PURPOSE:As risk stratification for patients with AML treated with lower-intensity venetoclax-based therapy remains suboptimal, we developed and validated a prognostic model integrating clinical, cytogenetic, and molecular features. METHODS:We assembled a multinational data set comprising 2,092 adults with newly diagnosed AML treated with hypomethylating agents plus venetoclax (HMA + VEN). One thousand nine hundred eighteen patients with complete data were randomly divided into training (70%) and internal validation (30%) cohorts. Two independent external validation cohorts were assembled (n = 500 and n = 222). Modeling overall survival (OS), Elastic Net regression was applied in 1,000 bootstrap samples from the training cohort to select variables for a Ridge regression, which generated a continuous Prognostic Risk Integration for Survival Modeling (PRISM) score and risk categories based on tertiles (PRISM-3: low, moderate, high). These PRISM indices were then computed for the validation cohorts and compared with the 4-gene classifier (based on mutations in FLT3-ITD, N/KRAS, and TP53). RESULTS:PRISM integrated 17 clinical and genomic variables and demonstrated a linear association with OS. PRISM-3 stratified survival consistently across all cohorts (median OS: 25.1-28.8 months for low risk, 12.5-14.7 months for moderate risk, and 5.8-6.7 months for high risk; P < .001). Compared with the 4-gene classifier, PRISM-3 reassigned approximately 40% of patients (and >50% of those with favorable risk) and demonstrated significantly better discrimination in validation cohorts (C-index 0.63-0.65 v 0.59-0.61; P < .05). CONCLUSION:PRISM is a validated prognostic model for patients with AML receiving HMA + VEN that improves survival risk stratification beyond current standard tools and supports individualized, risk-adapted clinical decision making. The model, the PRISM-AML Risk Calculator, is publicly available.

Abstract FLT3-internal tandem duplication measurable residual disease testing for patients in remission from acute myeloid leukemia is now recommended by the recently updated clinical standard-of-care guidelines. This companion technical note provides important laboratory and clinical recommendations regarding such testing.

Comparison of SF3B1-mutated MDS with del(5q) to subclonal SF3B1-mutated MDS without del(5q). (A-F) No significant differences in baseline clinical demographics or SF3B1 VAF were observed between cases with vs. without del(5q). (G,H) Whilst survival was superior in patients with clonal SF3B1 mutations, no significant difference in leukemia-free or overall survival was identified between cases of SF3B1-mutated MDS with del(5q) vs. subclonal SF3B1-mutated MDS without del(5q), suggesting survival outcomes in such cases are influenced by alternative molecular driver events. Reported p-values utilized the cox model Wald test.

WHO 2016 classification of included patients with mutated SF3B1

Molecular characteristics of SF3B1-mutated MDS. (A) Mixed violin/boxplot depicting the VAF of SF3B1 in patients with clonal vs. subclonal SF3B1 mutations. Box and whisker plot demonstrates median (solid bar), interquartile range, minimum, and maximum VAF values. (B) The number of cases based on the count of co-occurring mutations between SF3B1low vs. SF3B1high MDS. (C) Distribution of identified amino acid variants within the SF3B1 protein. Variant frequency is represented as Log2 values. Location of variants displayed within HEAT domains, conserved regions (1–20) of tandem repeats within the SF3B1 protein. Canonical MDS mutations are commonly associated with domains 4 to 7 (yellow highlight). (D) Barplot depicting clonality of SF3B1low vs. SF3B1high MDS cases. (E) Barplot depicting differences in canonical and non-canonical variants between SF3B1low vs. SF3B1high MDS. (F) Alternative SF3B1 variants identified in SF3B1low vs. SF3B1high MDS. VAF: variant allele frequency. Asterisk indicates Fisher’s exact p-value <0.05.

WHO 2016 classification of included patients with NPM1-mutated myeloid neoplasms (MN)

Venetoclax and hypomethylating agent combination therapy is now the standard of care in acute myeloid leukemia (AML) for patients ineligible for intensive therapy, including the elderly; however, venetoclax and low-dose cytarabine remain a viable option for select patients. Relapse in this cohort remains a significant challenge, with a poor prognosis and an unmet need for further treatment options. This case discusses an elderly patient with NPM1-mutated AML successfully retreated with time-limited venetoclax and low-dose cytarabine at relapse. The sustained response observed contributes to the limited literature on the efficacy of re-treatment with venetoclax-based therapy in this setting. However, prospective data are required to assess the efficacy and safety of this strategy as well as to establish the role of molecular monitoring. The role of time-limited venetoclax therapy for preventing treatment resistance and limiting treatment-related adverse effects remains an important question in the cohort ineligible for intensive therapies, given the poor prognosis and limited options of relapsed/refractory AML post-venetoclax and hypomethylating agent therapy.

NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) is generally classified as favorable-risk under the 2022 European LeukemiaNet (ELN-2022) guidelines, except in the presence of FLT3-internal tandem duplication or adverse-risk cytogenetics. However, the prognostic significance of co-occurring myelodysplasia-related gene (MRG) mutations remains unclear, with prior studies yielding inconsistent results. To clarify this issue, we conducted a systematic review and meta-analysis in accordance with PRISMA guidelines, searching PubMed, Embase, and MEDLINE through March 2025. MRG mutations were defined as pathogenic variants in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and RUNX1, and the primary analysis incorporated studies regardless of RUNX1 inclusion. Data from ten cohorts across nine studies (one of which included an independent validation cohort), encompassing a total of 4,363 patients, were analyzed. Of these, 655 patients (15.0%) harbored co-occurring MRG mutations. Among the patients with ELN-2022 intermediate risk (n=1,294), 108 (8.3%) had MRG mutations. The presence of MRG mutations was significantly associated with inferior overall survival (pooled hazard ratio [HR] 1.30; 95% confidence interval [CI], 1.11–1.51; p

Density plot depicting Bradley-Terry modeling of the estimated order of mutation acquisition in AML samples from the UKNCRI and AMLSG cohorts. Mutations in genes classified as MR mutations (SRSF2, ASXL1, RUNX1, U2AF1, ZRSR2, EZH2, STAG2, BCOR, SF3B1) tended to occur as earlier events relative to mutations in NPM1. VAF: Variant allele frequency

Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key endpoint in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the ELN 2022 genetic risk classification. Developed by members of the ELN-DAVID consortium, the guidelines incorporate expert consensus determined through a two-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity (UHS) NGS-based MRD assessment is now recommended for FLT3-ITD-mutated AML following intensive chemotherapy and prior to allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.

Comparison of SF3B1-mutated MDS groups with SF3B1a and SF3B1b subgroups. (A) Patients with SF3B1low and subclonal SF3B1 mutations were more frequently assigned to the SF3B1b subgroup (defined as having a co-occurring mutation in any gene including BCOR, BCORL1, NRAS, RUNX1, SRSF2, or STAG2) compared to patients with SF3B1high or clonal SF3B1 mutations, who were more frequently assigned to the SF3B1a group (defined as having any other co-mutation with SF3B1). (B,C) Leukemia-free and overall survival was shorter in patients with SF3B1b vs. SF3B1a mutations. (D) When comparing groups stratified based on SF3B1 VAF, significant survival differences were observed (E). Multivariable analysis demonstrating differences in outcomes based on SF3B1a and SF3B1b designation, clinical parameters, and SF3B1 VAF. Reported p-values utilized the cox model Wald test.

Measurable residual disease (MRD) is an increasingly vital tool in predicting the risk of relapse in patients with acute myeloid leukemia (AML), with a growing role in directing therapeutic choices. The vast phenotypic and genomic heterogeneity of AML precludes a universal MRD assay, thereby requiring multiple complementary assays with unique advantages and limitations. This review aims to provide hematologists and pathologists with guidance in the selection, use and interpretation of MRD testing across multiple modalities. Assay characteristics, laboratory considerations and MRD targets are reviewed, accompanied by case-based discussions.

Biplot of quantitative variables included in factor analysis of mixed data (FAMD) of myelodysplastic CMML cases (MD-CMML) including platelets, bone marrow blast (BM blasts) percentage, absolute neutrophil count (ANC), absolute monocyte count (AMC), relative monocytes, hemoglobin, and patient age at diagnosis. Arrow length and direction with respect to the circle indicates relative contribution to each quadrant. Closer proximity of an arrowhead to the circle indicates a stronger contribution of a variable to the quadrant.

Overall survival in patients with ELN 2022 favorable-risk, NPM1-mutated AML based on age and co-occurring MR mutations. Patients age <60 with vs. without co-occurring MR mutations experienced inferior survival, while no significant difference in survival was observed in patients age ≥60 years. Reported p-values utilized the cox model Wald test. MR: Myelodysplasia-related mutation.

Consort diagrams of included patient populations for each analysis representing the selection of patients based on filtering criteria from the IWG-PM cohort (N = 3,323 patients), the UK NCRI (N = 2,113), and AMSLG (N = 1,540) cohorts.

Comparison of clinical and molecular demographics and survival in patients with NPM1-mutated myeloid neoplasms with <20% blasts from the UK NCRI AML17/19 trials. (A) Density plots demonstrating no significant difference in baseline age or hematologic parameters between patients with <10% vs. 10% to 19% blasts. (B) Similarly, no significant difference was observed with respect to frequently identified mutations between patients with mutated NPM1 and <10% vs. 10% to 19% blasts. (C and D) Event-free and overall-survival was similar between patients with mutated NPM1 and <10% vs. 10% to 19% blasts. Reported p-values utilized the cox model Wald test.