groups. In conclusion, OS in the SR group was not always short, but SR in the HRCA and the reinduction therapy groups was predictive of short OS, so that therapeutic alternatives to ASCT are needed. OS in the PD group was significantly short, but ASCT improved clinical outcomes when early PD did not occur even in the PD group., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In Japan, only single-unit cord blood transplantations (CBTs) are typically performed, and their number has increased over the last 23 years, with ongoing improvement in results. In most cases, CBTs with multiple HLA mismatches are used, owing to a low HLA barrier, and lower engraftment rate is a problem that must be overcome. Here, as part of an effort to improve guidelines for the selection and processing of CB units for transplantation, we sought to assess the present status of CBT in Japan and to elucidate factors contributing to the favorable outcomes, focusing in particular on selection by cell components of CB unit and HLA allele matching. We conducted a nationwide study analyzing 13,443 patients who underwent first CBT between in Japan between December 1997 and December 2019 using multivariate regression analysis. Both patient- and transplantation-related variables, such as age and Hematopoietic Cell Transplantation Comorbidity Index, as well as selected CB unit characteristics, were included in the analysis. The interaction analysis elucidated that CB unit selection favoring higher counts of CD34 + cells and granulocyte macrophage colony-forming units (GM-CFU)/kg, but not of total nucleated cells, contributed to improved engraftment after transplantation. Moreover, a higher CD34 + cell dose was associated with improved overall survival (OS). Distinctive HLA allele matching was observed. A 0 or 1 HLA allele mismatch between patient and donor had favorable engraftment and carried significantly lower risks of acute GVHD and chronic GVHD but had a significantly higher leukemia relapse rate, compared with a 3-HLA allele mismatch. HLA-DRB1 mismatches were associated with reduced risk of leukemia relapse. Notably, the number of HLA allele mismatches had no incremental effect on engraftment, acute and chronic GVHD, or relapse incidence. As a result, 5-year overall survival did not differ significantly among patients receiving CB units with 0 to 7 HLA allele mismatches. The main points of CB unit selection are as follows. First, selection according to a higher number of CD34 + cells/kg and then of CFU-GM/kg is recommended to obtain favorable engraftment. A unit with .5 × 10 5 CD34 + cells/kg is minimally acceptable. For units with a CD34 + cell dose of .5 to 1.0 × 10 5 cells/kg, applying the parameter of ≥20 to 50 × 10 3 GM-CFU/kg (66.5% of transplanted CB units in this cohort) is associated with a neutrophil engraftment rate of approximately 90%. A unit with ≥1.0 × 10 5 CD34 + cells/kg can achieve a ≥90% mean neutrophil engraftment rate. Subsequently, HLA allele matching of HLA-A, -B, -C, and -DRB1 at the 2-field level should be searched for units with 0 or 1 HLA allele mismatch in the host-versus-graft direction for favorable engraftment. Units with 2 to 6 HLA allele mismatches are acceptable in patients age ≥15 years and units with 2 to 4 HLA allele mismatches are acceptable in patients age ≤14 years. Units with HLA-DRB1 and/or -B allele mismatch(es) might not be preferable owing to an increased GVHD risk. Our analysis demonstrates that single-unit CBT with the selection of adequate CD34 + /kg and GM-CFU/kg and HLA allele matching showed favorable outcomes in both pediatric and adult patients., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. 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., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Using a murine haploidentical bone marrow transplantation (BMT) model, we recently showed that peritransplantation administration of glucocorticoid (GC) redistributed donor T cells from the gastrointestinal tract to bone marrow, which resulted in a significant reduction of graft-versus-host disease (GVHD) while promoting graft-versus-leukemia effects. Furthermore, in a retrospective clinical study of patients with acute myelogenous leukemia (AML) undergoing transplantation in non-remission, we also showed that haploidentical stem cell transplantation (haplo-SCT) using peritransplantation GC administration led to a significantly lower relapse rate and better overall survival rate compared with haplo-SCT using post-transplantation cyclophosphamide. In the present study, using the same dataset of patients undergoing GC haplo-SCT, we retrospectively compared with patients with AML undergoing transplantation in non-remission using 3 other donor types: matched sibling donor (MSD), matched unrelated donor (MUD), and umbilical cord blood (UCB). For GC haplo-SCT, 44 patients underwent peripheral blood stem cell transplantation in a single center (Hyogo College of Medicine), with the conditioning treatment consisting of fludarabine, melphalan, anti-thymocyte