Abdelmagid, Maymona

ABSTRACTThe current study includes 910 patients with systemic mastocytosis (SM) seen at the Mayo Clinic from 1968 to 2024. The primary objective was to examine the prognostic contribution of the International Consensus Classification (ICC), in the context of the Mayo Alliance Prognostic System (MAPS) for SM. World Health Organization classification (WHO‐HAEM5) subcategories included (i) indolent/smoldering SM (ISM/SSM; N = 518), (ii) SM associated with another hematological neoplasm (SM‐AHN; N = 273), with the latter including both myeloid and lymphoid neoplasms, (iii) aggressive SM (ASM; N = 106), and (iv) WHO‐defined mast cell leukemia (MCL; N = 13), which included mast cells with both “mature” and “immature” morphology. The ICC‐defined subcategories were mostly similar with the exception that SM‐AHN was replaced by SM associated with another myeloid neoplasm (SM‐AMN; N = 235) and WHO‐defined MCL was replaced by ICC‐defined MCL (N = 8), which included only those with immature MC morphology. Overall survival (OS) was similar between WHO‐defined MCL (median 1.8 years) vs. SM‐AHN (median 2.3 years; p = 0.3) but significantly different between ICC‐defined MCL (median 0.08 years) vs. SM‐AMN (median 2.0 years; p < 0.01). Significant difference in OS was also apparent between ICC‐defined SM‐AMN and SM associated with lymphoid neoplasm (SM‐ALN; median 8.1 years; HR 3.4; p < 0.01). Multivariable analysis confirmed the inter‐independent prognostic contributions of both ICC‐defined morphologic subcategories and MAPS risk variables, including age > 60 years, anemia, alkaline phosphatase > ULN, and platelet count < 150 × 109/L (p < 0.03 in all instances); the same was not true for WHO‐HAEM5‐defined SM subcategories. The addition of mutational information into the multivariable model resulted in ousting anemia and inclusion of ASXL1 (p < 0.01), SRSF2 (p = 0.01), and NRAS (p = 0.01) mutations as additional risk factors. Classification of SM by ICC is prognostically more accurate, compared to WHO‐HAEM5, and strengthens the prognostic contribution of morphology to current clinical and molecular risk models.

6579 Background: Treatment strategies in chronic myelomonocytic leukemia (CMML) are not standardized and include hydroxyurea (HU) and hypomethylating agents (HMA). In a phase 3 study comparing HU and decitabine, in proliferative CMML, response rates were higher for decitabine (56% vs 31%; p<0.01) but overall survival was similar (p=0.67) between the two groups (Itzykson, R. JCO, 2023. 41:1888). In the current retrospective study, we examined the survival impact of different treatment strategies among 457 Mayo Clinic patients with CMML. Methods: The current study was conducted under institutional review board approved minimum risk protocols allowing retrospective patient data collection and analysis. Diagnostic criteria were according to the International Consensus Classification (Arber et al. Blood 2022. 140:1200). All statistical analyses were conducted using JMP 17 software. For survival analysis, patients were censored at time of allogeneic stem cell transplant (ASCT). Results: A total of 457 patients were considered (median age 72 years; 68% males). 209 patients received CMML-directed therapy: HU (N=102), HMA (N=78; azacitidine 32 and decitabine 46). Responses were adjudicated separately for leukocytosis and anemia; normalization of leukocyte count was achieved in 21% vs. 16 % (p<0.01) for HU vs. HMA and overall response in anemia in 1% vs. 9% (p=0.02), respectively. Overall survival did not appear to be impacted by different treatment strategies at any stage of CMML; (i) treated vs. untreated (p=0.3), (ii) HU vs. HMA for first-line therapy (p=0.3), and (iii) HU/HMAs vs. other drugs as first-line therapy (p=0.1). Blast transformation-free survival (BTFS) was also similar between HU vs. HMA as well as HU/HMA vs. other drugs. In