藤原 慎一郎

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.

Venetoclax-azacitidine chemotherapy is a key treatment for older or medically unfit patients with acute myeloid leukemia (AML). As venetoclax is metabolized via cytochrome P450 3 A, dose adjustments are required when combined with antifungal agents. However, data on venetoclax concentrations and their impact on safety and efficacy remain limited. This study analyzed the association between venetoclax trough levels and treatment outcomes in 152 AML patients (median age: 70 years). The median trough level was 1,518 ng/mL (range: 60-11,328 ng/mL), with significant interindividual variability, even after adjusting for antifungal use. High venetoclax trough levels were significantly associated with elevated creatinine and total bilirubin levels. Patients with trough levels below 1857.3 ng/mL had lower rates of hematologic toxicity during the first treatment cycle (92.9% vs. 100%, P = 0.041). In the second cycle, hematologic toxicity was lower in patients with concentrations below 1,299.3 ng/mL (68% vs. 90%, P = 0.009). In the treatment-naïve group, trough levels above 1857.3 ng/mL were associated with a higher composite complete remission rate (77.3% vs. 47.8%, P = 0.042). These findings highlight the need for venetoclax dose optimization based on drug levels to improve both safety and efficacy in AML treatment.