The European LeukemiaNet 2024 risk-stratification guidelines for patients with acute myeloid leukemia receiving hypomethylating agents combined with venetoclax were recently published. This analysis demonstrates reclassification and incorporation of new gene mutations in the present model can further improve and individualize prognostication.

Whether older HLA-matched sibling donors (MSD) are preferred over younger alternative donors for allogeneic hematopoietic cell transplantation (allo-HCT) with posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is unclear. We compared outcomes in allo-HCT recipients ≥50 years old after HCT from an older MSD (≥50 years) with recipients of younger (≤35 years) HLA-matched unrelated donor (MUD), haploidentical related donor (haplo), and HLA-mismatched unrelated donor (MMUD), grouped based on PTCy or calcineurin-inhibitor (CNI) based GVHD prophylaxis, that were reported to the Center for International Blood and Marrow Transplant Research between 2014 and 2021. The primary end point was overall survival (OS). Among 14 662 HCT recipients, 3746 received PTCy- and 10 916 CNI-based prophylaxis. In patients receiving PTCy-based HCT, the adjusted 5-year OS was similar between MSD and other donor types: 44% after MSD versus 52% after MUD (multivariable hazard ratio [HR]: 1.20; 95% confidence interval [CI], 1.03-1.41; P = .09), 45% after haplo donor (HR, 1.02; 95% CI, 0.88-1.18; P = 1.00), and 46% after MMUD (HR, 1.00; 95% CI, 0.83-1.21; P = 1.00). Compared with MSD, use of MUD associated with improved disease-free survival (DFS) with PTCy-based (HR, 1.21; 95% CI, 1.05-1.40; P = .048) and CNI-based (HR, 1.09; 95% CI, 1.04-1.15; P < .01) prophylaxis. Haplo donor use associated with worse OS compared with MUD use with PTCy (HR, 1.18; 95% CI, 1.05-1.33; P = .04). Older MSDs result in similar OS compared with younger alternative donors; however, use of a younger MUD associated with improved DFS in older-aged recipients.

Resistance to venetoclax (VEN)-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical VEN resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis, inclusive of 678 patients, comprehensively characterized the prognostic role of monocytic differentiation in patients with AML treated with hypomethylating agents combined with VEN. AML genetics and monocytic differentiation (HR = 1.89; 95% confidence interval, 1.35–2.66; P < 0.001) in NPM1 wild-type cases correlated with an increased risk of death, clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and antiapoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and antiapoptotic protein expression highlights the complementary role these factors impart following VEN-based therapy. Significance: AML with monocytic differentiation often occurs in the context of co-occurring mutations within signaling pathways. In certain AML subgroups (such as NPM1 wild-type and signaling pathway gene–mutated), a monocytic phenotype is associated with decreased overall survival following VEN-based therapy. See related commentary by Renders, p. 403

Acute myeloid leukemia (AML) is a complex hematopoietic clonal disorder with limited curative options beyond stem cell transplantation. The success of transplant is intimately linked with the graft versus leukemia effect from the alloreactive donor immune cells including, T and NK cells. The immune system plays a dynamic role in leukemia survival and resistance. Despite our growing understanding of the immune microenvironment, responses to immune-based therapies differ greatly between patients. Herein, we review the biology of immune evasion mechanisms in AML, discuss the current landscape of immunotherapeutic strategies, and discuss the implications of therapeutic targets. This review focuses on T and NK cell-based therapy, including modified and non-modified NK cells, CAR-T and CAR-NK cells, antibodies, and checkpoint blockades. Understanding the complex interchange between immune tolerance and the emergence of tumor resistance will improve patient outcomes.

The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state–independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses. Significance: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care. See related commentary by Becker, p. 437 . This article is featured in Selected Articles from This Issue, p. 419

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for older adults with hematologic malignancies. Concerns on nonrelapse mortality (NRM) in older adults limit allo-HCT utilization. We executed a prospective, observational study BMT-CTN 1704 (Blood and Marrow Transplant Clinical Trials Network) enrolling allo-HCT recipients aged ≥60 years from 49 centers in the United States. We analyzed associations between 13 measurements of older adult health and NRM within 1 year to construct a comprehensive health assessment risk model (primary-CHARM) using multivariate Fine-Gray model and grouped penalized variable selection. Two machine learning (ML) models (Cox and pseudo-value boosting) were also explored. Models’ performances were compared using area under the curve (AUC), with bootstrap and cross-validation sampling to correct for optimism, decision curve analysis (DCA), calibration, and Brier scores. Among 1105 patients with median age of 67 (range, 60-82) years who received allo-HCT, NRM was 14.4% and overall survival (OS) 71.7% at 1 year. Factors statistically selected for inclusion in primary-CHARM were higher comorbidity burden, lower albumin, higher C-reactive protein, older age, higher weight-loss percentage, lower patient-reported performance score, and cognitive impairment. Primary-CHARM scores were independently associated with higher NRM (hazard ratio [HR], 2.72; P < .0001) and worse OS (HR, 2.09; P < .0001). Bootstrap bias–corrected AUC for primary-CHARM was 0.591. Comparing primary-CHARM with HCT-comorbidity index and 2 ML-CHARM models, calibration, Brier score, and DCA analysis favored primary-CHARM. Primary-CHARM, with mostly simple and readily available parameters, risk stratifies older adults for allo-HCT. Adopting primary-CHARM in practice may promote broader use of HCT by quantifying risk and enhance the design of strategies to improve outcomes. This trial was registered at www.ClinicalTrials.gov as #NCT03992352.