univariate analysis, BTFS was inferior in patients receiving CMML-directed therapy (p<0.01); the particular association (HR 2; 95% CI 1.2-3.3) retained its significance in multivariable analysis that also included other risk factors for BTFS: bone marrow blast ≥10% (HR 4.3), circulating blast ≥2% (HR 2.7), WBC ≥13 x 10 9 /L (HR 1.8), and ASXL1 mutation (HR 1.7). Conclusions: In the current retrospective study that included a large number of patients with CMML, chemotherapy with HU or HMA did not appear to affect overall survival but might have increased the risk of blast transformation. The study also suggests superiority of HU for the treatment of leukocytosis and HMA for anemia. Predictors of blast transformation-free survival (BTFS) in 457 patients diagnosed with chronic myelomonocytic leukemia (CMML). BTFS Univariable analysis p-value (HR) Multivariable analysis p-value (HR) CMML-directed therapy <0.01 (2.9; 1.8-4.7) <0.01 (2; 1.2-3.3) Bone marrow blasts ≥10% <0.01 (12.4) 0.01 (4.3) Circulating blasts ≥2% <0.01 (5.2) <0.01 (2.7) WBC ≥13 x 10 9 /L <0.01 (2.9) 0.02 (1.8) ASXL1 mut <0.01 (2.1) 0.02 (1.7)

e18590 Background: TP53 mutations ( TP53 MUT ) are known to be associated with adverse prognosis in acute myeloid leukemia (AML) and multihit TP53 MUT in myelodysplastic syndromes (MDS). The prognostic relevance of multihit TP53 MUT in myeloproliferative neoplasms (MPN) was recently highlighted. The current study illustrates survival comparisons in multihit TP53- mutated MPN vs. AML and analysis of associated risk factors. Methods: A Mayo Clinic enterprise-wide database search identified 61 MPN and 81 AML cases with multihit TP53 MUT . Conventional statistical methods were used for analyses. Results: 142 patients with multihit TP53 MUT were included: i) chronic phase MPN (MPN-CP; N=19), ii) accelerated phase MPN (MPN-AP; N=14), iii) blast phase MPN (MPN-BP; N=28) and iv) AML, not including MPN-BP (N=81). Concomitant ASXL1 MUT , EZH2 MUT , IDH1 MUT and IDH2 MUT were more common in MPN-BP, compared to AML. At a median follow up of 0.6 years, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from time of TP53 MUT detection was similar between MPN-BP (median 4.6 months) and MPN-AP (5.6 months; p=0.5). OS in MPN-BP/AP (median 4.8 months) was inferior to that of AML (median 7.4 months; p=0.04) while that of MPN-CP (median 11.6 months) was similar to AML (0.07) but superior to that of MPN-BP/AP (p<0.01). Age-adjusted multivariable analysis (MVA) confirmed the independent prognostic significance of undergoing ASCT (HR 0.4, p=0.03), MPN-CP or achieving response to pre-transplant therapy (HR 0.2, p<0.01), and concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p<0.01) on OS. Based on these risk factors, a 3-tiered risk model was constructed: low (no risk factors; N=18; median OS 23.8 months); intermediate (1 risk factor; N=44; median 11.1 months); and high (2 or more risk factors; N=80; median 4 months; p<0.01). Comparative analysis of risk factors among distinct diseases confirmed the prognostic significance of ASCT (HR 0.3, p=0.03), achieving response to pre-transplant therapy (0.4, p<0.01) and concurrent TET2 MUT or DNMT3A MUT (HR 5.0, p<0.01) in AML. In MPN AP/BP, OS was influenced by having received chemotherapy vs. supportive care (HR 0.1; p<0.01) and achieving response to pre-transplant therapy (0.2, p<0.01). No significant risk factors for OS were identified in MPN-CP. In MVA, ASCT did not appear to influence OS in MPN AP/BP (p=0.7) and MPN-CP (p=0.4) but the number of informative cases was too low to make definitive conclusions. Conclusions: The current study highlights the equally detrimental impact of multihit TP53 MUT in securing long-term survival in MPN and AML. Short-term survival was positively influenced by ASCT, at least in AML, and disease stage or remission status at time of mutation detection and ASCT, respectively.

