McCullough, Kristen

Introduction: Telomere biology disorders (TBD) are multisystemic accelerated aging syndromes due to abnormal telomere length (TL) shortening and increased cancer risk. Pediatric-onset TBD is characterized by severely shortened TL and specific associations with germline pathogenic variants mainly in DKC1, TINF2, PARN genes and characteristic clinical features [bone marrow failure (BMF), abnormal nail/skin/oral mucosa]. Adult-onset TBD is genetically distinct (predominantly, TERT, TERC, and RTEL1 mutations) with varied organ involvement [interstitial lung disease (ILD), BMF, cirrhosis, or bone disease] and heterogenous outcomes. In our previous study of predominantly adult patients with short telomeres, multiple organ involvement (Mangaonkar A et al. Blood Cancer J 2021) predicted poor overall survival (OS). We sought to validate these findings in a larger, well annotated adult cohort of TBD patients. Methods: Patients with suspected TBD underwent comprehensive clinical and molecular evaluation through our TBD-dedicated clinic after regulatory approval. TL was assessed through clinical flow cytometry fluorescence in-situ hybridization (FlowFISH).Clinical and laboratory features, including pulmonary imaging, lung volumes/function testing, hepatic imaging (MR elastography/fibroscan) and bone density assessments were retrospectively abstracted. Germline and somatic genetic testing was performed on peripheral blood through targeted panels for known TBD and myeloid genes respectively. Cox proportional hazard model was used to identify significant variables that also retained independent prognostic impact. Results: Overall, 122 patients met criteria for TBD as defined by lymphocyte TL (LTL) <=10th percentile and/or a presence of a germline-TBD variant; 34 patients LTL <1st percentile, 84 1st and the 10th percentile (27 with TBD-germline variants) and 4 with only TBD-germline variants. Median age at diagnosis was 56 (18-77) years, with 72 (59%) males. Clinical features included presence of ILD (n=81, 66%), BMF (n=39, 32%), cirrhosis/hepatic fibrosis (n=19, 38%), bone disease osteopenia/osteoporosis/fractures, n=53, 70%), MDS/AML (n=11, 9%), non-hematological cancer (n=38, 31%), and head and neck cancer (n=2). Germline pathogenic variants were detected in 22 (18%), most frequently in TERT (n=10), RTEL1 (n=7) and TERC (n=2), while variants of uncertain significance (VUS) were seen in 35 (29%) patients, especially in TERT (n=20), TERC/RTEL1(n=6), NAF1 (n=4). Somatic variants in hematopoietic cells were detected in 37 (30%) patients with frequent alterations seen in DNA damage response and repair (PPM1D/TP53, n=11), and splicing component (U2AF1/SF3B1/ZRSR2, n=9) genes. At last follow-up [median of 3 (0-18) years], there were 26 (21%) deaths (most commonly, progressive ILD-18, cancer of lung/breast/pancreas-3, transplant-related complications-2). After censoring patients at the time of any transplantation (lung transplant-26, liver transplant-5, bone marrow transplant-8), the Kaplan-Meier estimate of median OS was not reached. Univariate survival analysis found adverse OS predicted by older age at diagnosis (P=0.006), presence of ILD (P=0.0002), hepatic fibrosis/cirrhosis (P=0.02), and somatic DNA repair variants (P=0.03). Multivariate model analysis found that only presence of ILD retained independent prognostic impact (HR=2, P=0.02). Among radiographic ILD subtypes, UIP was the most common (51%), followed by NSIP (10%), and others (6%), with median FEV1 of 2L (range: 0.5-4.6), FVC 2.4L (0.7-6.2), and TLC 4L (1.9-7.4). TBD-ILD patients were older (P<0.0001) with a male preponderance (P=0.03), 52 (64%) with multi-organ involvement, and had a less severe hematological phenotype [lower incidence of BMF (P<0.0001) and fetal hemoglobin elevation (P=0.01)], more frequent bone disease (P=0.0009), relatively longer telomeres in lymphocytes (P=0.04), and no particular association with any germline or somatic genetic alterations. Conclusions: Presence of ILD is an independent and significant predictor of adverse survival in adult TBD. Within adult TBD, patients with ILD represent a unique clinical subtype without any obvious genetic or pathologic correlates. Focusing on definitive therapeutic measures in this subgroup of adult TBD has the best chance to alter natural history and improve outcomes.

