Gangat, Naseema

e18523 Background: Allogeneic hematopoietic stem cell transplant (AHCT) remains the only curative option for genetically high-risk acute myeloid leukemia (AML). Venetoclax plus hypomethylating agents (Ven+HMA) is approved as frontline treatment in elderly patients with AML ( NEJM 2020; 383); however, less is known on the post-transplant outcomes following such therapy. Methods: Newly diagnosed (ND) AML patients who received Ven+HMA and underwent AHCT at Mayo Clinic from 2019 to 2024 were retrospectively recruited. Patients who required salvage therapy following Ven+HMA were excluded. Post-transplant survival (PTS) and relapse incidence were computed. Results: 55 ND-AML patients (60% male, 49% de novo , median age 69 [38-77]) received Ven+HMA (median cycles 3 [2-11]). ELN 2022 cytogenetic risk at time of diagnosis was non-adverse in 67% of patients, while 33% had adverse karyotype. Common mutations at diagnosis included: K/NRAS (88%), TP53 (26%), RUNX1 (23%), ASXL1 (16%), and IDH1/2 (17%). At the time of AHCT, 98% ( n=54 ) were in CR/CRi or MLFS; ELN cytogenetic risk was non-adverse in 91%, and adverse in 5 (9%) patients. Common mutations included: TP53 (16%), TET2 (18%), SRSF2 (15%), ASXL1 (13%), RUNX1 (18%), and DNMT3A (9%). Donor types included HLA-matched unrelated (75%), haplo-identical (11%), matched related (7%), mismatched unrelated (7%). 58% received fludarabine/melphalan conditioning and 54% GVHD prophylaxis with cyclophosphamide. At a median follow up of 25 months (0.7-68 mo), 20 patients (36%) have died, due to relapse in 10 (18%) cases. 3-year cumulative incidence of non-relapse mortality (NRM) was 17%. Median PTS was not reached (1/2/3-year survival 74%/66%/62%). Univariate analysis identified Karnofsky Performance Score <70% (3 vs. 21 months, p<0.01 ), TP53 (14 vs. 21 months p=0.02 ) and TET2 mutation at time of transplant (11 vs. 21 months , p=0.02 ) as risk factors. Multivariable analysis confirmed the prognostic impact of TP53 (HR 2.8) and TET2 mutations (HR 2.9). Age, adverse karyotype at transplant, and donor type did not impact PTS (p>0.1). 13 patients (24%) experienced post-transplant relapse; 1/2/3-year cumulative incidence of relapse was 10%, 21% and 25%, respectively. ELN-defined adverse karyotype at transplant increased risk of relapse (3 year cumulative incidence 80% vs. 17% for non-adverse , p<0.01 ). Overall, 51% of patients developed GVHD; 54%, 39% and 7% were acute, chronic GVHD and both, respectively. GVHD was protective against relapse (3 year incidence 15% vs. 36% in absence of GVHD [p=0.04]). Conclusions: Ven+HMA frontline treatment is associated with favorable post-transplant outcome in elderly ND-AML (3 year PTS 62%/cumulative incidence of relapse 25%/NRM 17%). TP53 mutation and ELN 2022-defined adverse karyotype at the time of transplant independently predicted PTS and relapse incidence, respectively.

