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ABSTRACT Patients with newly‐diagnosed acute myeloid leukemia (ND‐AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND‐AML patients receiving Ven‐HMA at Mayo Clinic, outcomes were compared across Ven 7‐ ( n = 33), 14‐ ( n = 117), 21‐ ( n = 96), and 28‐day ( n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow‐up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7‐, 14‐, 21‐, and 28‐day; p = 0.86). Median transplant‐censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low‐risk and all Mayo risk groups. Among ELN high‐risk patients, 14‐day Ven was associated with inferior transplant‐censored survival compared to 21‐ and 28‐day schedules ( p < 0.01). Notably, 30‐ and 60‐day mortality were higher with shorter Ven schedules (7‐day: 9%/18%; 14‐day: 7%/15%) versus 28‐day (2%/6%), which likely reflects treatment selection bias. In ND‐AML, no significant difference in transplant‐censored survival was observed across the 7‐, 14‐, 21‐, and 28‐day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk‐adapted Ven dosing strategies.

e18524 Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved front-line therapy for elderly or unfit patients with newly-diagnosed acute myeloid leukemia (ND-AML); however, majority relapse or are refractory ( Pratz AJH 2024 ). We examined survival outcomes in the setting of frontline Ven-HMA failure. Methods: ND-AML patients with failure to achieve complete remission (CR/CRi) or loss of CR/CRi after front-line Ven+HMA, excluding post-transplant relapse were retrospectively studied. Response was evaluated per European Leukemia Net 2022 criteria ( Dohner Blood 2022 ). Results: 356 patients with ND-AML (median age 75 years; 65% males; 55% secondary) receiving frontline Ven+HMA (median; 3 cycles (1-26), had refractory [n=219 (62%)], or relapsed disease [137 (38%)]. At diagnosis, karyotype was complex in 142/347 (41%). Mutations involved TP53 (29)%, ASXL1 (19%), RUNX1 (17%), SRSF2 (15%), KRAS/NRAS (13%), IDH2 (7%), FLT3-ITD (7%), NPM1 (6%) and IDH1 (5%). At treatment failure, complex karyotype was present in 72/180 (40%), including 55 from baseline. In 137 patients with paired NGS, mutations persisted in TP53 (88%), IDH1 (86%), IDH2 (78%), NPM1 (75%), K/NRAS (73%), RUNX1 (70%), FLT3-ITD (65%) mutations. Mutations were acquired in a minority [ IDH1 / IDH2 (2% each) TP53 (3%), NPM1 (4%), FLT3-ITD (5%) K/NRAS (6%)]. Clearance of mutations were infrequent for TP53 (12%) and IDH1 (14%). At median follow-up of 4 months (mo) (0-80) from the time of relapse/refractory disease, 320 (90%) patients have died, with median survival of 4 mo (1-2-3 yr survival 19%/8%/5%). On multivariate analysis, peripheral blasts >20%, complex karyotype, and wild-type IDH1 were independent predictors of inferior survival, while allogeneic stem cell transplant (ASCT) was associated with improved survival. A 3-point prediction model based on peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 stratified patients into low-, intermediate-, and high-risk groups, with median survival of 7, 3, 2 months, respectively (p<0.01). 13 patients underwent ASCT (median survival; 22.5 mo; 3-yr survival 33%), from low (n=10) or intermediate-risk groups (n=3). Salvage therapy (n=170, 48%) yielded CR/CRi of 31% for Ven+HMA (n=36), 54% intensive chemotherapy (n=26), 50% FLT3 inhibitors (i) (n=22), 37% IDH1/2i (n=19), 25% other regimens (n=69). Median survival was similar: Ven+HMA 8 mo, intensive chemotherapy 10 mo, FLT3i 6.5 mo, IDH1/2i 14 mo, other regimens 6 mo, but inferior with supportive care (2 mo; p<0.01). Conclusions: The current study identifies peripheral blasts ≥20%, complex karyotype, and wild-type IDH1 as predictors of inferior survival in ND-AML relapsed/refractory to front-line Ven+HMA and underlines that while no specific salvage therapy conferred superior outcomes, ASCT was indispensable for long-term survival.