Background Venetoclax + hypomethylating agent (Ven-HMA) therapy has demonstrated improved outcomes in elderly/unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML) (N Engl J Med 2020;383). However, ~50% of patients who respond to Ven-HMA, eventually relapse (Am J Hematol 2024;99). In the current study we examined the prognostic contribution of gene mutations, karyotype, measurable residual disease (MRD) status and clinical risk factors for relapse in patients with ND-AML treated with Ven-HMA therapy. Methods Our study population of ND-AML was retrospectively recruited from Mayo Clinic (MN, AZ, FL), after institutional review board approval and based on documentation of complete remission with/without count recovery (CR/CRi) following Ven-HMA therapy. Relapse-free survival was determined from the time of remission to relapse or last follow-up. Survival analysis was censored for transplant. The 2022 European LeukemiaNet (ELN) criteria was used to assign cytogenetic risk and classify treatment response (Blood 2022;140). Standard statistical analyses were performed using JMP Pro (Version 17.0.0). Results 247 ND-AML patients treated with Ven-HMA (median age 73 years, 62% male, 64% de novo) who achieved CR (n=153), or CRi (n=94) were included. MRD by multiparameter flow cytometry (sensitivity 0.01%) performed at the time of CR/CRi, was negative in 117 (70%) of 166 informative cases. ELN cytogenetic risk categories at diagnosis included favorable 2%, intermediate 69%, or adverse 29%. Mutations involved TET2 21%, SRSF2 21%, TP53 19%, ASXL1 18%, DNMT3A 18%, NPM1 17%, IDH2 15%, RUNX1 15%, K/NRAS 12%, IDH1 8%, FLT3-ITD 7%, and DDX41 in 6% of informative cases. Relapse was documented in a total of 99 (40%) patients who achieved CR (39%) or CRi (41%) after a median remission duration of 6 months (1-31). Patients that relapsed within the first-year vs those that did not, were more likely to be males (75% vs 55%), MRD positive (44% vs 24%), and harbor TP53 mutations (23% vs 16%). Univariate analysis for RFS identified male gender (12 vs 29 months; p=0.02), secondary AML (10 vs 21 months; p<0.01), adverse karyotype (9 vs 22 months; p<0.01), TP53 mutations (6 vs 18 months, p<0.01) and MRD positive remission (13 months vs not reached; p<0.01) as risk factors for relapse; on the other hand, IDH2 mutations (not reached vs 15 months; p<0.01) were associated with a lower risk of relapse. Multivariable analysis confirmed male gender (HR 2.2), TP53 mutations (HR 3.0) and MRD positive remission (HR 1.7) as unfavorable predictors of relapse. Subsequently, in a three-tiered relapse prediction model, RFS was significantly inferior in the presence of three risk factors (male gender, TP53 mutations, MRD positive remission) (n=10, median 4 months), vs two (n=34, median 10 months) vs ≤ 1 risk factor (n=122, median 31 months) (p<0.01); 1-year cumulative incidence of relapse was 100%, 56%, and 26% in the presence of three, two and ≤ 1 risk factors, respectively. 50 of 99 (65%) patients received salvage therapy which included cladribine-cytarabine-Ven (n=19), intensive induction chemotherapy (n=9), FLT3 inhibitors (n=5), Ven-HMA-FLT3 inhibitor (n=1), IDH1/2 inhibitors (n=5), glasdegib-cytarabine (n=4), gemtuzumab (n=3), lenalidomide (n=1), or investigational therapies (n=3); in addition, Ven-HMA was resumed in 14 patients in whom treatment had been discontinued for a median of 5 months (2-12). Overall, 20 (31%) of patients achieved second CR/CRi and response rates were similar with intensive vs less intensive therapy (CR/CRi; 44% vs 29%; p=0.37). Median follow up after relapse was 3.4 months (1-66), during which 73 (74%) deaths, and 4 (5%) ASCT were recorded. Median transplant-censored survival was 4.2 months (1-year; 22%), and inferior in patients with adverse karyotype (median 4.6 vs 3.4 months; p=0.02), and TP53 mutations (3.6 vs 4.4; p=0.11); on the other hand, male gender (3.5 vs 6.8 months; p=0.51), MRD positive remission (4.6 vs 4.2; p=0.56), and IDH2 mutations (6.7 vs 4.2; p=0.28), did not influence post-relapse survival. Conclusions The current study identifies male gender, TP53 mutations, and MRD status as powerful predictors of relapse and proposes a relapse prediction model for ND-AML patients receiving Ven-HMA therapy. Furthermore, relapse following Ven-HMA was associated with uniformly poor outcomes, regardless of salvage treatment strategy.