e18600 Background: Recent studies have suggested that basophilia in myeloproliferative neoplasms (MPN), in general, and in primary myelofibrosis (PMF), in particular, might be associated with poor prognosis. In the current study, we examined for clinical and genotype correlates as well as the prognostic impact of absolute eosinophil (AEC) and basophil (ABC) counts in essential thrombocythemia (ET) and polycythemia vera (PV). Methods: Diagnostic criteria were according to the International Consensus Classification. Study patients were selected based on the availability of information on AEC and ABC. Institutional reference range for AEC was 0.03 to 0.48 x 10 9 /L and for ABC 0.01 to 0.08 x 10 9 /L. "Eosinophilia" was defined as an AEC of ≥0.5 x 10 9 /L. "Basophilia" was evaluated both at an ABC of ≥0.1 x 10 9 /L and ABC of ≥0.3 x 10 9 /L, the latter representing 3 x the upper limit of the normal reference range. Results: Essential thrombocythemia 660 patients were considered. Median (range) values for AEC and ABC were 0.2 x 10 9 /L (0-2.8) and 0.07 x 10 9 /L (0-1.7), respectively. On univariate analysis, AEC and ABC, as continuous variables, were predictive of inferior overall (OS; p<0.01 for both) but not leukemia-free (LFS), myelofibrosis-free (MFFS), venous thrombosis-free (VTFS), or arterial thrombosis-free (ATFS) survival. In univariable analysis, AEC ≥0.5 x 10⁹/L and ABC ≥0.1 x 10⁹/L negatively impacted OS (p<0.01 for both); significance was sustained during multivariate analysis that included IPSET risk variables: AEC ≥0.5 x 10⁹/L (p<0.01; HR 1.9) and ABC ≥0.1 x 10 9 /L (p<0.01; HR 1.7). Polycythemia vera 478 patients were considered. Median (range) values for AEC and ABC were 0.27 x 10 9 /L (0-6.5) and 0.12 x 10 9 /L (0-3.2), respectively. In univariable analysis, neither AEC nor ABC, as continuous variables were predictive of OS, LFS, MFFS, VTFS, or ATFS. AEC ≥0.5 x 10⁹/L also did not have any impact on disease progression or thromboses. However, ABC ≥0.1 x 10 9 /L was associated with a lower risk of post-diagnosis arterial thrombosis (p=0.03; HR 0.6), and ABC ≥0.3 x 10 9 /L was predictive of inferior LFS (p<0.01; HR 6.5) and MFFS (p<0.01; HR 2.5). ABC ≥0.3 x 10 9 /L sustained prognostic relevance in LFS (p<0.01; HR 7.6) during multivariable analysis that included leukocytosis, platelet count, basophil percentage, age, and palpable splenomegaly. Similar findings were noted with regards to MFFS for ABC ≥0.3 x 10 9 /L (p=0.01; HR 2.3) when compared against palpable splenomegaly and age. Conclusions: The current study suggests that AEC ≥0.5 x 10 9 /L and ABC ≥0.1 x 10 9 /L in ET are independently associated with shortened overall survival, while basophilia (ABC ≥0.3 x 10 9 /L) in PV is an independent predictor of leukemic and myelofibrotic disease progression.

