Spectrum of clonal hematopoiesis in VEXAS syndrome.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic autoinflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 patients with VEXAS for CH in their peripheral blood (PB) and correlated the findings with clinical outcomes in 77 of them. UBA1mut were most common at hot spot p.M41 (median variant allele frequency [VAF] = 75%). Typical CH mutations cooccurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mut was the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed 2 major patterns: with either typical CH preceding UBA1mut selection in a clone (pattern 1) or occurring as an UBA1mut subclone or in independent clones (pattern 2). VAF in the PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.

TP53 variant allele frequency and therapy-related setting independently predict survival in myelodysplastic syndromes with del(5q).

Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.

Cardiac events in newly diagnosed acute myeloid leukaemia during treatment with venetoclax + hypomethylating agents.

Among 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.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Cladribine plus cytarabine plus venetoclax in acute myeloid leukemia relapsed or refractory to venetoclax plus hypomethylating agent.

Not available.

Prognostic impact of SF3B1 mutation and multilineage dysplasia in myelodysplastic syndromes with ring sideroblasts: a Mayo Clinic study of 170 informative cases.

The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RS-MLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (p<0.01) but not between MDS-RS with and without SF3B1 mutation (p=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (HR 1.8, 95% CI 1.1-2.8; p=0.01) and also identified age (p<0.01), transfusion need at diagnosis (p<0.01), and abnormal karyotype (p<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (p<0.01), RUNX1 (0.02) and IDH1 (p=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDSSF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutationbased, disease classification for MDS-RS might be prognostically more relevant.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Aspirin therapy is associated with a lower risk of pregnancy loss in both JAK2- and CALR-mutated essential thrombocythemia-A Mayo Clinic study of 200 pregnancies.

Two-hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990-2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704-369 × 109/L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first-trimester loss was predicted by prior fetal loss (43% vs. 18%; p < .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p < .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p < .01) risk scenarios. The benefit of aspirin therapy, in preventing first-trimester loss, was significant in both JAK2-mutated (18% vs. 50%; p < .01) and CALR-mutated (8% vs. 43%; p < .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first-trimester loss in ET, independent of driver mutation status or other risk factors.

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases.

The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.

Reappraisal of mast cell leukemia based on a single institution review of 16 cases: Mast cell morphology determines clinical outcome.

Cytologic abnormalities of atypical mast cells in mastocytosis. The mature mast cells have oval-shaped nuclei, cytoplasmic hypogranulation and spindle-shaped cytology. or well-differentiated displaying a round nucleus with condensed chromatin, and abundant dense cytoplasmic granulations. Immature mast cells include promastocytes and metachromatic blast-like forms.

Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.

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.

Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival.

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).

The clinical and molecular spectrum of ETV6 mutated myeloid neoplasms.

ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high-risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia-related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co-mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild-type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia.

Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival.

We retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor-naïve at the time of study entry to a phase-1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple-negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex-adjusted reference range (n = 72), 48% of those with hemoglobin <10 g/dl (n = 54), and 46% of those who were transfusion-dependent at the time of study entry (n = 28). Anemia response was more likely with post-essential thrombocythemia MF (83% vs 37%; p = .001), lower serum ferritin (p = .003), and shorter time from diagnosis to momelotinib therapy (p = .001); the first two variables were also predictive in transfusion-dependent patients. Post-momelotinib median survival was 3.2 years; in univariate analysis, survival was superior in anemia responders (median 3.8 vs. 2.8 years; p = .14) and in the presence of type 1/like CALR mutation and inferior in the presence of age > 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS-plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p = .02; HR 0.5, 3/5/10-year survival; 69%/38%/25%). This survival advantage was also noted in transfusion-dependent patients (3.7 vs. 1.9 years; p = .01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short-term survival benefit associated with anemia response in momelotinib-treated patients with MF.

A phase II study of combination daunorubicin, cytarabine (Ara-c), and nilotinib (TAsigna) (DATA) in patients newly diagnosed with acute myeloid leukemia with KIT expression.

Acute myeloid leukemia (AML) is a challenging cancer in terms of achieving and maintaining long-duration remissions. Many novel therapies have been added to the standard regimen (combining cytarabine and anthracycline "7 + 3") to achieve such goals. Nilotinib is an oral multikinase inhibitor that is active against KIT tyrosine kinase, an important stem cell target. In this trial, we combined nilotinib with 7 + 3 induction (daunorubicin 60 mg/m2), high-dose cytarabine consolidation, and subsequently, if the patient was a candidate, for 2 years' maintenance therapy in patients with AML and KIT (CD117) expression. Patients were allowed to proceed to allogeneic hematopoietic cell transplantation (HCT) if deemed necessary. Our primary goal was increased complete remission rate with this combination. Thirty-four patients (with a median age 58.5 years) were enrolled on a single-arm phase II bi-institutional study; 21 (62%) patients achieved remission. The complete remission rate was 78% in evaluable patients. Thirteen of 34 (38%) patients had allogeneic HCT, all thirteen of which are still alive (100%). Common (>20%) grade 3 non-hematological toxicities included febrile neutropenia, hypophosphatemia, elevated liver enzymes, and hypertension. Only one patient (3%) died in induction due to liver failure, which was thought secondary to daunorubicin. Our current study reveals good outcomes in patients who received HCT and may warrant a larger study to confirm our findings in that specific population.

Cladribine therapy for advanced and indolent systemic mastocytosis: Mayo Clinic experience in 42 consecutive cases.

We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment-emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.

Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases.

We retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv-SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM-AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3-41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM-AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow-up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5-123) and response duration 21.5 months (range 2.9-123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.

Outcomes following venetoclax-based treatment in therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN. We retrospectively analyzed 378 t-MN patients, of which 96 (25.4%, 47 therapy-related acute myeloid leukemia, 1 therapy-related chronic myelomonocytic leukemia, 48 therapy-related myelodysplastic syndrome) received venetoclax. Median interval from t-MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7-12) months, and patients received a median of 3 (IQR 1-4) cycles. The composite complete remission (CRc) rate, median progression-free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53-status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53-mutated clone. In a propensity-matched analysis, the use of venetoclax-based regimen as the first-line therapy was associated with a superior survival compared to hypomethylating agent (HMA)-based first-line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t-MN phenotypes.

A dynamic 3-factor survival model for acute myeloid leukemia that accounts for response to induction chemotherapy.

The current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre-treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively-treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy-related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow-up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1-4.8), adverse karyotype (2.2, 1.8-2.8), and age >55 years (2.1, 1.6-2.7) as main risk factors for survival. HR-weighted scoring resulted in four-tiered risk stratification: low (0 points; N = 183), intermediate-1 (1 point; N = 331), intermediate-2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5-year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3-ITD mutation was associated with inferior survival in intermediate-1 (p = .004) and TP53 in intermediate-2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3-ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate-1 (p < .001), intermediate-2 (p = .03), and high (p = .01) risk disease. The proposed 3-factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively-treated AML patients.