Warraich, Momna

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.

ABSTRACT Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND‐AML) patients unfit for intensive chemotherapy and is also considered in younger, fit patients. However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines posttransplant outcomes in patients with ND‐AML treated with frontline Ven‐HMA who subsequently underwent ASCT. A total of 111 ND‐AML patients (58% male, 60% secondary/therapy‐related, median age 70 years [range, 37–80]) received a median of 3 cycles of Ven‐HMA. Mutations at the time of diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS , TET2 (14% each), STAG2 (11%), DNMT3A (8%). All patients were in CR/CRi at the time of transplant including 88% after Ven‐HMA. Measurable residual disease (MRD) by flow cytometry was detectable in 18/76 (24%) patients. Donors were mostly HLA‐matched unrelated (75%); 51% receiving fludarabine/melphalan conditioning and 67% posttransplant cyclophosphamide. At a median follow‐up of 15 months, 42 (38%) of patients have died and 18 (16%) experienced posttransplant relapse. Median posttransplant survival was not reached (NR), with 1‐, 2‐, 3‐year survival rates of 69%/60%/57%, respectively. On multivariate analysis, age ≥ 65 years, STAG2 mutation ( STAG2 MUT ) , and DNMT3A MUT were associated with superior posttransplant survival. Patients were stratified into low‐ (0–1 point), intermediate‐ (2 points), and high‐risk (3 points); age < 65 years, STAG2 wild type, and DNMT3A wild type, with 3‐year survival rates of 89%, 59%, and 19%, respectively ( p < 0.01). Taken together, age, STAG2 MUT and DNMT3A MUT stratified posttransplant survival in Ven‐HMA treated patients with ND‐AML.

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.

e16021 Background: Esophageal cancer (EC) remains highly lethal in the United States, with approximately 22,370 new cases in 2024. Respiratory failure (RF) frequently complicates advanced disease, and deaths involving both conditions have risen substantially since 1999, necessitating population-based mortality analysis. This study aimed to characterize national mortality trends involving EC and RF, with a focus on demographic, geographic, and urban–rural disparities. Methods: We conducted a retrospective analysis of U.S. deaths associated with EC (C15) and RF (J96) among adults aged ≥45 years using data from the Centers for Disease Control and Prevention WONDER database. Age-adjusted mortality rates (AAMRs) per 1 million were computed and stratified by year of death, sex, race, census region, and urbanization. Joinpoint regression estimated Average Annual Percent Changes (AAPC) with 95% confidence intervals (CI). Results: Between 1999 and 2024, 32,348 deaths were attributed to EC and RF. National AAMRs increased during this period from 8.2 to 13.7 (AAPC: 2.18*; 95% CI: 1.70 to 2.67). Males bore a higher mortality burden than females (AAPC: 2.23*; 95% CI: 1.7 to 2.7). Mortality was elevated in both examined age groups (45-64 and 64-85+), with the most significant impact observed among individuals aged 65-85+ years (AAPC: 2.52*; 95% CI: 2.02 to 3.02). Race-stratified analysis revealed non-Hispanic (NH) White individuals demonstrated the most pronounced increase across the study period (AAPC: 2.72*; 95% CI: 2.19 to 3.25). Geographically, the Midwestern census region showed the steepest rise in mortality, with rural counties nationwide exhibiting a similar increase(In Table). Conclusions: Mortality due to EC and RF has increased insidiously over the past two decades, while the literature on the combined effects of diseases remains limited. The burden is disproportionately higher among males, adults aged ≥65 years, and NH White individuals, particularly in Midwestern and rural regions. These disparities highlight a growing public health burden and emphasize the need for targeted prevention, early detection, optimized respiratory and oncologic care, and region-specific policies to mitigate inequities. Variable AAMR 1999 AAMR 2024 AAPC (95% CI) Overall 8.2 13.7 2.18*(1.70-2.67) Gender:FemaleMale 3.714 5.123.8 1.73*(0.89-2.56)2.23*(1.71-2.75) Census region:NortheastMidwestSouthWest 8.277.510.8 15.513.412.214.9 2.43 *(2.05-2.82)3.22 *(2.38-4.07)1.91*(1.06-2.77)1.30 (-0.16-2.80) Age:45-64years65-85+years 415.5 5.727.7 1.37(-0.01-2.78)2.52*(2.02-3.02) Race:HispanicNH WhiteNH Black 5.27.712.8 9.514.411.2 2.54*(1.76-3.33)2.72*(2.19-3.25)-0.41(-1.33-0.52) Urbanization: (1999-2020)MetroNon-Metro 1999 8.56.9 2020 11.313.8 1.34*(0.83-1.85)3.47*(2.25-4.71) *Indicates p<0.05.