ABSTRACTPolycythemia vera (PV) is invariably associated with a JAK2 mutation, with over 50% of patients harboring additional non‐JAK2 mutations. In the current study, 319 patients with PV underwent NGS at diagnosis or in chronic phase PV (Group A: N = 270, 85%) or at the time of fibrotic (Group B; N = 37, 12%) or leukemic (Group C; N = 12, 4%) transformation. Mutational frequencies involving TP53/SRSF2/IDH1/U2AF1 were significantly (p < 0.05) different between patients in the mutually exclusive Groups A (2%/4%/2%/0.4%), B (8%/0%/0%/5%), and C (50%/25%/17%/8%). Analyses on phenotype/genotype associations and prognostic impact on overall (OS), leukemia‐free (LFS), and myelofibrosis‐free (MFFS) survival were limited to Group A patients. ASXL1MUT was associated with younger age (p < 0.01), SRSF2MUT with older age and leukocytosis (p < 0.01), and TP53MUT with leukocytosis (p < 0.01). Mutation co‐segregation was apparent between ASXL1 and IDH2 (p < 0.01) or SRSF2 (p < 0.01), SRSF2 and IDH2 (p < 0.01), and TP53 and NRAS (p = 0.01). Multivariable analysis identified SRSF2MUT (p < 0.01; HR, 4.2, 1.9–9.5), IDH2MUT (p = 0.01; HR, 5.3, 1.8–15.3), ASXL1MUT (p = 0.04; HR, 2.0, 1.1–3.7), leukocyte count ≥ 15 × 109/L (p < 0.01; HR 2.0, 1.3–3.1), and advanced age (p < 0.01) as risk factors for OS. Median OS in the presence (N = 235; 87%) or absence (N = 35; 13%) of any adverse mutation (i.e., SRSF2MUT, ASXL1MUT, or IDH2MUT) was 8.8 versus 17.8 years (p = 0.01; HR 1.8, 1.1–2.9). In addition, ASXL1MUT (p = 0.02; HR, 1.6–24.9), SRSF2MUT (p = 0.06; HR, 11.9, 1.1–126.2), and advanced age (p = 0.04) were associated with inferior LFS, and SRSF2MUT (p < 0.01; HR, 24.0, 5.5–103.8) and abnormal karyotype (p < 0.01; HR 3.8, 1.6–8.9) with inferior MFFS. The number of non‐JAK2 mutations was significant in predicting outcome in univariate but not multivariable analysis. The observations from the current study highlight the prognostic significance of non‐JAK2 mutations in PV and the prospect of their inclusion in future prognostic models.

We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.

ABSTRACTA total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53 MUT) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN‐CP; N = 19), (ii) accelerated phase MPN (MPN‐AP; N = 14), (iii) blast phase MPN (MPN‐BP; N = 28), and (iv) AML (N = 81). Concurrent ASXL1 MUT, EZH2 MUT, IDH1,MUT and IDH2 MUT were more common in MPN‐MUTBP‐mTP53 compared to AML‐mTP53 MUT. At median of 11.6 months follow‐up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of mTP53 MUT detection, was similar between MPN‐BP‐mTP53 MUT (median 4.6 months) and MPN‐AP‐mTP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN‐CP‐mTP53 MUT (11.6 months, p < 0.01). OS in MPN‐CP‐mTP53 MUT was similar to that of AML‐mTP53 MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre‐transplant chemotherapy (HR 0.2, p < 0.01) and unfavorably by the presence of concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p < 0.01). Based on these risk factors, a 3‐tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p < 0.01). The current study highlights the equally detrimental impact of mTP53 MUT on long‐term survival in MPN and AML and identifies predictors of short‐term survival.