6525 Background: Venetoclax plus hypomethylating agent (Ven-HMA) is the standard treatment for unfit patients with newly diagnosed acute myeloid leukemia (ND-AML), with Ven typically administered for 28 days (d) per cycle (DiNardo NEJM 2020) . However, the optimal duration of Ven across risk groups remains unclear. We examined survival outcomes with Ven 7, 14, 21, and 28d in ND-AML, in the context of European LeukemiaNet (ELN) and Mayo Genetic risk models. Methods: ND-AML patients receiving Ven-HMA at the Mayo Clinic were retrospectively studied. Patients were stratified by ELN 2024 (Döhner Blood 2024) and Mayo Genetic risk (Gangat Am J Hematol 2025) , and analyzed using standard statistical methods. Results: 540 patients (median age 75 years, 52% de novo) received HMA with Ven for 7d ( n =33), 14d ( n =117), 21d ( n =96), or 28d ( n =294). ELN and Mayo risk distributions were 22%/35% high, 18%/56% intermediate, 60%/9% low risk, respectively. Baseline characteristics were comparable. CR/CRi rates were comparable across Ven durations, with the exception of lower CR/CRi with 7d vs 21d (p=0.04). Risk-stratified CR/CRi showed variations across Mayo and ELN groups but without significant differences based on Ven duration (Table). Allogeneic transplant rates were 15%, 18%, 18%, 20% for 7, 14, 21, 28d (p=0.86). At a median followup of 37.7 months, median overall survival (OS) differed by ELN risk (6.6, 11.9, 20 months) and Mayo genetic risk (7.8, 17.4 months, not reached (NR)), for high, intermediate, low risk (p<0.01), respectively. Median OS was comparable across Ven 7, 14, 21, 28 d (13, 13, 17, 14 months; p=0.84), with corresponding 1/3/5-year survival rates (Table). 30/60d mortality differed by Ven duration; 7d 10%/20%, 14d 7%/15%, 21d 4%/13%, 28d 4%/6%. Compared with 28d, 30d mortality was higher with 7d and 14d (p=0.07/0.03), and 60d mortality was higher with 7d, 14d, and 21d (p=0.02/0.01/0.05). OS was comparable across Ven durations within ELN intermediate/low risk and all Mayo risk groups, except among ELN high risk, patients receiving 14d Ven had inferior OS compared with 21d and 28d (p<0.01). Cumulative incidence of relapse at 1 year was similar among patients receiving 14, 21, 28d Ven (16%, 18%, 18%;p >0.1). Conclusions: Survival outcomes were comparable across Ven 7, 14, 21, 28 d in ND-AML, with outcomes driven by Mayo Genetic and ELN risk. Despite differences by Ven duration in high-risk groups, higher early mortality with 7d and 14d likely reflects treatment selection. Prospective trials are needed to establish risk adapted Ven dosing strategies. 7 (N=33) 14 (N=117) 21 (N=96) 28 (N=294) P-value CR/CRi (%) 52 63 72 65 0.19 7≠21 Mayo Risk High 33 49 58 55 0.53 - Intermediate 55 69 80 69 0.17 7≠21 Low 100 85 80 84 0.84 - ELN Risk High 33 30 57 53 0.21 - Intermediate 33 59 64 56 0.63 - Low 62 74 80 73 0.46 - Median OS (months) 13 13 17 14 0.84 - 1/3/5-year survival (%) 53/NR/NR 51/25/22 56/23/20 55/27/20 >0.1 -

Abstract The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary ( de novo ) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (46%), post-myelodysplastic syndrome (MDS) (19%), post-myeloproliferative neoplasm (MPN) (12%), post-MDS/MPN (6%), therapy-related (17%) and AML with myelodysplasia-related genetic abnormalities (AML-MR; 46%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including in AML-MR (60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p = 0.02), or CEBPA MUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1 MUT (not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

