Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect.

Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor-recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect.

Germ line DDX41 mutations define a unique subtype of myeloid neoplasms.

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.

The impact of daratumumab pretreatment on multiple myeloma patients undergoing autologous transplantation.

The anti-CD38 antibody daratumumab (Dara) has been reported to improve the prognosis of multiple myeloma (MM) patients, but its use before autologous stem cell transplantation (ASCT) remains controversial. To clarify the prognostic impact of Dara before ASCT on MM, we performed a retrospective observational analysis. We analyzed 2626 patients who underwent ASCT between 2017 and 2020. In the comparison between patients not administered Dara (Dara- group) and those administered Dara (Dara+ group), the 1-year progression-free survival (PFS) rates were 87.4% and 77.3% and the 1-year overall survival (OS) rates were 96.7% and 90.0%, respectively. In multivariate analysis, age <65 years (p = 0.015), low international staging system (ISS) stage (p < 0.001), absence of unfavorable cytogenic abnormalities (p < 0.001), no Dara use before ASCT (p = 0.037), and good treatment response before ASCT (p < 0.001) were independently associated with superior PFS. In matched pair analysis, the PFS/OS of the Dara- group were also significantly superior. For MM patients who achieved complete or very good partial response (CR/VGPR) by Dara addition before ASCT, both PFS and OS significantly improved. However, in patients who did not achieve CR/VGPR before ASCT, the PFS/OS of the Dara+ group were significantly inferior to those of the Dara- group.

The prognosis and risk factors for patients with complex karyotype myelodysplastic syndrome undergoing allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (HCT) is the curative treatment for myelodysplastic syndrome with a complex karyotype (CK-MDS). However, only a few studies have been limited to patients with CK-MDS undergoing allogeneic HCT. This study aimed to identify the risk factors for patients with CK-MDS undergoing allogeneic HCT. We included 691 patients with CK-MDS who received their first allogeneic HCT. The overall survival (OS) was the primary end-point, estimated using the Kaplan-Meier method. Prognostic factors were identified using a Cox proportional hazards model. The 3-year OS was 29.8% (95% confidence interval [CI]: 26.3-33.3). In the multivariable analysis, older age (hazard ratio [HR]: 1.44, 95% CI: 1.11-1.88), male sex (HR: 1.38, 95% CI: 1.11-1.71), poor haematopoietic cell transplant comorbidity index (HR: 1.47, 95% CI: 1.20-1.81), red blood cell transfusion requirement (HR: 1.58, 95% CI: 1.13-2.20), platelet transfusion requirement (HR: 1.85, 95% CI: 1.46-2.35), not-complete remission (HR: 1.55, 95% CI: 1.16-2.06), a high number of karyotype abnormality (HR: 1.63, 95% CI: 1.18-2.25) and monosomal karyotype (HR: 1.49, 95% CI: 1.05-2.12) were significantly associated with OS. Thus, the 3-year OS of allogeneic HCT was 29.8% in patients with CK-MDS, and we identified risk factors associated with poor OS.

Low- versus standard-dose post-transplant cyclophosphamide as GVHD prophylaxis for haploidentical transplantation.

Haploidentical haematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GVHD) prophylaxis is the standard of care for various haematological malignancies. The original PTCY dose after haplo-HCT was 100 mg/kg, but no dose-finding studies have been performed to identify the optimal dose. We performed a retrospective analysis to compare standard-dose PTCY (100 mg/kg) with reduced-dose PTCY (80 mg/kg): 969 in the standard-dose group and 538 in the reduced-dose group. As there was a significant difference between the two groups regarding patient and transplant characteristics, we performed propensity score (PS) matching. After PS matching, 425 patients in each group were included. The probabilities of 2-year OS were 55.9% in the standard-dose group and 47.0% in the reduced-dose group (p = 0.36). The cumulative incidences of 2-year non-relapse mortality were 21.3% in the standard-dose group and 20.5% in the reduced-dose group (p = 0.55). There was no significant difference in the incidence of acute (grade II-IV 29.2% [95% CI, 24.9-33.6] vs. 25.3% [95% CI, 21.3-29.6]; grade III-IV 7.3% [95% CI, 5.1-10.0] vs. 6.6% [95% CI, 4.5-9.3]) or chronic GVHD. In conclusion, reduced- and standard-dose PTCY were comparable in terms of major clinical outcomes.