globulin (2.5 mg/kg), and TBI 3 Gy. Methylprednisolone was given from the start of conditioning treatment, and the GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). The transplantation outcomes were compared with data of 1889 patients undergoing MSD-SCT (n = 449), MUD-BMT (n = 493), or UCB transplantation (UCBT) (n = 947) in non-CR, which were extracted from the Transplant Registry Unified Management Program data, the largest data registry in Japan. For donor engraftment, significantly faster neutrophil and platelet engraftment was achieved with GC haplo-SCT compared with allo-SCT using the 3 other donor types. Neutrophil engraftment was achieved at a median of 10 days for GC haplo-SCT, and 20 days for MSD-, MUD-, and UCB-transplants. Platelet engraftment was achieved at a median of 19.5 days for GC haplo-SCT, 42 days for MSD-SCT and MUD-BMT, and 43 days for UCBT, respectively. The incidence of grade II-IV acute GVHD was lower after allo-SCTs using MSD (hazard ratio [HR] = 0.465, P = .003), MUD (HR = 0.524, P = .010), and UCB (HR = 0.647, P = .067) compared with GC haplo-SCT. There was no significant difference in the incidence of chronic GVHD between GC haplo-SCT and allo-SCT using the other 3 donor types. Regarding relapse, GC haplo-SCT was associated with a significantly lower risk compared with MSD-SCT (P < .001) or MUD-BMT (P = .004). GC haplo-SCT tended to have a lower risk compared with UCBT (P = .063). Especially, all the 43 evaluable GC haplo-SCT recipients achieved CR after transplantation, whereas 23.9%, 22.8%, and 27.0% of patients who underwent MSD-SCT, MUD-BMT, and UCBT could not achieve CR after transplantation, respectively. Regarding non-relapse mortality, GC haplo-SCT was associated with a significantly higher risk compared with MUD-BMT (P = .014), and tended to have a higher risk compared with MSD-SCT (P = .061). There was no significant difference between GC haplo-SCT and UCBT (P = .600). Allo-SCTs using MSD (HR = 2.548, P < .001), MUD (HR = 2.134, P = .005), and UCB (HR = 2.376, P = .001) lead to significantly higher overall mortality compared with GC haplo-SCT; the adjusted overall survival at 3 years was 19.8% for MSD, 26.1% for MUD, 28.0% for UCB, and 65.1% for GC haplo. Thus GC haplo-SCT is a promising treatment option for patients with AML with a high leukemic burden., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reported on the outcomes of large clinical studies of HSCT targeting these age groups. This study aimed to identify prognostic factors for the outcomes of HSCT, including reduced-intensity conditioning (RIC)-HSCT, for children and AYAs with CML in the TKI era. We performed a registry analysis for 200 patients with CML aged <30 years who underwent pretransplant TKI therapy from the observational nationwide database established by the Japanese Society for Transplantation and Cellular Therapy. The patients received bone marrow (BM), peripheral blood (PB), or cord blood (CB) from either related or unrelated donors. The indication for HSCT for individual patients was determined by the institution according to European LeukemiaNet recommendations and other guidelines. The 5-year overall survival (OS) rates for patients with chronic phase (CP) (n = 124), accelerated phase (AP) (n = 23), and blastic phase (BP) (n = 53) at diagnosis were 82.8%, 71.1%, and 73.3%, respectively, with no significant difference (P =.3293). The strongest predictor of engraftment was transplant source, with CB (hazard ratio [HR], 0.33) and PB (HR, 2.00) (compared with BM) being independent unfavorable and favorable predictors, respectively. Transplant source was also an independent predictor of chronic GVHD, with PB (HR, 1.81) and CB (HR, 0.39) (compared with BM) being unfavorable and favorable predictors, respectively. The strongest predictor of OS rate for patients with CP at diagnosis was disease phase at HSCT, with second or greater CP, AP, or BP (HR, 2.81) (compared with first CP [CP1]) being an unfavorable predictor. In addition, patients with CP at diagnosis who had major and complete molecular responses at HSCT had excellent outcomes, with 5-year OS rates of 100% and 94.4%, respectively. The 5-year OS rate was compared between RIC (n = 31) and myeloablative conditioning (MAC) (n = 58) in patients with CP1, both of which were 89.3%, with no significant difference (P = .9440). On univariate analysis for the RIC cohort with CP at diagnosis, the age at HSCT (HR, 1.27) (increase per year) and the time from diagnosis to HSCT (HR, 1.83) (increase per year) were significant predictors for OS. Our study demonstrates that RIC may be an appropriate alternative to MAC for children and AYAs with CP1. As for the transplant source, we recommend first selecting BM because of a higher engraftment rate compared to CB and a lower incidence of chronic GVHD compared to PB. Although HSCT in the status of a major molecular response is desirable, it is not advisable to continue TKI pointlessly long because age at HSCT and timing of HSCT are prognostic