Pardanani, Animesh

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.

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 Introduction Management of acute leukemia (AL) during pregnancy remains challenging. In the first trimester, chemotherapy is toxic to the fetus, while delaying treatment may endanger maternal health, often prompting recommendations for pregnancy termination. In later trimesters, although the risk of congenital malformations decreases, complications such as preterm labor remain prevalent. Delivery prior to chemotherapy may be considered in advanced gestation. This study aimed to describe maternal and fetal outcomes of patients diagnosed with AL during pregnancy. Methods Following institutional review board approval, we retrospectively identified pregnant patients diagnosed with AL between 1995 and 2025 across Mayo Clinic sites (Minnesota, Arizona, Florida). We recorded leukemia subtype, treatment course, maternal and fetal outcomes. Results We identified 18 patients diagnosed with AL during pregnancy, including 11 with acute myeloid leukemia (AML) and 7 with acute lymphoblastic leukemia (ALL). Ten were diagnosed in the first trimester, 3 in the second, and 5 in the third. In the AML group (n=11; median age 30 years, range 18-42), one patient had acute promyelocytic leukemia (APL). ELN 2022 risk stratification was favorable in 5 (45%), intermediate in 4 (36%), and adverse in 2 (18%). In the ALL group (n=7; median age 23 years, range 19-34), 5 had B-ALL (one Philadelphia chromosome-positive) and 2 had T-ALL. All ALL cases were diagnosed in the first trimester. Among first-trimester AMLs, 2 of 3 had core-binding factor (CBF) AML. All eight patients diagnosed in the second and third trimesters had AML (1 APL, 2 CBF AML, 1 KMT2A-rearranged, 1 with DEK::NUP214 fusion, 1 complex karyotype including t(8;21), 2 with normal karyotype). Overall, 15 (83%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) after initial induction. One patient had refractory disease and achieved partial remission after salvage, another had refractory disease and achieved CR after multiple lines of therapy, and a third achieved CR after FLAG-idarubicin and revumenib. Five patients received chemotherapy during pregnancy (3 in the first trimester, 1 in the second, 1 in the third); two of these resulted in live births. Among the 10 patients diagnosed in the first trimester, all underwent therapeutic or spontaneous abortion. Of the 3 second-trimester diagnoses, 2 underwent spontaneous or therapeutic abortion at 15 weeks. The third received 7+3 induction at 24 weeks for KMT2A-rearranged AML, followed by preterm delivery at 26 weeks and re-induction with FLAG-idarubicin plus revumenib, achieving CR. Among the 5 third trimester diagnoses, 4 delivered preterm infants (median gestational age 33 weeks) prior to chemotherapy. One patient received 7+3 at 29 weeks and delivered a viable preterm infant at 36 weeks. At a median follow-up of 6.5 years, 5 of 11 patients with AML (45%) and 3 of 7 patients with ALL (43%) died, mostly due to disease progression. Median overall survival was not reached in either group. Causes of death were as follows: 1 of AML, 1 of ALL, 3 of acute stem cell transplant (SCT) complications, 1 of chronic SCT complications, 1 of Hodgkin lymphoma, and 1 of pneumonia. Among patients diagnosed in the second and third trimesters (n=8, all with AML), 6 (75%) resulted in live births: 5 of 5 (100%) third-trimester diagnoses and 1 of 3 (33%) second-trimester diagnoses. All received intensive induction: 7+3 (n=5), 7+3 + ATRA (n=1), 7+3 + gilteritinib (n=1), and 7+3 + nilotinib (n=1). Of the second-trimester group, only one received induction prior to delivery; she later achieved CR with FLAG-ida and revumenib. Among the third-trimester group, one patient received chemotherapy prior to delivery and achieved CR followed by SCT. All but one of the 8 AML patients achieved CR after initial therapy. Conclusions Successful pregnancy outcomes were achieved in 75% of patients diagnosed with AML during the late second or third trimester. Notably, 5 (28%) of patients received chemotherapy during pregnancy. Larger, multi-institutional cohorts are warranted to further characterize the incidence and outcomes of AL in pregnancy.