ABSTRACT The clinical relevance of TP53 mutations ( TP53 MUT ) in myeloproliferative neoplasms (MPN) and their prognostic interaction with MPN subtype designation has not been systematically studied. In the current study, 114 patients with MPN harboring TP53 MUT (VAF ≥ 2%) were evaluated for overall survival (OS), calculated from the time of TP53 MUT detection: chronic phase myelofibrosis (MF‐CP; N = 61); blast‐phase (MPN‐BP; N = 31) or accelerated‐phase (MPN‐AP; N = 16) MPN, and polycythemia vera/essential thrombocythemia (PV/ET; N = 6). Sixty‐five (57%) patients harbored International Consensus Classification (ICC)‐defined multihit TP53 MUT and 56 (49%) monosomal/complex karyotype (MK/CK). Majority of MPN‐BP (90%) and MPN‐AP (81%) while 39% of MF‐CP and none of PV/ET patients harbored multihit TP53 MUT . OS in MPN‐BP and MPN‐AP was equally dismal (median 6 vs. 4.5 months, respectively; p = 1.0), regardless of multihit configuration ( p = 0.44), while OS in TP53 MUT MPN‐BP/AP ( N = 47; median 4 months) was inferior to that of a separate cohort ( N = 49) with TP53 wild‐type MPN‐BP/AP (median 11 months; p < 0.01). OS in MF‐CP was significantly shorter with multihit versus non‐multihit TP53 MUT (median 10 vs. 35 months; HR 2.9; p < 0.01), independent of other MF‐relevant genetic risk factors, including ASXL1/SRSF2/U2AF1 mutations. Multihit TP53 MUT was also associated with inferior survival following allogeneic stem cell transplant (ASCT): median 9 months versus “not reached” in patients with ( N = 9) versus without ( N = 8) multihit TP53 MUT ( p < 0.01). The presence of multihit or non‐multihit TP53 MUT in MPN‐BP/AP or multihit TP53 MUT in MF‐CP is associated with exceptionally poor prognosis and justifies inclusion into the ICC category of “myeloid neoplasms with mutated TP53 .” By contrast, detection of non‐multihit TP53 MUT , by itself, might not endanger short‐term survival in MF‐CP, PV, or ET.

ABSTRACT Patients with newly diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax + hypomethylating agent (Ven‐HMA) therapy. The primary objective in the current study was to develop genetic risk models that are predictive of survival and are applicable at the time of diagnosis and after establishing treatment response. Among 400 ND‐AML patients treated with Ven‐HMA at the Mayo Clinic, 247 (62%) achieved complete remission with (CR) or without (CRi) count recovery. Multivariable analysis–derived hazard ratios (HR), including 1.8 for European LeukemiaNet (ELN) adverse karyotype, 4.7 for KMT2Ar , 1.7 for TP53 MUT , 2.6 for KRAS MUT , and 2.1 for IDH2 WT were applied to develop an HR‐weighted risk model: low, intermediate, and high; respective median survival censored for allogeneic stem cell transplant (ASCT) (3‐year survival) were “not reached” (67%), 19.1 (33%), and 7.1 months (0%). In patients achieving CR/CRi, adverse karyotype, KMT2Ar , KRAS MUT , IDH2 WT predicted inferior survival, allowing for a complementary response‐stratified risk model. The model was externally validated and was shown to be superior to the ELN 2024 risk model (AIC 179 vs. 195 and AUC 0.77 vs. 0.69). Survival was inferior with failure to achieve CR/CRi or not receiving ASCT; 3‐year survival for high‐risk with or without ASCT was 42% versus 0% ( p < 0.01); intermediate 72% versus 43% ( p = 0.06); and low‐risk 88% versus 78% ( p = 0.53). The Mayo genetic risk models offer pre‐treatment and response‐based prognostic tools for ND‐AML treated with Ven‐HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