Background Blast or accelerated phase myeloproliferative neoplasm (MPN-BP/AP) carries a dismal prognosis, with 3-year survival estimates of <5% (BCJ 2023;108). Patients with MPN-BP/AP were excluded from venetoclax (Ven) plus hypomethylating agent (HMA) clinical trials for acute myeloid leukemia (NEJM 2020;383:617). In the current retrospective study, we examined response patterns and long-term survival of newly-diagnosed MPN-BP/AP patients who received treatment with Ven+HMA, outside of clinical trials. Methods Newly-diagnosed patients with MPN-BP/AP treated with Ven+HMA at the Mayo Clinic, between March 2019 and May 2024, were retrospectively reviewed. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Cytogenetic and molecular studies were performed by conventional karyotype and next-generation sequencing, respectively. All patients received at least one cycle of Ven+HMA (azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5). Response was assessed according to the 2022 European Leukemia Net criteria (Blood 2022;140:1345). Standard statistical analyses were performed using JMP Pro (Version 17.1.0). Results Patient characteristics 70 patients (median age 73 years, 59% males, 48% splenomegaly >14 cm, 4% isolated myeloid sarcoma) with newly-diagnosed MPN-BP (n=58) or AP (n=12) received Ven+HMA with (n=13) or without (n=57) concomitant JAK2 inhibitor. Driver mutation distribution was 69% JAK2, 21% CALR, 6% MPL, and 4% triple negative. Mutations involved ASXL1 (31%), TP53 (28%), TET2 (28%), RUNX1 (25%), SRSF2 (18%), IDH2 (12%), U2AF1 (11%), DNMT3A (9%), IDH1 (7%), and K/NRAS (7%). Karyotype was abnormal in 50 (76%) of 66 informative cases, of which 28 (56%) were complex (CK). Median TP53 mutation variant allele frequency (VAF) was 30% (8-96%) and all evaluable cases displayed CK (n=18). Response and Survival Complete remission (CR; 21%) or CR with incomplete count recovery (CRi; 19%) was documented in 28 (40%) patients with residual MPN in 18 (64%) patients. Median response duration was 5.5 months (1-60 months). After a median follow up of 7 months (1-62 months), 48 (69%) deaths, 13 relapses (46%), and 15 (21%) allogeneic stem cell transplants (ASCT; 12 in CR/CRi) were recorded. Median overall survival (OS) was 9 months and was superior with ASCT (median 22 vs. 8 months; p=0.01). In univariate analysis, transplant-censored survival was superior with CR/CRi (12 vs. 5 months; p<0.01) and IDH1 mutation (33 vs. 8 months; p=0.04) and inferior with CK (7 vs. 10 months; p=0.05), TP53 mutation (5 vs. 10 months; p<0.01), post polycythemia vera myelofibrosis (post-PV MF) (3 vs. 9 months; p=0.01), and splenomegaly >14 cm (5 vs. 16 months; p<0.01). Multivariable analysis confirmed the negative survival impact of not achieving CR/CRi (HR 3.8; p<0.01) and presence of TP53 mutation (HR 4.0; p<0.01); median survival (1/3-year survival rate) was 3 months (10%/0%) in TP53 mutated patients not achieving CR/CRi (n=11) vs. 27 months (65%/28%) in TP53 unmutated cases achieving CR/CRi (n=19) (p < 0.01). Median survival in patients with TP53 mutations or CK who achieved CR/CRi (n=7; 7 months) was inferior to that in treatment responders without TP53 mutations or CK (n=18; 23 months; p=0.01). CR/CRi rates in the presence vs. absence of TP53 mutations were 42% vs. 39% (p=0.80) and of CK (25% vs. 50% (p=0.04). Importantly, responses in the presence of TP53 mutations or CK were too short-lived to allow successful bridging to ASCT (median 2 vs. 9 months; p<0.01). Additional predictors of inferior treatment response included splenomegaly >14 cm (24% vs. 53%; p=0.01), and post-PV MF (0% vs. 46%; p<0.01) while SRSF2 (67% vs. 34%; p=0.04) and IDH2 mutations (75% vs. 35%; p=0.03) were associated with favorable