神田 善伸

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.

ABSTRACT While venetoclax‐based combinations have shown promising results in acute myeloid leukemia (AML), the remission duration is generally short, warranting strategies to further improve efficacy and overcome resistance. Here, we show that the natural quassinoid brusatol induces cell‐cycle arrest and apoptosis in multiple AML cell lines while enhancing venetoclax efficacy irrespective of inherent or acquired resistance. Mechanistically, brusatol increased p53 protein expression, leading to upregulation of its target genes/proteins, including CDKN1A (p21) and BBC3 (PUMA). Genetic deletion of TP53 attenuated brusatol‐induced apoptosis and its synergy with venetoclax, supporting p53 activation as a central mechanism underlying the anti‐leukemia response. Furthermore, the combination synergistically decreased mitochondrial membrane potential and respiratory activity, causing accumulation of reactive oxygen species in AML cells. Although brusatol and venetoclax exhibited limited effects individually, their combination markedly reduced leukemia burden and significantly prolonged survival in three independent cell line‐derived xenograft models, including venetoclax‐resistant and ‐refractory models. Notably, brusatol increased normal leukocyte and platelet counts while reducing leukemic infiltration in both bone marrow and extramedullary sites. These findings provide mechanistic insight into the synergistic effects of the brusatol‐venetoclax combination, supporting further evaluation of this therapeutic strategy in myeloid leukemias.

Post-transplant relapse remains a major cause of treatment failure in adult B-cell acute lymphoblastic leukemia (ALL). The introduction of inotuzumab ozogamicin (InO) and blinatumomab (Blina) has expanded salvage options; however, their impact on outcomes and safety in patients relapsing after allogeneic stem cell transplantation has not been fully defined. To evaluate the impact of the availability of InO and Blina on clinical outcomes in adult B-cell ALL patients with post-transplant relapse, and to assess the safety of these agents in the post-transplant setting. We retrospectively analyzed 150 adult patients with B-cell ALL who relapsed after the first allogeneic stem cell transplantation. Patients were divided according to the time of their post-transplant relapse based on the approvals of InO and Blina in Japan: the pre-InO/Blina group (n = 95) and the post-InO/Blina group (n = 55). Outcomes were analyzed separately for Philadelphia chromosome (Ph)-negative and Ph-positive ALL. Overall survival (OS) after post-transplant relapse, complete remission (CR) rates as the best response before a second transplantation or last follow-up, and outcomes after a second transplantation were compared between groups. Adverse events associated with post-transplant use of InO and Blina were also evaluated. Among 95 patients with Ph-negative ALL, outcomes were significantly better in the post-InO/Blina group than in the pre-InO/Blina group, with the 2-year OS after post-transplant relapse improving from 19% to 51% (P = .003) and, among 88 treated patients, the CR rate increasing from 36% to 77% (P < .001). Multivariable analyses identified the time of post-transplant relapse and disease status at the first transplantation as independent prognostic factors for OS. Among 43 patients who underwent a second transplantation, the 2-year OS after second transplantation improved from 27% in the pre-InO/Blina group to 55% in the post-InO/Blina group (P = .029). In contrast, among 55 patients with Ph-positive ALL, OS after post-transplant relapse did not differ between groups. Among 32 patients treated with InO after post-transplant relapse, no patient developed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) during InO therapy; however, 5 of 17 patients (29%) who subsequently underwent the second transplantation developed VOD/SOS. An interval of <2.5 months between InO and the second transplantation was associated with a higher VOD/SOS risk (56% versus 0%, P = .029). Among 30 patients treated with Blina, cytokine release syndrome occurred in 53% (grade 3 to 4, 7%) and immune effector cell-associated neurotoxicity syndrome in 13% (grade 3, 3%), with no fatal events. The prognosis of adult Ph-negative B-cell ALL after post-transplant relapse improved substantially in the post-InO/Blina era, including improved survival after a second transplantation. Overall, the safety profiles of InO and Blina in the post-transplant setting were acceptable, although VOD/SOS remains an important concern in patients proceeding to a second transplantation after InO.

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.

Registry analysis of first allogeneic transplant in HLA-homozygous recipients.Overall survival did not significantly differ with related donor hetero-to-homo or cord blood hetero-to-homo transplantation.Cord blood homo-to-homo transplantation was associated with inferior survival in the primary analysis.