First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Effect of peptide-binding motif on survival of HLA-haploidentical transplantation with post-transplant cyclophosphamide.

Peptide-binding motif (PBM) model, a hierarchical clustering of HLA class I based on their binding specificity, was developed to predict immunopeptidome divergence. The effect of PBM mismatches on outcomes is unknown in HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo). We therefore conducted a retrospective study using national registry data in PTCy-haplo. Overall, 1352 patients were included in the study. PBM-A bidirectional mismatch was associated with an increased risk of overall mortality in multivariable analysis (hazard ratio, 1.26; 95% confidence interval, 1.06 to 1.50; p = 0.010). None of relapse, non-relapse mortality (NRM) and graft-versus-host disease showed significant differences according to PBM-A bidirectional mismatch status in the entire cohort. The impact of PBM-A bidirectional mismatch on overall survival (OS) was preserved within the HLA-A genotype bidirectional mismatch population, and their lower OS stemmed from higher relapse rate in this population. The worse OS due to high NRM with PBM-A bidirectional mismatch was prominent in lymphoid malignancies receiving reduced-intensity conditioning. The PBM model may predict outcomes more accurately than HLA genotype mismatches. In conclusion, this study demonstrated that the presence of PBM-A bidirectional mismatch elevated the risk of mortality of PTCy-haplo. Avoiding PBM-A bidirectional mismatch might achieve better outcomes in PTCy-haplo.

Continuous and differential improvement in worldwide access to hematopoietic cell transplantation: activity has doubled in a decade with a notable increase in unrelated and non-identical related donors.

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-Governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (six WHO regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT number increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/ten million population was observed for autologous HCT (r=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation (r=0.51) was detected from related donors. The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period.

BACKGROUND: Mobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. OBJECTIVE: The objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003-2008, 2009-2014, or 2015-2020). STUDY DESIGN: We retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. RESULTS: The adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003-2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70-0.91; P < 0.001) and the middle period of 2009-2014 (adjusted HR, 0.80; 95% CI, 0.70-0.91; P < 0.001). However, during the late period of 2015-2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79-1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II-IV and grades III-IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. CONCLUSIONS: PBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015-2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

Center effect on allogeneic hematopoietic stem cell transplantation outcomes for B-cell acute lymphoblastic leukemia.

This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9-55.5) versus 46.8% (95% CI: 43.8-49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72-0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61-0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48-0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2-62.7] vs. 54.9% [95% CI: 51.3-58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy.

BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

Scoring system for optimal cord blood unit selection for single cord blood transplantation.

BACKGROUND: We conducted a retrospective study to categorize the cord blood unit (CBU)s to identify the optimal units. METHODS: A total of 8503 adults (female, n = 3592; male, n = 4911) receiving their first single cord blood transplantation (CBT) in 2000-2019 were analyzed. Factors associated with CBUs affecting overall survival (OS) and neutrophil engraftment were selected to create ranked categorization for each outcome, followed by comparison with transplantation using HLA-matched bone marrow (BMT)/peripheral blood stem cell (PBSCT) from unrelated (n = 6052) and related donors (n = 4546). RESULTS: Sex-mismatch, CD34+ cell and CFU-GM counts were selected in the OS analysis. Considering the strong interaction between sex mismatch and CD34+ cell counts, we analyzed females and males separately. For females, female CBU with CD34+ cell counts {greater than or equal to} 0.5 × 10e5/kg and CFU-GM counts {greater than or equal to} 15 × 10e3/kg offered the best OS (Group I), followed by other groups with any (Groups II-IV) or all (Group V) of the risk factors. Group I consistently showed favorable OS (Group IV: HR1.22, P = 0.027; Group V: HR1.31, P = 0.047), comparable to those of rBMT/PBSCT (OS: HR1.02, P = 0.654) and uBM/PBSCT in patients with higher rDRI (HR1.07, P = 0.353). Male patients lacked significant factors affecting OS. Categorization for neutrophil engraftment consisting of CD34+ cell and CFU-GM counts, sex-mismatch, presence of donor-specific antibodies, and the number of HLA-mismatches was effective but not predicted OS. CONCLUSION: Our ranked categorizations sufficiently predicted female OS and engraftment. The best-ranked CBUs offered preferable outcomes comparable to conventional BM/PB donors in female but not in male patients.