factors that determine survival. The decision to perform RIC-HSCT instead of continuing TKI should be carefully made, considering the possibility of transplant-related complications., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n = 4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6 × 10 7 /kg and .8 × 10 5 /kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Autologous stem cell transplantation (ASCT) is the standard of care for eligible patients with light-chain (AL) amyloidosis, but little is known about it in Asian populations. To investigate the outcome of and prognostic factors for ASCT, we retrospectively analyzed ASCT cases registered to the Transplant Registry Unified Management Program between December 1999 and December 2015, with extra clinical information collected through a secondary survey. The primary endpoint was overall survival (OS). Hematologic response, organ response, and transplantation-related mortality were analyzed as secondary endpoints. The database search identified 330 patients (median age, 57 years; range, 31 to 74), and the secondary survey provided details for the 110 patients (33.3%) included in the study cohort. Fewer than 3 organs were involved in 56.4% of the patients, with cardiac involvement in 57.3%. Performance status (PS) was 0 to 1 in 83.6%. The conditioning melphalan dose was reduced in 54.6%. Overall hematologic response was a partial response or better in 77.6% of the patients and a complete response in 49.3%. The 5-year OS was 70.1%. A PS of 0 to 1 was associated with a significantly better prognosis in terms of OS. Although survival after ASCT for AL amyloidosis improved over time, poor PS and cardiac involvement had negative impacts on prognosis. The early mortality after ASCT was 6.4%. Poor PS and cardiac involvement led to high early mortality. A brain natriuretic peptide (BNP) level of 400 pg/mL was associated with worse OS. Our study has several limitations inherent to a retrospective analysis using a questionnaire. The depth of response and biomarker responses were significantly limited by the degree of missing data. Nonetheless, our data support the importance of careful patient selection for good outcomes of ASCT in patients with AL amyloidosis. In our cohort, poor PS and cardiac involvement had a negative impact on prognosis, and BNP level was a useful prognostic factor., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Antithymocyte globulin (ATG) decreases chronic graft-versus-host disease (cGVHD) in peripheral blood stem cell transplantation (PBSCT); however, the optimal ATG dose has not been elucidated. We conducted a matched-pair analysis to evaluate whether low-dose ATG could inhibit cGVHD in HLA-matched PBSCT after myeloablative conditioning. A total of 70 patients who were enrolled in the JSCT-ATG15 study, a multicenter phase II clinical trial of 2 mg/kg of ATG (thymoglobulin) given on days -2 and -1, were compared with 210 patients not receiving ATG, who were matched for age, sex, disease, and calcineurin inhibitor selected from the database in Japan. The primary endpoint, cumulative incidence of extensive cGVHD at 2 years was significantly less in the ATG group than that in the non-ATG group (8.7% [95% CI, 3.5%-16.8%] versus 26.2% [95% CI, 20.3%-32.5%], P = .002). ATG significantly reduced the incidence of overall cGVHD and inhibited multiple organ involvement. The ATG group had favorable outcome compared to the non-ATG group in GVHD-free, and relapse-free survival at 2 years. In conclusion, low-dose ATG effectively inhibits chronic GVHD in PBSCT., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In the absence of HLA-matched related and unrelated donors, alternative donors must be found for patients in need of allogeneic hematopoietic cell transplantation (HCT). There are at least 3 donor options: a mismatched unrelated donor (MMUD), umbilical cord blood (UCB), and a haploidentical related donor (haplo); however, the optimal alternative donor type remains to be established. This study aimed to address how the outcomes of patients receiving these 3 alternative donor HCTs differ, and whether these outcomes change over time post-transplantation. We retrospectively analyzed Japanese nationwide transplantation registry data of adults with acute myelogenous leukemia (AML) undergoing allogeneic HCT while in first complete remission (CR) from an MMUD with a 7/8 match at the allele level (n = 601), with UCB (n = 1110), or from a haploidentical related donor (n = 221) between 2007 and 2018. For patients who underwent transplantation between 2007 and 2014, the 3-year overall survival (OS) for the MMUD, UCB, and Haplo groups was 60%, 54%, and 47%, respectively (P = .022). For those who underwent transplantation between 2015 and 2018, the 3-year OS in these groups was 60%, 66%, and 63%, respectively (P = .693). Multivariate analysis revealed that the risks of both overall mortality and nonrelapse mortality (NRM) were significantly lower in the later period than in the earlier period in the