e18508 Background: BPDCN is a rare and aggressive hematologic malignancy. Despite the advent of targeted therapies, median overall survival (mOS) remains <1 year (y) in the absence of stem cell transplant (SCT). This study evaluates clinical and molecular predictors of outcomes in a large cohort of BPDCN patients at a tertiary center. Methods: BPDCN patients seen at Mayo Clinic (AZ, FL, MN) between 2000-2024 were identified retrospectively. Analyses considered parameters at diagnosis. Next generation sequencing (NGS) was performed using a 47-gene assay. Standard statistical methods were used; calculations used R. Results: Among 69 patients, the median age was 70y (range 19-94) with male predominance (83%). At presentation, skin (80%), bone marrow (73%), lymph nodes (52%), spleen (27%), and CNS (12%) were involved; 26% had a concurrent hematologic malignancy. Among 20 cases with NGS, the median number of mutations was 3 (range 0-5), most frequently TET2 (n=16), ASXL1 (n=13), SRSF2 (n=7), and NRAS (n=5). Frontline therapy (Table) yielded a complete response (CR) rate of 63% and overall response rate of 76%. CR rates were similar among regimens, but patients who received an ALL (hyper-CVAD based) regimen (8/13) or tagraxofusp (6/9) were more likely to be bridged to SCT (6/29, p<0.01). After median follow up of 38 months (mo), mOS for all was 15 (95% CI 12-21) mo; 44 (64%) were deceased at last follow up. Among 62 evaluable patients, 20 (32%, median age 60 vs 74y, p<0.01) underwent SCT which improved survival (mOS 51 vs 10 mo, 3y OS 52% vs 5%, p<0.01); mOS was not different between allogeneic (n=17) and autologous (n=3) SCT (54 vs 38 mo, p=0.45). When censored for SCT, the 1y OS for patients receiving an ALL regimen, tagraxofusp, or other regimen was 82%, 67%, and 47%, respectively (p=0.15). In univariate analysis, age ≥50y, lymph node involvement, bone marrow involvement, hemoglobin <10 g/dL, leukocytes (WBC) >11 x10 9 /L, abnormal karyotype, and HCT were significantly associated with OS. In multivariate analysis, WBC >11 x10 9 /L (HR 3.7, p<0.03), abnormal karyotype (HR 5.4, p<0.01), and SCT (HR 0.23, p<0.01) remained significant. Separately, SRSF2 mutation was associated with inferior OS (15 vs 51 mo, p=0.02), but significance was lost when adjusted for age, abnormal karyotype, and SCT. Conclusions: Newly-diagnosed BPDCN patients treated with an ALL regimen or tagraxofusp followed by SCT had longer OS compared to those treated with all other regimens. WBC >11 x10 9 /L and abnormal karyotype were independent predictors of inferior survival whereas SCT was beneficial. Regimen N Age (y) ANNOVA CR Chi Sq HCT Chi Sq 1y OS mOS (mo) Log-rank Tagraxofusp 9 68 (40-70) <0.001 7 (78%) 0.548 6 (67%) 0.018 88% 20.8 0.121 ALL 13 43 (20-72) 8 (67%) 8 (62%) 74% 50.7 Hyper-CVAD 11 43 (20-72) 6 (60%) 6 (60%) 67% 35.8 AML 18 70 (48-80) 13 (76%) 5 (28%) 58% 14.2 Intensive 8 66 (48-77) 7 (88%) 3 (38%) 57% 12.4 HMA+Venetoclax 8 69 (65-80) 6 (75%) 2 (25%) 50% 14.0 Lymphoma 8 74 (49-85) 3 (43%) 1 (13%) 50% 14.0 CHOP 6 74 (49-85) 3 (50%) 1 (17%) 50% 17.7 Other 3 66 (63-73) 1 (33%) 0 (0%) 33% 12.0

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)

6558 Background: Allogeneic stem cell transplantation (ASCT) is currently the only curative therapy in chronic myelomonocytic leukemia (CMML). Methods: A Mayo Clinic enterprise-wide database search identified 138 CMML cases who underwent ASCT. Conventional statistical methods were used for analyses. Results: 138 CMML patients (transplanted between 1995-2024) were included (median age 63 years; males 62%);104 (group A) received ASCT before and 34 (group B) after blast transformation (BT). At initial diagnosis, CMML-1/CMML-2 and dysplastic/proliferative representations were 78%/22% and 54%/46%; 31% displayed abnormal karyotype and most frequent mutations were ASXL1 (56%), TET2 (44%) and SRSF2 (38%). At time of initial diagnosis, CPSS-Mol risk categories were low (17%), intermediate-1 (11%), intermediate-2 (40%), and high (32%). Median time from diagnosis to ASCT was 11 months (range 0-201). Median overall survival (OS) from the time of initial diagnosis was 67 months (range 4-239) and from the time of ASCT 54 (range 0-212) months. Occurrence of BT before ASCT was associated lower post-transplant survival (PTS; 16 vs 95 months, P=0.01, HR 1.9, 95%CI 1.2-3.2). Bone marrow (BM) blasts, at the time of ASCT, <5%, 5-9%, and 10-19% correlated with median OS of 171, 81, and 18 months in group A (p=0.01) and 50, 25, and 13 months in group B (P=0.07), respectively. Pre-ASCT hypomethylating agent exposure was associated with lower PTS in group A (P=0.02). PTS was also adversely affected by DNMT3A and SETBP1 mutations. In group A, PTS was the longest with myeloablative busulfan-based (median not reached) and the shortest (median 22 months) with Cy-TBI-based conditioning (p=0.1). Donor type did not impact PTS: matched unrelated (63%), matched sibling (23%), mismatched unrelated (7%), or haplo-identical (7%). Post-transplant cyclophosphamide was associated with a numerically lower median PTS (22 months), compared to other forms of GVHD prophylaxis (107 months; p=0.1) and significantly higher non-relapse mortality (p=0.02). Documentation of morphologic CR at day 100 was associated with significantly longer PTS in both groups A (92%,164 vs. 18 months; p=0.01) and B (84%, 42 vs. 11 months; p=0.01). The presence of abnormal karyotype at day 100 was associated with shorter PTS in group A (p=0.01). Grade ≥3 acute and moderate to severe chronic GVHD occurred in 20% and 34%, respectively, in group A patients and in 26% and 44% in group B. GRFS at 1/3 years were 42/21% in group A and 31/16% in group B. At last follow up, 44% in group A and 65% in group B were dead. Causes of death were relapse/non-relapse related in 36/64% in group A and 39/61% in group B. Conclusions: ASCT is effective in securing long-term survival in CMML, especially when the procedure is performed prior to BT and in the setting of <5% BM blasts/promonocytes. Response assessment at day 100 was highly informative of outcome.