Abstract Background: The International Consensus Classification (ICC) for systemic mastocytosis (SM) recognizes mast cell leukemia (MCL) and SM with associated myeloid neoplasm (SM-AMN) as distinct categories of advanced SM (SM-Adv; Arber et al. Blood 2022;140:1200). Contemporary risk models in SM, including the Mayo Alliance Prognostic System (MAPS), do not account for the prognostic heterogeneity among ICC-defined SM-Adv subcategories. Methods: Mayo Clinic databases were utilized to access patient information. Diagnoses of SM and its morphological subcategories were confirmed through clinical evaluations and review of BM pathology. Diagnostic criteria were retrospectively fitted to be consistent with those of the ICC (Arber et al. Blood 2022;140:1200); diagnosis of MCL required the presence of immature cytomorphology of mast cells and only myeloid neoplasms were listed under the category of SM-AMN.Next-generation sequencing and cytogenetic studies was performed in a subset of the study patients according to previously described methodologies. Statistical analyses were conducted on clinical and laboratory data collected at the time of initial diagnosis while survival analysis was censored at the time of allogeneic stem cell transplant (ASCT). Results: A total of 910 Mayo Clinic patients with SM (median age 56 years, range 12-89; males 50%) were accessed in order to conduct a series of multivariable analyses (MVA) in search of independent risk factors for transplant-censored overall survival (OS). All patients were evaluable for assignment to specific ICC categories of SM: indolent (ISM; N=553), aggressive (ASM; N=114), SM-AMN (N=235), and MCL (N=8); the AMN components in SM-AMN included acute myeloid leukemia (N=18), chronic myelomonocytic leukemia (N=70), myelodysplastic syndromes (N=32), MDS/myeloproliferative overlap (N=81), myelofibrosis (N=7), polycythemia vera or essential thrombocythemia (PV/ET; N=19), and others (N=8). In addition, subsets of patients were evaluable for hemoglobin level (N= 865), white blood cell count (WBC; N=858), platelet count (N= 859), serum alkaline phosphatase (ALP; N=761), serum tryptase level (N=706), karyotype (N=574), and mutations (N=240). Median follow-up for living patients was 70 months (range, 0-520); during this time 346 (38%) deaths, 16 leukemic transformations, and 20 ASCTs were documented. ROC analysis-determined optimal cutoff levels for predicting OS included age at ≥60 years, platelet count &lt;150 x 109/L, tryptase level ≥100 ng/mL, WBC ≥10 x 109/L, hemoglobin below sex-adjusted lower limit of normal (anemia), and ALP &gt;210 U/L in women or &gt;170 U/L in men (increased). All except WBC ≥10 x 109/L retained significance during MVA that included ICC-specified SM categories: MCL (HR 74.8, 26.0-215.3; p&lt;0.01); SM-AMN (HR 3.9, 2.5-6.0; p&lt;0.01); ASM (HR 2.2, 1.4-3.5; p&lt;0.01); age ≥60 years (HR 3.3, 2.2-4.7; p&lt;0.01); platelets &lt;150 x 109/L (HR 2.8, 2.0-3.9; p&lt;0.01); tryptase ≥100 ng/mL (HR 2.1, 1.5-2.9; p&lt;0.01); anemia (HR 1.7, 1.1-2.4; p&lt;0.01); and increased ALP (HR1.5, 1.1-2.0; p=0.01). A subsequent HR-weighted risk model effectively delineated 5 risk levels ranging in median survivals from 11 months to 372 months (Figure 1). Figure 2 outlines complementary subtype-specific risk models; to that end, risk factors for ISM included age ≥60 years (HR 4.5, 2.5-7.9), tryptase ≥100 ng/mL (HR 3.5, 2.1-6.0); platelets &lt;150 x 109/L (HR 3.4, 1.5-7.9), and anemia (HR 2.4, 1.2-4.8); for ASM age ≥60 years (HR 2.3, 1.3-4.3), platelets &lt;150 x 109/L (HR 2.4, 1.4-4.0), and anemia (HR 2.0, 1.2-3.4); and for SM-AMN age ≥60 years (HR 2.9, 1.6-5.2), platelets &lt;150 x 109/L (HR 2.5, 1.6-3.9), and tryptase ≥100 ng/mL (HR 2.5, 1.6-3.9) [Figure 2]. In SM-AMN, additional prognostic relevance from subcategorization into PV/ET vs. all other types of AMN was appreciated (Figure 3; HR 4.0, 1.6-3.9) and incorporated into the risk model for SM-AMN (Figure 2). Abnormal karyotype (AK) and high risk mutations(HRM; ASXL1, SRSF2, RUNX1, NRAS)clustered withSM-AMN with AK and ASXL1MUT displaying independent prognostic relevance that was most apparent in SM-AMN. Conclusions : MAPS-R relies on the prognostic eminence of ICC-defined morphologic subcategories and allows for additional SM subtype-specific risk stratification. SM associated with ET or PV is a prognostically unique subcategory of SM-AMN and should be recognized as such in future classification schemes. SM-AMN must be thoroughly ruled out in the presence of AK or HRM.

