仲宗根 秀樹

BACKGROUND: Sex-mismatched allogeneic hematopoietic cell transplantation (allo-HCT), particularly with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). This adverse effect of FtoM allo-HCT is considered to result from allo-immunity against Y-chromosome antigens. However, it has not been elucidated whether the adverse impact of FtoM allo-HCT varies by recipient age. OBJECTIVE: This study aims to examine the effect of sex-mismatch on clinical outcomes in allo-HCT from human leukocyte antigen (HLA)-matched donors, stratified by recipient age group. STUDY DESIGN: Using a Japanese transplantation registry database, we analyzed 10392 patients (n = 2169, 2573, and 5650 in FtoM, MtoF, and sex-matched allo-HCT, respectively) with standard-risk hematological malignancies who had undergone their first allo-HCT from HLA-matched related or unrelated donors without in vivo T-cell depletion between 2008 and 2022. The impact of sex-mismatch on clinical outcomes was separately assessed by recipient age groups: ≤ 15, 16-39, and ≥ 40 years. The primary endpoint was overall survival (OS). Secondary endpoints included disease-free survival, NRM, and the cumulative incidences of acute and chronic GVHD. RESULTS: In recipients aged ≥ 40 years, OS and NRM at 5 years post-HCT were significantly worse in the FtoM group compared with the MtoF and sex-matched groups (5-year OS 49.5% vs 59.6% vs 57.1%, P < 0.001; 5-year NRM 27.9% vs 21.9% vs 23.0%, P < 0.001), while no differences were observed among the FtoM, MtoF, and sex-matched groups in recipients aged ≤ 15 years or 16-39 years. Multivariate analyses confirmed that FtoM allo-HCT was significantly associated with increased mortality only in recipients aged ≥ 40 years (hazard ratio [HR] for OS 1.31, P < 0.001; HR for NRM 1.44, P < 0.001). The FtoM group in recipients aged ≥ 40 years frequently experienced fatal infection and fatal non-infectious pulmonary complications. In addition, we confirmed that the adverse effect of FtoM allo-HCT on OS similarly appeared only in recipients aged ≥ 40 years in both sub-cohorts divided by a median of donor age (40 years). CONCLUSION: The adverse impact of FtoM allo-HCT on survival outcomes differed according to recipient age. Our findings suggest that female donors should be avoided, especially in older male recipients undergoing allo-HCT.

OBJECTIVES: Bacteraemia and cytomegalovirus (CMV) infection are major infectious complications after allogeneic haematopoietic cell transplantation (HCT). However, their bidirectional relationship, particularly in the setting of letermovir (LTV) prophylaxis, remains unclear. We investigated the bidirectional associations between bacteraemia and CMV infection and their impact on transplantation outcomes. We also evaluated the effect of LTV prophylaxis on these associations. METHODS: Using a nationwide Japanese transplant registry database, we analysed 23,841 patients who underwent their first allogeneic HCT between 2008 and 2022. Multivariable Cox proportional hazards models with time-dependent covariates were used to evaluate bidirectional associations between bacteraemia and clinically significant CMV infection (csCMVi). RESULTS: csCMVi was associated with an increased risk of subsequent bacteraemia (adjusted hazard ratio [aHR], 1.48; 95% CI, 1.33-1.64), with a stronger association among patients in the LTV group (aHR, 2.59; 95% CI, 1.87-3.60) than among those in the no-LTV group (aHR, 1.30; 95% CI, 1.16-1.46). Conversely, bacteraemia was modestly associated with an increased risk of csCMVi overall (aHR, 1.06; 95% CI, 1.01-1.11), but this association was observed only in the LTV group (aHR, 1.61; 95% CI, 1.40-1.85). These bidirectional associations were consistent in the LTV era and in patients without grade II-IV acute graft-versus-host disease. The findings were robust in sensitivity analyses, including landmark and propensity score-matched analyses. In propensity score-matched cohorts, both bacteraemia and csCMVi were associated with higher nonrelapse mortality (NRM; defined as death without relapse of the underlying malignancy) and inferior overall survival (OS), regardless of LTV use. CONCLUSIONS: Bacteraemia and csCMVi were bidirectionally associated after allogeneic HCT, particularly in the LTV group. Both bacteraemia and csCMVi were consistently associated with higher NRM and inferior OS, regardless of LTV prophylaxis. These findings highlight the need for integrated infection management strategies, particularly in the LTV era.

UNLABELLED: Post-transplant cyclophosphamide (PTCy) is now being increasingly applied to HLA-matched donor (MD) transplantation. Prior studies in Western countries have demonstrated that allogeneic hematopoietic cell transplantation (allo-HCT) employing PTCy yields better outcomes with HLA-matched donors (MDs) than with haploidentical donors (HIDs). However, the effect of HLA mismatch may differ among racial groups. We retrospectively analyzed adult patients with hematological malignancies who underwent their first allo-HCT with PTCy from MDs or HIDs registered to the Japanese registry database between 2013 and 2021. Among 63 (related, n = 33; unrelated, n = 30) and 1261 patients who received MD and HID allo-HCT with PTCy, 50 (related, n = 30; unrelated, n = 20) and 100 patients were assigned to MD and HID groups by 1:2 propensity score matching (PSM). The results showed that MD recipients had better neutrophil recovery (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.04–2.10; P = 0.031) and lower risk of non-relapse mortality (NRM) (HR, 0.19; 95% CI, 0.05–0.81; P = 0.024) than HID recipients. Multivariable analyses in the entire cohort before PSM confirmed these findings. Fatal infection was the primary cause of NRM in the HID group. This study is the first to demonstrate that, within a homogeneous Asian cohort, MD may have an advantage over HID in PTCy-based allo-HCT in facilitating neutrophil engraftment and reducing the risk of NRM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00277-026-07014-z.

Using data from a nationwide Japanese registry, we evaluated the impact of the total body irradiation (TBI) dose in reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute myeloid leukemia (AML). Adults undergoing their first allo-HCT with RIC between 2010 and 2021 were classified into three groups: non-TBI, low-TBI (2 to < 4 Gy), or moderate-TBI (4-8 Gy). Outcomes were analyzed separately for patients in complete remission (CR, n = 1949) and those in the non-CR group (n = 1484). Non-TBI was associated with higher overall mortality than low-TBI (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.03-1.56 in CR; HR, 1.19; 95% CI, 1.00-1.42 in non-CR). Moderate-TBI showed no significant difference in overall mortality compared to low-TBI (HR, 0.96; 95% CI, 0.80-1.15 in CR; HR, 0.89; 95% CI, 0.77-1.05 in non-CR). Among patients in the CR group with matched sibling donors, moderate-TBI reduced overall mortality (HR, 0.33; 95% CI, 0.17-0.64) and relapse (HR, 0.29; 95% CI, 0.12-0.69). In cord blood transplantation, non-TBI increased relapse in CR (HR, 2.73; 95% CI, 1.48-5.06) and overall mortality in non-CR (HR, 1.62; 95% CI, 1.19-2.19). In haploidentical transplants, non-TBI increased relapse (HR, 5.52; 95% CI, 1.72-17.72 in CR; HR, 1.54; 95% CI, 1.04-2.30 in non-CR). The incidence of secondary primary malignancies did not differ according to the use or dose of TBI. In conclusion, adding low- or moderate-TBI to RIC may improve disease control and survival without increasing non-relapse mortality.