e18596 Background: The International Consensus (ICC), but not the 5 th edition of the WHO classification (WHO5), distinguishes mature from immature mast cell leukemia (MCL) and systemic mastocytosis (SM) associated with myeloid neoplasm (SM-AMN) from SM associated with myeloid or lymphoid neoplasm (SM-AHN). The objectives of the current study were i) to assess prognostic input from disease classification by ICC vs. WHO5, and ii) to compare the predictive performance of the Mayo Alliance Prognostic scoring (MAPS) with other prognostic models and its prognostic interaction with the ICC-based morphologic classification. Methods: Study patients met diagnostic criteria per ICC/WHO5. MAPS risk variables included i) age >60 years, ii) hemoglobin below sex-adjusted lower limit of normal, iii) platelets <150 × 10⁹/L, iv) alkaline phosphatase above upper limit of normal, and v) advanced, including MCL, SM-AMN, and aggressive (ASM) vs. indolent/smoldering (ISM/SSM) SM. ICC-defined MCL includes only MCL-immature whereas WHO-defined MCL includes both MCL-immature and MCL-mature. WHO-defined SM-AHN includes SM-AMN and SM associated with lymphoid neoplasm (SM-ALN). Results: 910 Mayo Clinic patients with SM were diagnosed between 1968 and 2024 (median age 56 years). ICC categories were ISM/SSM (N=552), ASM (N=115), SM-AMN (N=235), and MCL (N=8). At median follow-up of 4 years, 345 (38%) deaths and 35 (3.8%) leukemic transformations were documented. Overall survival (OS) predictive performance at 5 years was superior with ICC (AUC 0.85), compared to WHO5 (AUC 0.83); median survival was 24.3 years in ISM/SSM, 5.8 years for ASM, 2.0 years for SM-AMN, 2.3 years for SM-AHN, 1.8 years for MCL-mature and 0.08 years for MCL-immature; the difference in OS was significant between MCL-immature and SM-AMN (p<0.01) but not between MCL-mature and SM-AHN (p=0.3). Similarly, OS was similar between MCL-mature and ASM (p=0.8) and between SM-ALN and ASM (p=0.08) but different between MCL-immature and ASM (p<0.01), SM-AMN and ASM (p<0.01), and MCL-mature and MCL-immature (p<0.01). Predictive performance at 5 years was superior with MAPS (AUC 0.91) and MAPS-molecular (AUC 0.91), compared to the mutation-adjusted risk score (MARS; AUC 0.82). Median OS estimates were not reached, 24.2, 11.7, 5.7, 2.6, and 0.7 years, in the presence of 0, 1, 2, 3, 4, or 5 of the forementioned MAPS risk factors. Among informative cases, ASXL1 mutation was the only genetic risk factor with MAPS-independent prognostic relevance. Prognostic inter-independence between ICC and MAPS was confirmed by multivariable analysis. Conclusions: The current study confirms the superior performance of MAPS, in regard to survival prediction, with little additional contribution from mutations. SM sub-classification by the ICC is prognostically independent of MAPS and more valuable than classification by WHO5.

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.

9024 Background: Comprehensive hematology education during fellowship is essential for delivering high-quality healthcare. Variability in individual learning experiences can lead to trainee dissatisfaction and suboptimal clinical acumen. Fellowship programs must strive for a well-rounded and equitable educational experience for all fellows to prepare them for real-world practice in the increasingly dynamic field of hematology. Methods: Hematology fellows (n=30) at Mayo Clinic (Rochester) were invited to complete a survey about the inpatient Fellow Hematology Curriculum (FHC) during 2021-2022. Responses were recorded in a five-point Likert scale and free-text. Using the initial results, we implemented a structured inpatient hematology curriculum starting in 2022 and conducted a post-implementation survey in Spring 2024 to assess its success and sustainability. Results: The initial survey was completed by twenty fellows, with a response rate of 66%. All respondents agreed that the FHC could be improved. Only 45% agreed that structured education is adequately paired with clinical duties. In the open-ended responses, a structured curriculum covering a set list of topics was the most common recommendation given to improve the FHC. This prompted a longitudinal QI initiative to implement standardized rotation-specific lectures created by fellows and distributed to faculty and fellows prior to the associated 4-week rotations. Twelve fellows (40%) completed the post-implementation survey. Summary of key responses are shown in table 1. Although there remained high variability among consultants regarding their engagement in education, significant improvements were noted. Agreement that the curriculum has well-defined objectives for each rotation increased from 25% to 58%. Additionally, 83% of fellows agreed that structured education was effectively paired with clinical duties, up from 45%. Open-ended responses highlighted variability in consultants' utilization of the curriculum but reflected overall satisfaction. Conclusions: The need for a well-structured FHC was identified as a gap in equitable hematology education. This was addressed through a fellow led longitudinal QI project generating easily accessible educational material relevant to weekly themes on inpatient hematology services. The introduction of a structured and clinically relevant curriculum was well-received. Summary of survey responses. Pre-implementation Post-implementation Statement Agreed or strongly agreed (%) Agreed of strongly agreed (%) I know what topics and to what extent I’m expected to learn 25 67 The FHC has well-defined objectives for each rotation 25 55 There is high variability among consultants with engagement in education 95 75 Structured education is paired with clinical duties 45 83 I can easily locate lectures given by hematology consultants 5 42

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.