Treatment paradigms for acute myeloid leukemia (AML) have evolved at a rapid pace in recent years. The combination of venetoclax with a hypomethylating agent prolonged survival in clinical trials when compared to hypomethylating agent monotherapy. However, little is known about the performance of venetoclax‐based regimens outside of clinical trials, given conflicting safety and efficacy data. Even less is known about the impact of the hypomethylating agent backbone. In this study, we demonstrate that decitabine‐venetoclax is associated with a significantly higher rate of grade three or higher thrombocytopenia, but lower rates of lymphocytopenia compared to azacitidine‐venetoclax. There was no difference in response or survival across ELN 2017 cytogenetic risk categories in the overall cohort. Significantly more patients succumb to relapsed or refractory disease than death from any other cause. We demonstrated that a Charlson comorbidity index score threshold of seven identifies exceptionally high‐risk patients, providing evidence for clinical use to reduce the risk of early treatment‐related mortality. Lastly, we provide evidence that measurable residual disease negativity and an IDH mutation predict a significant survival benefit outside clinical trials. Taken together, these data illuminate the real‐world performance of venetoclax and decitabine or azacitidine in the treatment of AML.

e19048 Background: The recently revised risk classification schema in ELN 2022 for acute myeloid leukemia (AML) now includes a more prominent presence of secondary-type mutations (STMs): ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. However, the risk classification schema of ELN 2022 is based on the outcomes of patients treated with intensive chemotherapy. The impact of STMs in patients treated with lower-intensity venetoclax-based strategies is unknown. Furthermore, IDH and NPM1 mutations are associated with a significant survival benefit in those treated with venetoclax-based strategies, but it is unknown how these mutations impact outcomes when they cooperate with STMs. The purpose of this study was to determine the impact of STMs included in ELN 2022 and cooperating mutations on lower-intensity venetoclax-based strategies. Methods: We retrospectively analyzed 79 patients with AML treated with front-line venetoclax and a hypomethylating agent (HMA; decitabine or azacitidine) at VCU Massey Cancer Center from January 1, 2018 to January 1, 2022. We excluded nine patients without available NGS at diagnosis. We recorded doses and dates of chemotherapy regimens, molecular profiles at diagnosis, and overall survival. We analyzed survival by the Kaplan-Meier method and compared groups with the Mantel-Cox test. The date of death was used to calculate overall survival; patients were censored at the date of the last contact. Results: We identified 32 patients with STMs and compared them to 38 patients without STMs; the median overall survival was nonsignificantly shorter in those with STMs (5.3 m. with STMs versus 8.2 m. without, p = 0.323). The presence of mutated TP53, RAS, or FLT3-ITD appeared to be associated with shorter overall survival in patients with STMs: co-mutated STMs with TP53, RAS, or FLT3-ITD had an overall survival of 2.6 m. compared to 8.6 m. for those with STMs but no additional adverse mutations ( p = 0.093). However, when we excluded patients with mutated TP53, NRAS, KRAS, and FLT3-ITD, there was no significant difference in overall survival in those with and without STMs (8.5 m. with STMs versus 14.7 m. without, p = 0.323). The presence of STMs did not appear to reduce the favorable prognosis associated with IDH mutations without cooperating mutated TP53, RAS, or FLT3-ITD (20.0 m. with STMs versus 23.4 m. without STMs, p = 0.493). Conclusions: While the presence of secondary-type mutations was associated with shorter survival, the association was nonsignificant in those treated with front-line venetoclax + HMA. Additionally, the presence of STMs did not appear to worsen survival in patients that respond favorably to venetoclax-based strategies, such as IDHmut AML. These findings, together with those of larger studies, may contribute to a refined risk classification schema for patients treated with lower-intensity strategies.