Background Venetoclax + hypomethylating agent (Ven-HMA) therapy results in favorable response rates (CR/CRi 66%) and overall survival (OS; median 14.7 months) in unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML; N Engl J Med 2020;383). However, there is substantial heterogeneity in individual patient outcomes based on response to treatment. The objective of the current study was to develop a genetic risk model to predict survival outcome in treatment responders and non-responders, analyzed separately, and also account for allogeneic stem cell transplant (ASCT). Methods Treatment-naïve AML patients receiving Ven-HMA, outside of a clinical trial, at the Mayo Clinic, USA (MN, AZ, FL) were retrospectively recruited. Molecular studies (48-gene panel) were performed by next-generation sequencing. Response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Blood 2022;140). Standard statistical analyses were performed using JMP Pro (Version 17.0.0). Results 400 ND-AML patients (median age 73 years, 64% male, 60% de novo) received Ven-HMA. ELN cytogenetic risk included favorable 2%, intermediate 60%, or adverse 38%. Mutations involved TP53 in 26%, TET2 19%, RUNX1 19%, SRSF2 18%, ASXL1 18%, DNMT3A 15%, K/NRAS 13%, NPM1 12%, IDH2 12%, FLT3-ITD 10%, IDH1 7% and DDX41 in 4% of informative cases. 153 (38%) patients achieved CR, 94 (24%) CR with incomplete count recovery (CRi), resulting in CR/CRi in 247 (62%) patients. CR/CRi rates were higher with NPM1 (86% vs 59%), IDH2 (77% vs 60%), and DDX41 mutations (93% vs 61%) and lower with TP53 (45% vs 67%), FLT3-ITD (41% vs 64%), RUNX1 (49% vs 65%) mutations and adverse karyotype (48% vs 71%), with all retaining significance in multivariable analysis. CR/CRi rate was highest (87%) in 75 patients with one or more favorable mutations (NPM1, IDH2, DDX41) and no unfavorable mutation (TP53, FLT3-ITD, RUNX1). CR/CRi rate was lowest in 171 patients with at least one unfavorable mutation and no favorable mutation (44%; p&lt;0.01). After a median follow up of 10.5 months (0.5-66), 105 relapses (43% of patients in CR/CRi), 248 (62%) deaths and 65 (16%) ASCT were documented. Univariate analysis for transplant-censored OS disclosed superior survival in patients achieving CR/CRi (median 21 vs 3.6 months; HR 5.4, 95% CI 4.1-7.1). Among patients achieving CR/CRi, IDH2 mutation was associated with superior (median not reached vs 20.5 months) and male gender (median 17.6 vs 29.2 months), TP53 mutations (median 11.9 vs 24.3 months) and adverse karyotype (median 12.6 vs 29.4 months) with inferior survival; multivariable analysis resulted in HRs (95% CI) of 2.1 (1.3-3.4) for male gender, 2.1 (1.2-3.8) for adverse karyotype, and 2.5 (1.1-5.7) for absence of IDH2 mutations. Male gender did not show an association with karyotype, or TP53 mutations (p&gt;0.1). Accordingly, an HR-weighted genetic risk model was generated with assignment of one point each to male gender, adverse karyotype, and absence of IDH2 mutation: high risk = 3 risk factors (n=38; median 9.6 months; 3-year survival 0%); intermediate risk = 2 risk factors (n=129; median 22 months; 3-year survival 38%); and low-risk = ≤1 risk factor (n=78; median not reached; 3-year survival 69%; p&lt;0.01). In patients bridged to ASCT (n=60), post-transplant survival was inferior in the presence of ≥ 2 risk factors (n=42; median 46 months) vs. ≤1 risk factor (n=18; median not reached; p=0.1). In patients not achieving CR/CRi, risk factors for OS included male gender (median 3.4 vs 6.1 months), adverse karyotype (median 3.3 vs 4.5 months) and TP53 mutation (median 3.1 vs 4.5 months) while those with IDH2 mutations lived longer (median 8.4 vs 3.4 months). In multivariable analysis, HRs (95% CI) were 1.9 (1.3-2.9) for male gender, 2.0 (1.4-2.9) for adverse karyotype, and 2.1 (1.1-4.3) for absence of IDH2 mutations. OS was shortest for non-responders harboring 3 risk factors (n=45; median 3 months; 1-year survival 0%) and longer for those harboring two (n=80; median 6 months, 1-year OS 15%) or ≤ 1 risk factor (n=25; median 14 months; 1-year OS 56%; p&lt;0.01). Conclusion The current study describes a molecular profile for predicting response to Ven-HMA in ND-AML and also introduces a novel approach to survival prediction that considers treatment response as the starting point. In both responders and non-responders, male gender and adverse karyotype were identified as unfavorable and IDH2 mutation favorable risk factor for OS.