Abstract Venetoclax (Ven) in combination with hypomethylating agents (HMA) is widely used as frontline treatment in older or unfit patients with acute myeloid leukemia (AML). Liposomal cytarabine and daunorubicin (CPX-351) is FDA-approved for the treatment of secondary AML, including therapy-related (t-AML) and AML with myelodysplasia-related changes (AML-MR). The current study aimed to provide a comprehensive comparison between the two treatment strategies to better inform clinical decisions. Methods The current retrospective analysis was performed under an institutional review board approved minimal risk protocol at Mayo Clinic (MN, AZ, FL). AML-MR gene mutations or cytogenetic abnormalities were categorized according to the International Consensus Classification (Arber et al. Blood 2022;140:1200). Treatment response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Dohner et al. Blood 2022;140:1345). Overall survival (OS) analysis was censored for allogeneic stem cell transplant (ASCT). Statistical analyses were performed using JMP Pro (Version 18.0.0). Results A total of 600 patients with newly diagnosed AML (ND-AML) treated with CPX-351 (N-112, 19%), or Ven-HMA (N=488, 81%) were included. AML subtypes included de novo (N=277, 46%), post-myelodysplastic syndrome (post-MDS, N=114,19%), post-myeloproliferative neoplasm (post-MPN, N=70, 12%), post-MDS/MPN (N=36, 6%), t-AML (N=103, 17%) and AML-MR (N=274, 46%). Compared with those treated with Ven-HMA, patients receiving CPX-351 were younger (median age 65 vs 73 years; p&lt;0.01), more likely to be female (50% vs 38%; p=0.02), more frequently diagnosed withsecondaryAML (68% vs 51%; p&lt;0.01), and less likely to have NPM1MUT (5% vs 12%; p=0.02) whereas ELN 2022 cytogenetic risk distribution was similar between the two (adverse risk; 43% vs 40%; p=0.5). Comparison of treatment response and survival Complete response rates with (CR) or without (CRi) count recovery were similar between CPX-351 and Ven-HMA overall (55% vs 60%) as well as specifically in patients with AML-MR (60% vs 63%), adverse karyotype (44% vs 44%), NPM1MUT (100% vs 89%), TP53MUT(32% vs 45%), IDH1MUT (60% vs 76%), IDH2MUT (63% vs 77%), SF3B1MUT(71% vs 45%), and CBLMUT (33% vs 69%) [p&gt;0.05 in all instances]. Compared to those with CPX-351, CR/CRi rates with Ven-HMA were superior in males (60% vs. 45%; p=0.04) and in patients with de novo AML (68% vs. 50%; p=0.03), STAG2MUT (86% vs. 44%; p=0.02), or CEBPAMUT (88% vs. 50%; p=0.03); infectious complications were significantly more frequent with CPX-351 (83% vs 62%, p&lt;0.01). At a median follow-up of 12 months (range; 1-88), 416 (69%) deaths, 179 relapses (44% in CPX-351 and 52% in Ven-HMA responders) and 149 ASCTs (53% in CPX-351 and 18% in Ven-HMA) were documented. OS rates were similar between CPX-351 and Ven-HMA, in general (median 10 vs 13 months), as well as in patients with adverse karyotype, TP53MUT, IDH1MUT, and IDH2MUT (p&gt;0.05 in all instances). By contrast, OS was superior in Ven-HMA-treated patients with post-MDS AML (median 12 vs. 7 months; age-adjusted p=0.02) and in CPX-351-treated patients harboring SF3B1MUT(median not reached vs 14 months; age-adjusted p&lt;0.01). In addition, a borderline-significant OS advantage for CPX-351 was apparent in patients with PTPN11MUT (13.5 vs 8 months; p=0.08). Comparison in ICC defined AML-myelodysplasia-related CR/CRi and OS rates were comparable between patients treated with CPX-351 (N=57) or Ven-HMA (N=217), with response rates of 60% vs 63% (p=0.68) and median OS of 10 vs 14 months (p=0.61), respectively. However, OS was superior with Ven-HMA in patients with post-MDS AML (15 vs 8 months; age-adjusted p=0.02) and with CPX-351 in those with SF3B1MUT (NR vs 14 months; age-adjusted p=0.02). Conclusions: The current study suggests that Ven-HMA was as effective and possibly less toxic than CPX-351 for the treatment of ND-AML, including AML-MR, despite the bias for younger and fitter patients treated with the latter regimen. Observed differences involving patients with SF3B1MUT or post-MDS AML require validation in prospective studies and provide parameters for developing treatment-specific predictive models that will be presented at the meeting.

