Outcomes of therapy-related AML (T-AML) with venetoclax-based therapies.

6549 Background: T-AML refers to AML in patients (pts) with prior exposure to cytotoxic chemotherapy (CT) and/or radiotherapy (RT) and is often associated with adverse risk (AR) genomics. Evaluation of outcomes of T-AML with respect to type of prior therapy exposure, AML genomics, and contemporary AML therapy, especially with venetoclax (VEN), is warranted. Methods: We retrospectively analyzed pts aged ≥18 years with newly diagnosed T-AML. Pts with an antecedent myeloid disorder (MDS/CMML) prior to AML diagnosis were excluded; thus, including only pure T-AML. Composite complete response (CRc) included CR and CRi and overall response (OR) included CRc + morphologic leukemia free state. Results: From 1/2012 to 12/2023, 317 pts were included; median (med) age was 69 years (range 21-92). Overall, 120 (38%) received prior CT alone, 77 (24%) received prior RT alone (RT), and 114 (36%) received both (CRT). The most common prior malignancy was non-Hodgkin lymphoma (37%) in the CT group, prostate cancer (60%) in the RT group, and breast cancer (45%) in the CRT group.Among 286 pts with complete cytogenetic data, 180 (63%) were adverse, of whom 132 (46%) had complex karyotype (CK; 42% of CT, 48% of RT, and 61% of CRT groups). TP53 was mutated in 113/286 patients (40%) tested (36% of CT, 35% of RT, and 47% of CRT groups). Stratified by type of CT received, CK and TP53 mutation were seen in 5/5 (100%) and 3/5 (60%) of PARP inhibitor-exposed, 98/184 (53%) and 78/183 (43%) of alkylator-exposed, and 21/36 (58%) and 16/37 (43%) of topoisomerase inhibitor-exposed. Overall, 217/304 (71%) were ELN 2017 AR. In total, 251 pts (79%) received low-intensity AML therapy (LIT). CRc and OR was achieved in 122 (49%) and 146 (58%) pts treated with LIT (vs 58% and 65% with LIT+VEN). In pts treated with intensive chemotherapy (IC), the CRc and OR rate was 64% and 68% (vs 68% and 73% with IC+VEN). Overall, med RFS was 7.2 months (mos; 95% CI 5.6-8.9), and med OS was 11.8 mos (10.0-13.7). Med OS was 5.7 vs 9.0 mos (p=0.02) with LIT and LIT+VEN, respectively (resp), and med OS was 10.9 vs 48.9 mos (p=0.03) for IC vs IC+VEN, resp. Among pts treated with LIT+VEN, med OS was 14.0, 12.4, and 9.6 mos in those who had received prior CT, RT and CRT, resp; when stratified by ELN 2017 criteria, med OS was 24.6, 9.4 and 4.8 mos in the favorable, intermediate and AR groups, resp. Sixty-seven (21%) pts underwent HSCT with a landmarked comparison showing improved OS with HSCT (28.5 months vs 9.4, p<0.001). On multivariate Cox analysis in the LIT+VEN group, with forward model selection, using variables age </≥ 60, adverse cytogenetics, ASXL1, IDH1/2, FLT3-ITD, RAS, RUNX1, TP53 status , HSCT, and prior therapy group, HSCT was favorable (HR=0.19, 95% CI 0.01-0.37), along with IDH2 and NPM1 mut, while RAS and TP53 mut was associated with higher hazards of death. Other factors were not significant. Conclusions: Venetoclax improves outcomes in T-AML. In LIT+VEN treated patients, ELN 2024 risk stratification is prognostic.