response. In multivariable analysis, CK (p=0.04) and splenomegaly >14 cm (p=0.01) remained independent predictors of inferior response. The use of concomitant JAK2 inhibitor therapy did not impact treatment response (CR/CRi 46% vs. 39%; p=0.62) or survival (median 9 vs. 8 months; p=0.71). Conclusions TP53 mutations and CK undermine the value of Ven+HMA, with or without concomitant JAK2 inhibitor, in enabling successful bridging of newly-diagnosed MPN-BP/AP to ASCT. An alternative treatment approach is advised, in the particular scenario, while the observed 3-year survival rate of 28%, in treatment responders without TP53 mutations, is encouraging.

Background: Age-related clonal hematopoiesis (ARCH) is a precursor state to blood cancers and is associated with epigenetic age acceleration (EpiAgeAccel) (Aging Cell, 2021). While ARCH in combination with AgeAccel has the highest risk for all cause mortality and cardiovascular disease, not much is known about context-relevant clonal hematopoiesis (CRCH) - CH occurring in the context of prior chemo/radiation, bone marrow failure and germline predisposition syndromes. CRCH has a unique mutational signature enriched in genes in DNA damage response and repair (TP53 and PPM1D). To answer this question, we assessed EpiAge in a prospective cohort of patients with both ARCH and CRCH. Methods: Patients were prospectively recruited for CH and EpiAge assessment from the Mayo Clinic CH clinic between 2022 and 2024. Demographic and clinical data including chronologic age, BMI, sex, blood counts, and medical history were recorded at the time of enrollment. CH status was determined using error corrected sequencing on peripheral blood (PB) DNA. All somatic variants with a variant allele frequency (VAF) ≥0.5% were considered as CH. For EpiAge analysis PB DNA was analyzed using the Illumina MethylationEPIC array. The resulting beta values were used to obtain epigenetic age estimates using Horvath's clock (Genome Biol., 2013), Hannum's Clock (Mol Cell., 2013), PhenoAge (Aging, 2018), DunedinPACE (eLife, 2022), and predicted telomere length (Aging, 2019). Results: 106 (62%) of 170 patients assessed were found to have CH, with the most frequent mutations being TET2 (19%), PPM1D (17%), DNMT3A (16%), ASXL1 (9%), and TP53 (6%); median VAF 9.5%. Except for a higher median chronologic age (68 vs 60 years, p<0.001) in the CH group, baseline characteristics including BMI, comorbidities, baseline blood counts, sex and tobacco use history were similar between the two groups. The CH group demonstrated significant EpiAgeAccel by all three clocks: Horvath (p=0.001), Hannum (p<0.001), and PhenoAge (p<0.001); with an increase in biological age of 4.9 years (95% CI 2-7.7) by Horvath clock, 4.8 years (95% CI 2.2-7.5) by Hannum clock, and 7 years (95% CI 2.9-10.5) by PhenoAge, after adjusting for chronologic age, sex, smoking status, and cancer history. CH was also associated with increased DunedinPACE of aging by 0.13 biological year per chronologic year (bioyear/chronoyear) (95% CI 0.06-0.2, p<0.001), and shortened telomere lengths by 0.24kb (95% CI 0.11-0.35, p<0.001) after adjusting for chronologic age and excluding patients with telomere biology disorders. CH patients were then further classified into ARCH-63 (59%) and CRCH-43 (41%). While the median chronological age (69 vs 67 years) was similar between the 2 groups, CRCH patients had lower Hgb [10.9g/dL vs. 13g/dL (p=0.0001)] , lower platelet [146x109/L vs. 192x109/L (p=0.0132)] and lower WBC [4.4x109/L vs. 5.2x109/L (p=0.0345)]. The median BMI, comorbidities, and tobacco use history were similar between the 2 groups. The 3 most common ARCH mutations were TET2 (20%), DNMT3A (19%), and ASXL1 (14%), while, PPM1D (27%), TET2 (18%), and DNMT3A (14%) were frequent in CRCH. There was no significant difference found in median EpiAge via Horvath (68 vs 67.5years p=0.2826), Hannum (65 vs 66 years p=0.9333), or PhenoAge (55 vs 56 years p=0.618) between ARCH and CRCH. However, DunedinPACE of aging was higher in CRCH (1.27 vs 1.18 bioyear/chronoyear p=0.0148) and median telomere length was shorter in CRCH (6.35 vs 6.49kb p=0.0247), in comparison to ARCH. Multivariable regression analysis was completed for both ARCH and CRCH compared to non-CH, adjusting for chronologic age, smoking status, and male sex. While both ARCH and CRCH demonstrated EpiAgeAccel via Horvath(5.8years p=0.0001, 3.4 years p=0.051), Hannum(5years p=0.001, 4.5 years p=0.007), and PhenoAge (6.7years p=0.002, 7.6 years p=0.002) clocks, CRCH more than doubled DunedinPACE (0.2 bioyear/chronoyear, p<0.001) of aging compared to ARCH (0.08 bioyear/chronoyear, p=0.026). CRCH also demonstrated double the decrease in telomere length (0.34kb, p<0.001) compared to ARCH (0.17kb, p=0.015). Conclusion: Our prospective CH cohort study validates the association between CH and EpiAgeAccel using several different methylation clocks and for the first time, highlights increased pace of aging and shorter telomere lengths in CRCH versus ARCH. Correlations with cardiovascular disease and mortality outcomes are ongoing.

Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN), further categorized as MD (WBC < 13 x 109/L) and MP (≥ 13 x 109/L) subtypes with an inherent risk for AML transformation (Am J Hematol 2024; 99: 1142). Hypomethylating agents (HMA), decitabine (DAC) and azacitidine, are the only FDA approved agents for the management of CMML, with complete remission rates of <20%, and a recent prospective study showing no event free survival benefit of DAC over hydroxyurea in MP-CMML (J Clin Oncol 2023; 41: 1888). TET2 mutations (TET2MT) occur in approximately 60% of CMML cases. TET2 converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), resulting in DNA demethylation (Nat Rev Gen 2017; 18: 517). IV ascorbic acid (AA) at pharmacologic concentrations demonstrates anti-cancer activity via H2O2-induced oxidative stress and DNA demethylation mediated by TET-activation. AA, a cofactor of TET2, binds to its catalytic domain, restores, and enhances TET1/2/3 activity. Given the synergistic impact of IV AA and HMA on DNA methylation, we designed a phase II clinical trial testing the safety and efficacy of standard dose decitabine and high dose IV AA in HMA-naïve CMML patients. Methods: LS1781 (NCT03418038) is an investigator-initiated, prospective, single-arm, single-institution, phase II trial assessing the safety and preliminary efficacy of high-dose IV AA in combination with DAC for patients with TET2MT CMML. DAC 20 mg/m2 Days 1-5 of each 28-day cycle is given as standard of care. With each cycle, IV AA (1g/kg, maximum 100g) is given 3 times on Days 1, 3, 5 via central line within 2 hours after DAC. Patients are encouraged to take oral AA 1000 mg once daily on non-treatment days. The primary endpoint is overall response rate determined by IWG MDS/MPN 2015 criteria after 4 cycles of therapy. Secondary endpoints include safety and side effects. Exploratory endpoints include the impact of AA on TET2MT variant allele fraction, plasma cytokine levels, DNA methylation and hydroxymethylation (as measured by Infinium MethylationEPIC array), and hematopoietic progenitor colony forming assay assessment (colony counts and impact on differentiation). Inclusion criteria include patients ≥ 18 years with TET2MT CMML, ≤1 cycle of HMA or ESA (hydroxyurea allowed), platelets ≥ 20,000/m3, ANC ≥ 500/mm3, and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Twenty-three patients will