Satoshi Wakita

Background: Venetoclax‐based regimens (VEN) have been widely adopted as frontline therapeutic options for elderly patients with acute myeloid leukemia (AML). However, comprehensive real‐world comparisons of VEN with conventional intensive or reduced‐intensity chemotherapy remain limited. Methods: In this multicenter retrospective study, we evaluated treatment patterns and outcomes in 1370 patients with newly diagnosed AML. Patients were classified into three cohorts according to their frontline treatment: intensive chemotherapy (IC), reduced‐intensity chemotherapy (rIC), or VEN. Analyses were performed in both the overall cohort and elderly patients (aged ≥ 60 years), including baseline comparisons, uni‐ and multivariable analyses, and subgroup analyses. Results: Baseline characteristics differed substantially among treatment cohorts; patients treated with VEN were older and had a higher prevalence of adverse‐risk disease than those receiving IC or rIC . In the overall cohort, VEN achieved an overall response rate ( ORR ) comparable to IC and higher than rIC (74.3% vs. 60.2%, p = 0.034). Among elderly patients, VEN was associated with a higher ORR than rIC (75.7% vs. 50.5%, p = 0.001), and the favorable ORR findings remained significant after correction for multiple testing. VEN was also associated with a lower 60‐day early‐death rate than rIC in elderly patients (1.4% vs. 20.0%, p < 0.001), suggesting better early treatment tolerability. Median event‐free survival was longer with VEN than with rIC in the primary elderly cohort analysis (9.6 vs. 6.6 months, p = 0.031), and this difference persisted in a sensitivity analysis censoring at allogeneic hematopoietic stem cell transplantation, although it was attenuated in landmark and propensity‐score‐based sensitivity analyses. Overall survival did not differ significantly between the two cohorts (15.9 vs. 11.0 months, p = 0.102). Conclusion: The higher response rate and lower early mortality with VEN were the most consistent findings, whereas comparative survival outcomes were considered supportive but exploratory.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1‐mutated AML. Although patients with NPM1‐mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A^R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1‐mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A^R882 mutations and the co‐occurrence of internal tandem duplication in FMS‐like tyrosine kinase 3 (FLT3‐ITD), NPM1 mutations, and DNMT3A^R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A^R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A^R882 mutations and triple mutations on prognosis and according to the classification of NPM1‐mutated AML into three risk groups based on DNMT3A^R882/FLT3‐ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A^R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A^R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Background: Liver dysfunction occurring after allogeneic hematopoietic stem cell transplantation (HSCT) may have various causes, but since these causes are difficult to identify in the early stages, therapeutic intervention may be delayed. It is, therefore, important to identify unfavorable prognostic factors of liver dysfunction as soon as possible. The objective of this study was to identify the unfavorable prognostic factors of liver dysfunction in the early post-transplant period. Methods: We defined liver dysfunction as the detection within 30 days of transplantation of elevated liver or biliary enzyme levels corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. We retrospectively investigated 82 patients who had undergone allogeneic HSCT at our institution. Results: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor, having the greatest impact on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without elevated T-Bil level versus that in patients with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in proportion to the degree of T-Bil elevation and the absence of improvements over time in the T-Bil level. Conclusion: Our study showed that elevated T-Bil level is a major unfavorable prognostic factor of liver dysfunction after allogeneic HSCT.