Abstract Background Momelotinib, a small-molecule Janus kinase 1 and 2 (JAK1/2) inhibitor (JAKi), is FDA-approved (September 15, 2023) for use in anemic patients with myelofibrosis (MF). The drug appears to have an edge over other FDA-approved JAKis in regard to its unique erythropoietic effect that has been attributed to its inhibitory activity on activin A receptor type-1 (ACVR1). In clinical trials, anemia response to momelotinib in JAKi-naïve MF patients has been reported in more than a third of patients with or without transfusion-dependent anemia (TDA). The current study examines the drug's efficacy and toxicity in JAKi-naïve patients treated outside of clinical trials and after the drug was commercially approved. Methods The current study was conducted under an institutional review board approved minimum risk protocol. Diagnostic criteria were according to the International Consensus Classification (Arber et al. Blood 2022; 140:1200). Study inclusion criteria included a hemoglobin level of &lt;10 g/dL and absence of previous treatment with JAKi. Responses were adjudicated by the Revised International Working Group-European LeukemiaNet criteria (IWG-ELN; Blood 2024; 144:1813). Conventional statistical methods were used (JMP Pro 18.0.0 software SAS Institute, Cary, NC, USA). Results A Mayo Clinic enterprise-wide search identified 60 patients (median age 73 years; 55% males) with primary or secondary MF who received momelotinib outside of clinical trials as their first JAKi for treatment of anemia and associated symptoms. Driver mutation distribution included JAK2 42%, CALR 30%, MPL 18%, and triple-negative 10%. Table 1 outlines clinical and laboratory findings at the time of momelotinib treatment initiation; Dynamic International Prognostic Scoring System (DIPSS)-plus risk distribution included high (72%) and intermediate 1/2 (28%) risk. Twenty-seven (45%) patients were transfusion-requiring, 24 (40%) displayed peripheral blood (PB) blast ≥2%, 10 (17%) platelet count &lt;100 x 109/L, and 14 (25%) marked palpable splenomegaly (≥20cm). Unfavorable karyotype was seen in 9 (16%) of 58 patients. NGS-derived mutations were assessed in 57 cases and included ASXL1 (35%), TET2 (19%), SF3B1 (16%), SRSF2 (14%) and 7% (N=4) each for EZH2, IDH2, SH2B3, and ZRSR2. Baseline plasma cytokine levels were assessed in 17 patients with elevated TNF-a in 88%, IL-2 soluble 65%, IL-6 29% and IL-18 53%. Anemia response and predictors Fourteen (23%) patients met revised IWG-ELN criteria for anemia response (TDA 15% and non-TDA 30%; p=0.15). The anemia response was within 3 months in 10 (71%) patients. Median (range) durations of momelotinib exposure and anemia response were 8 (1-23) and 5 (1-13) months, respectively. The drug was discontinued in 29 (48%) patients (39% due to side effects; Table 2). In age-adjusted univariate analysis, predictors of anemia response included circulating blasts &lt;2% (33% [12/36] vs. 8% [2/24]; p=0.02), presence of SH2B3 mutation (100% [4/4] vs. 19% [10/53]; p&lt;0.01), and elevated IL-2 soluble (36% [4/11] vs. 0% [0/6]; p=0.02). The correlation with SH2B3 mutation remained significant (p&lt;0.01) after accounting for circulating blasts. Treatment emergent neuropathy and nephropathy Sensory peripheral neuropathy (PN) was reported by 12 (20%) patients with a median onset of 2 months (range 1-7); CTCAE v5.0 grades 1 (N=8), 2 (N=3), and 3 (N=1); reversibility was documented only for grade 1 severity and did not appear to be consistently affected by drug discontinuation or dose reduction (Table 3). Seventeen (29%) patients experienced a &gt;20% treatment-emergent decrease in estimated glomerular filtration rate from baseline, including 14 (23%) whose serum creatinine level crossed from the normal to abnormal range with pre- and post-treatment median (range) values of 1.05 (0.60-1.26) and 1.53 (1.1-3.31), respectively, with the majority reverting back to the normal range upon drug discontinuation. Conclusion In routine practice, momelotinib therapy might alleviate anemia in about a quarter of JAKi-naive patients with MF but is associated with non-trivial rates of treatment-emergent peripheral neuropathy and nephropathy. The latter appeared to be reversible on treatment discontinuation. Our novel observation regarding association of anemia response with SH2B3 mutation requires validation in a larger group of informative cases.