be enrolled at Mayo Clinic Rochester and the Mayo Clinic Health System, based on power calculations to demonstrate enhanced complete response and overall response rates, in comparison to those seen historically with decitabine alone. Dose modifications have been established and will be considered based on adverse events. Treatment will be discontinued for disease progression or in the event of ≥ Grade 3 adverse events that do not resolve promptly. After completion of up to 12 cycles, patients with stable disease or better may continue single agent DAC with or without oral AA. Enrollment to the trial began in February 2024, with 2 patients enrolled at the time of abstract submission.

Abstract This phase 2 trial assessed high-dose IV ascorbic acid in TET2 mutant clonal cytopenia. Eight of 10 patients were eligible for response assessment, with no responses at week 20 by International Working Group Myelodysplasia Syndromes/Neoplasms criteria. This trial was registered at www.clinicaltrials.gov as #NCT03418038.

Abstract Clonal cytopenia of undetermined significance (CCUS) is defined by a myeloid driver mutation in the context of otherwise unexplained cytopenia. CCUS has an inherent risk of progressing to myeloid neoplasm. However, it is unknown how exposure to previous cytotoxic therapy may impact the risk of progression and survival. We stratified patients with CCUS by prior exposure to DNA-damaging therapy. Of 151 patients, 46 (30%) had received cytotoxic therapy and were classified as therapy-related CCUS (t-CCUS), whereas 105 (70%) had de novo CCUS. A lower proportion of t-CCUS had hypercellular marrows (17.8% vs 44.8%, P = .002) but had higher median bone marrow blast percentages. After a median follow-up of 2.2 years, t-CCUS had significantly shorter progression-free survival (PFS, 1.8 vs 6.3 years; hazard ratio [HR], 2.1; P = .007) and median overall survival (OS; 3.6 years vs not reached; HR, 2.3; P = .007) compared with CCUS. Univariable and multivariable time-to-event analyses showed that exposure to cytotoxic therapy independently accounted for inferior PFS and OS. Despite the similarities in clinical presentation between CCUS and t-CCUS, we show that exposure to prior cytotoxic therapies was an independent risk factor for inferior outcomes. This suggests that t-CCUS represents a unique clinical entity that needs more stringent monitoring or earlier intervention strategies.

SummaryAmong 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non‐ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A‐mutated cases less likely (p < 0.01) to be affected. Treatment‐emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.

Abstract Venetoclax + hypomethylating agent (Ven‐HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND‐AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND‐AML was to identify molecular predictors of treatment response to Ven‐HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, “favorable” predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and “unfavorable” TP53 (40% vs. 67%), FLT3‐ ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy‐related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow‐up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5–4.8), adverse karyotype (1.6, 1.1–2.6), TP53 mutation (1.6, 1.0–2.4), and absence of IDH2 mutation (2.2, 1.0–4.7); these risk factors were subsequently applied to construct an HR‐weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low ( n = 130; median survival 28.9 months), intermediate ( n = 105; median 9.6 months), and high ( n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3‐tiered, CR/CRi‐based, and genetics‐enhanced survival model for AML patients receiving upfront therapy with Ven‐HMA.