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 -

6530 Background: Venetoclax (Ven) plus hypomethylating agents (HMA) is standard frontline therapy for newly diagnosed AML (ND-AML) patients unfit for intensive chemotherapy and is also being considered in younger and fit patients (Fathi, Blood 2025). However, consolidation with allogeneic stem cell transplant (ASCT) is often required to secure durable remission. The current study examines predictors of post-transplant survival (PTS) in the particular scenario. Methods: ND-AML patients who received upfront Ven+HMA and underwent ASCT were retrospectively studied. PTS, relapse rate, and non-relapse mortality (NRM) were evaluated. Results: 111 ND-AML patients (58% male, 60% secondary/therapy-related, median age 70 [37-80 years]) received median 3 cycles of Ven-HMA. 22% had complex karyotype. Mutations at diagnosis included RUNX1 (18%), SRSF2 (17%), TP53 (16%), ASXL1 , IDH2 , K/NRAS and TET2 (14% each), STAG2 (11%), DNMT3A (8%) and at time of ASCT (N=78 evaluable); RUNX1 (8%), NPM1 (6%), TP53 and ASXL1 (5% each), and SRSF2 and TET2 (4% each). At ASCT, all patients were in CR/CRi; 88% after Ven-HMA and 12% after additional bridging therapy. MRD by flow cytometry was detected in 18 (24%) of 76 evaluable patients and complex karyotype in 8 (9%) of 94. Donors were mostly HLA-matched unrelated (75%), with 51% receiving fludarabine/melphalan conditioning and 67% post-transplant cyclophosphamide (PTCy). At a median follow-up of 30 months, 42 patients (38%) have died including 18 (40%) from relapse. Median PTS was not reached (NR) with 1-2-3-year survival of 69%/60%57%. On multivariate analysis, age ≥65 years (median NR vs 10 months p<0.01), STAG2 (NR vs 44 months; p=0.04), and DNMT3A mutations (NR vs.NR p=0.05) were associated with superior PTS. In analysis limited to variables at time of ASCT, age ≥65 years remained significant (p<0.01) while TP53 mutations, donor type, and MRD status were not (p>0.1). Patients <65 years more often received bridging therapy compared to ≥65 years (23% vs 7%; p<0.05); excluding salvage-treated patients did not change survival results. 18 patients (16%) experienced post-ASCT relapse with median RFS of 7 months. Relapse rates at 1/2/3 years were 22%, 30% and 31% and NRM 13%, 24%, 46%, respectively. Patients <65 years had a higher 1 yr relapse incidence than those ≥65 years (36% vs 18%; p=0.01), with similar NRM (p=0.58). PTCy was not associated with relapse (p=0.66) but showed a borderline association with higher NRM (1-/2-/3-year 17%/31%/58% vs 4%/7%/16% in non-PTCy recipients; p=0.06). GVHD rate was 44% (50% ≥grade 2) with no association with relapse (p=0.43) or NRM (p=0.99). Conclusions: In the current study, older age (>65 years), including >75 years, was independently associated with superior PTS in ND-AML patients receiving Ven-HMA. By contrast, PTS was not affected by genetic profile at the time of ASCT, donor type, conditioning regimen, or GVHD prophylaxis.