Abstract Introduction: CSF3R mutations (CSF3RMUT), most commonly T618I, represent the defining genomic alteration in chronic neutrophilic leukemia (CNL), present in ~80% of cases. Despite emerging real-world data, information on treatment outcomes and prognostic factors remains limited due to rarity of the disease. In this two-center retrospective study, we examined clinical and molecular predictors of treatment response, overall survival (OS), and blast transformation (BT) and outcome following allogeneic stem cell transplant (ASCT). Methods: The study was approved by the institutional review boards of the Mayo Clinic (USA) and the University of Montreal (Canada). Electronic medical records were reviewed to identify patients with CSF3R mutated CNL at both institutions and extract relevant data. Statistical analyses were conducted using JMP Pro 17.0.0 software (SAS Institute, Cary, NC, USA). Results: Forty-four patients (68% male, median age 68 years [range: 26-93]) were included. At diagnosis, 20 (56%) were asymptomatic, 13 (36%) presented with constitutional/non-specific symptoms, and 20 (50%) had antecedent leukocytosis at a median of 13 months(mo) prior. Splenomegaly (palpable or radiological) was observed in 28 (67%) patients, hepatomegaly in 7 (17%) and lymphadenopathy in 4 (9.8%). Median white blood cell count (WBC) was 52×10⁹/L (range: 17-390). CSF3RMUT/variants included 39 (89%) with T618I (7 of the 39 had additional CSF3RMUT), 2 (5%) with M696T, and 1 (2%) each for I598I, Q739* and T640N. Frequent co-mutations included ASXL1 in 25 (63%) patients, SETBP1 in 14 (36%), and SRSF2 in 8 (31%), with overlapping occurrence; 10 (38%) patients had ≥2 of these 3 mutations. Ten patients (median WBC 29 x10⁹/L [range: 19–58]), were initially observed without treatment for a median of 8.6 mo; 2 remained on observation alone at 46 and 77 mo. Hydroxyurea (HU) alone or in combinations excluding ruxolitinib (Ruxo) was the most common first-line treatment (68%). Second-line therapies included Ruxo (39%), HU (25%), and hypomethylating agents (14%). WBC response (≥50% reduction from baseline) was 78% with HU vs. 60% with Ruxo (p=0.2). WBC response to HU was lower with abnormal karyotype (40% vs. 94%; p=0.02). WBC response to Ruxo was lower with SETBP1MUT (0% vs. 72%; p=0.05) and with male sex (40% vs. 100%; p=0.04). Seven patients underwent ASCT, including 2 after BT; four (57%) of the 7 remain alive, including 2 without evidence of disease (both 45 mo post-ASCT; one harbored ASXL1MUT) and the other 2 with active disease (both harbored ASXL1MUT). Three patients died from veno-occlusive disease (Day+34), CNS relapse with AML (at 105 mo post-ASCT), or unrelated causes (at 44 mo post-ASCT). Median OS was longer in transplanted patients (115 vs 23 mo; p=0.03). At a median follow-up of 44 mo for living patients, disease transformation occurred in 10 patients, including 7 with BT (6 with T618I, 1 T640N) and 3 with chronic myelomonocytic leukemia (2 M696T, 1 T618I). BT rate at 2, 3, and 5 years was 15%, 31%, and 43%, respectively. Univariate analysis (UVA) identified male gender (p&lt;0.01), &gt;5% immature WBCs (p=0.02), platelets &lt;160×10⁹/L (p=0.04), higher WBC (p=0.02), and ASXL1 or SETBP1 mutation (p&lt;0.01) as risk factors for BT. On multivariable analysis (MVA), only the latter remained significant. Median OS was 26 mo (95% CI: 21-43) for the entire cohort; 24 mo for patients with T618I CSF3RMUT vs 53 mo with other CSF3RMUT, p=0.1. In UVA, age &gt;60 years (HR 5.0, p=0.03), platelets &lt;160×10⁹/L (HR 3.4, p=0.006), WBC &gt;50×10⁹/L (HR 2.6, p=0.02), and ASXL1 or SETBP1 mutations (HR 4.2, p=0.01) were associated with shorter OS. In MVA, age &gt;60 (HR 6, p=0.03), WBC &gt;50×10⁹/L (HR 12, p&lt;0.01), and the presence of ASXL1MUT or SETBP1MUT (HR 9.5, p=0.01) remained significant. Based on the HRs on MVA, one adverse point was allocated for age &gt;60 years, and two adverse points each for WBC &gt;50×10⁹/L and presence of ASXL1 or SETBP1 mutations. Patients were accordingly stratified into low (0-2 points), intermediate (3) and high (4-5) risk groups with corresponding median OS of “not reached”, 29 mo, and 16 mo (p&lt;0.01). Causes of death included disease progression (82%), infection/bleeding (9%), and ASCT complications (9%). Conclusion: The current study highlights the prognostic relevance of “SETBP1 or ASXL1” mutation for both overall survival and risk of blast transformation. The study also signifies variable natural history and potential benefit from ASCT.

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.