Prognostic factors in haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia.

BACKGROUND AIMS: Haploidentical hematopoietic stem cell transplantation (haplo-HCT) is an appropriate option when an HLA-matched related or unrelated donor is not available. Haplo-HCT using post-transplant cyclophosphamide (PTCy) is being increasingly performed worldwide due to its effective suppression of GVHD and its safety. METHODS: We conducted a large nationwide cohort study to retrospectively analyze 366 patients with acute myeloid leukemia undergoing haplo-HCT with PTCy between 2010 and 2019 and to identify prognostic factors. RESULTS: A multivariate Cox analysis revealed that an older recipient age (≥60 years), a male donor to a male recipient, a cytomegalovirus IgG-negative donor to a cytomegalovirus IgG-positive recipient, a poor cytogenetic risk, a noncomplete remission status at the time of transplantation, and a history of HCT were independently associated with worse overall survival (OS). Based on each hazard ratio, these factors were scored (1-2 points) and stratified by their total score into three groups: favorable (0-1 points), intermediate (2-3 points), and poor (4 points or more) groups, and 2-year OS rates were 79.9%, 49.2%, and 25.1%, respectively (P < 0.001). CONCLUSIONS: The present study revealed significant prognostic factors in haplo-HCT with PTCy, and a scoring system based on these factors may be used to predict outcomes.

Superiority of BM over PBSC for recipients with pre-transplant lung dysfunction in HLA-matched allogeneic HCT.

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

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n = 331) or single-unit unrelated cord blood (UCB) (n = 668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P = 0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P = 0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P = 0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P = 0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P < 0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P < 0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P < 0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P < 0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Outcomes of allogeneic hematopoietic cell transplantation under letermovir prophylaxis for cytomegalovirus infection.

Cytomegalovirus (CMV) infection is a major infectious complication following allogeneic hematopoietic cell transplantation (allo-HCT). Although letermovir (LMV) prophylaxis dramatically reduces the incidence of early clinically significant CMV (csCMV) infection, it remains unclear whether it has a beneficial effect on nonrelapse mortality (NRM) and overall survival (OS). Herein, we evaluated the impact of LMV prophylaxis on posttransplant outcomes using the registry database of the Japanese Society for Transplantation and Cellular Therapy. Adult patients who underwent allo-HCT between 2017 and 2019 were analyzed (n = 6004). LMV prophylaxis was administered to 1640 patients (LMV group) and it significantly reduced the incidence of csCMV infection compared with those not administered LMV prophylaxis (15.4% vs 54.1%; p < 0.01). However, it did not improve the 1-year NRM (hazard ratio [HR], 0.93; p = 0.40) and OS (HR, 0.96; p = 0.49). In the LMV group, 74 patients had breakthrough csCMV infection and showed inferior NRM (HR, 3.44; p < 0.01) and OS (HR, 1.93; p = 0.02) compared with those without infection. After completing LMV prophylaxis, 252 patients had late csCMV infection and showed inferior NRM (HR, 1.83; p < 0.01) and OS (HR, 1.58; p < 0.01). Our findings suggest that managing breakthrough and late csCMV infections is important for improving long-term outcomes.

Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Significance of absolute neutrophil count before allogeneic hematopoietic stem cell transplantation in adult patients with aplastic anemia.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m2 ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.