UCB group (hazard ratio [HR], 0.66 [P < .001] for OS; HR, 0.64 [P < .001] for NRM) and the Haplo group (HR, 0.58 [P = .019 for OS; HR, 0.39 [P = .004] for NRM), but not in the MMUD group (HR, 1.07 [P = .631] for OS; HR, 1.26 [P = .175] for NRM). The results of a test for interaction showed a significant difference in the effect of transplantation period on OS and NRM between the MMUD and UCB groups (P = .014 for OS; P = .004 for NRM) and between the MMUD and Haplo groups (P = .034 for OS; P = .003 for NRM). These findings demonstrate the recent improvements in the outcomes of UCB and Haplo transplantations in patients with AML in first CR that have resulted in a similar OS in patients undergoing HCT with grafts from MMUDs, UCB, and haploidentical donors in the later period of the study., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative post-remission therapy for adult patients with acute myeloid leukemia (AML) in complete remission (CR). The availability of alternative human leukocyte antigen (HLA)-mismatched donors, such as cord blood and haploidentical related donors, could allow patients to receive allogeneic HCT who are without an HLA-matched sibling or unrelated donor. The use of these alternative donors is preferable for patients with advanced disease due to the rapid availability. However, comparative data for cord blood transplantation (CBT) and haploidentical related donor transplantation (haplo-HCT) are limited for adult patients with AML in CR. We sought to compare overall survival (OS); leukemia-free survival (LFS); graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); and chronic GVHD-free, relapse-free survival (CRFS) between single-unit CBT (SCBT) and haplo-HCT recipients for adult patients with intermediate- or poor-risk AML in CR. We retrospectively analyzed and compared the results of allogeneic hematopoietic cell transplantation in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan. Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients (P < .001 for neutrophil, P < .001 for platelet). SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT (P = .013 for grades II to IV acute GVHD; P = .006 for extensive chronic GVHD). Haplo-HCT recipients developed a higher incidence of cytomegalovirus (CMV) antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD (hazard ratio [HR], 1.17; 95% confidence interval [CI], .88 to 1.57; P = .26), relapse incidence (HR, 1.09; 95% CI, .76 to 1.58; P = .61), non-relapse mortality (HR, .83; 95% CI, .58 to 1.18; P = .32), OS (HR, .92; 95% CI, .70 to 1.20; P = .56), LFS (HR, .94; 95% CI, .73 to 1.21; P = .67), GRFS (HR, 1.12; 95% CI, .90 to 1.40; P = .27), or CRFS (HR, 1.15; 95% CI, .92 to 1.44; P = .19) between the two donor types. In the propensity score matching analysis, which identified 180 patients in each cohort, there were no significant differences in transplant outcomes between the two donor types, except for delayed neutrophil (P < .001) and platelet recovery (P < .001) and a higher incidence of grades II to IV acute GVHD (P = .052) in SCBT. SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Limited data exist regarding the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) among adolescent and young adult (AYA) patients with acute myeloid leukemia (AML). Here we analyzed the features and outcomes of AYA patients with AML who had achieved complete remission (CR) and those who had not (non-CR) at allo-HCT. We retrospectively analyzed 2350 AYA patients with AML who underwent allo-HCT with a myeloablative conditioning regimen and who were consecutively enrolled in the Japanese nationwide HCT registry. The difference in overall survival (OS) between younger (age 16 to 29 years) and older AYA (age 30 to 39 years) patients in CR at transplantation was not significant (70.2% versus 71.7% at 3 years; P = .62). Meanwhile, this difference trended toward a statistical significance between younger and older AYA patients in non-CR at transplantation (39.5% versus 34.3% at 3 years; P = .052). In AYA patients in CR and non-CR, the age at transplantation did not affect relapse or nonrelapse mortality (NRM). In AYA patients in CR, no difference in OS was observed between those who received total body irradiation (TBI) and those who did not (71.1% versus 70.5% at 3 years; P = .43). AYA patients who received TBI-based conditioning had a significantly lower relapse rate and higher NRM than those who underwent non-TBI-based conditioning (relapse: 19.8% versus 24.1% at 3 years [P = .047]; NRM: 14.7% versus 11.1% at 3 years [P = .021]). In contrast, among the non-CR patients, there were no differences between the TBI and non-TBI groups with respect to OS (P = .094), relapse (P = .83), and NRM (P = .27). Our data indicate that outcomes may be more favorable in younger AYA patients than in older AYA patients in non-CR at transplantation, and that outcomes of TBI-based conditioning could be comparable to those of non-TBI-based conditioning for AYA patients., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)