e19054 Background: Acute myeloid leukemia (AML) with alterations in core binding factor (CBF) has a favorable prognosis. The impact of complex cytogenetics or ELN 2022 adverse genetic risk markers — such as ASXL1, RUNX1, EZH2, SRSF2, (and the rest of the secondary-type mutations [STMs]) and TP53 — in CBF-AML is unclear. Additionally, treatment outcomes in CBF-AML using front-line novel approaches, such as a hypomethylating agent (HMA; decitabine or azacitidine) with venetoclax, are unknown. This study analyzed outcomes of CBF-AML with respect to higher-risk molecular and cytogenetic cohorts and treatment approaches. Methods: We identified 58 consecutive patients with CBF-AML treated at VCU Massey Cancer Center from January 1, 2013 to January 1, 2022. We used Fisher’s exact test for between-group comparisons. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. The date of death was used to calculate overall survival; patients were censored at the date of the last contact. Measurable residual disease (MRD) was assessed using PCR-based methods or multiparameter flow cytometry with a minimum sensitivity of 10-3. Results: We analyzed 58 patients with inv(16) or t(8;21) AML treated in the front-line setting. Seven of these patients had concomitant genetic or molecular abnormalities typically considered high risk, including complex cytogenetics or TP53mut. Forty-nine (84.5%) patients received intensive chemotherapy (IC) with FLAG, CPX-351, or conventional 7+3 with or without gemtuzumab ozogamicin; nine patients (15.5%) received lower-intensity therapies with HMAs with or without venetoclax. No differences in overall survival were seen between the patients with CBF-AML with or without complex cytogenetics or TP53mut (not reached for either cohort, median follow-up time of 6.1 y. and 5.0 y., respectively, p = 0.969). There was no difference in the rates of MRD negativity in CBF-AML with or without complex cytogenetics or TP53mut ( p = 0.544). The presence of secondary-type mutations also did not appear to significantly impact survival in CBF-AML ( p = 0.654). There was no difference in the rates of MRD negativity in CBF-AML with STMs and those without STMs ( p = 0.500). Patients that were ineligible for IC and were treated with venetoclax + HMA or HMA monotherapy had significantly reduced composite complete remission rates (CRR; CR + CRi; 25% vs 91.3%, p = 0.007) and median overall survival (3.7 m. versus not reached, p = 0.038). Conclusions: Our data confirm the superior outcomes in induction candidates of CBF-AML treated with IC. The presence of complex cytogenetics, TP53mut, or secondary-type mutations did not appear to influence the rates of MRD negativity or overall survival in CBF-AML.

Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS, KRAS, and FLT3-ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.

e19043 Background: Venetoclax and IDH inhibitors provide novel treatment options for acute myeloid leukemia (AML). The optimal sequencing of these therapies in the relapsed or refractory setting remains unknown. The purpose of this study was to analyze the overall survival of patients receiving IDH inhibitors, venetoclax-based lower-intensity therapy, and conventional chemotherapy with fludarabine-based regimens in patients undergoing salvage following failure of intensive chemotherapy. Methods: We identified 74 patients with IDH1mut or IDH2mut mutated AML treated from January 1, 2013 to January 1, 2022 at VCU Massey Cancer Center in this single-institution, retrospective study. Forty-eight patients were treated with front-line intensive induction, 19 of whom had relapsed or refractory disease. These were grouped into three salvage cohorts: IDH inhibitors with or without a hypomethylating agent (HMA) (N = 3), intensive fludarabine-based salvage (FLAG) (N = 9), and venetoclax + HMA (N = 7). Patients who received more than one of these salvage therapies were excluded from the analysis. Performance status, disease characteristics, and treatment regimens at salvage were recorded. Demographics of the three cohorts were compared using the Kruskal-Wallis test; we computed the overall survival with the Kaplan-Meier method, using the log-rank test for comparison. Patients alive at the end of the study or lost to follow-up were censored on the date of last contact. Results: Patients in the FLAG cohort were significantly younger than the IDH inhibitor or venetoclax cohorts ( p = 0.009). Patients in the venetoclax cohort had significantly more comorbidities assessed by the Charlson Comorbidity Index score ( p = 0.026) than the intensive chemotherapy salvage cohort. ELN 2022 genetic risk was not significantly different between cohorts ( p = 0.263). In the IDH inhibitor cohort, the median overall survival was not reached at a median follow-up time of 11.8 months. The median overall survival of the FLAG cohort was 14.3 months, and the median survival of the venetoclax cohort was 9.4 months. Overall survival significantly favored the IDH inhibitor cohort ( p = 0.030). The FLAG cohort was associated with significantly improved survival compared to the venetoclax cohort ( p = 0.048). Conclusions: Despite patients in the IDH inhibitor cohort being significantly older, the use of IDH inhibitors, with or without a hypomethylating agent, in the second line following the failure of intensive chemotherapy was associated with significantly superior overall survival compared to FLAG or venetoclax-based salvage. These findings should be interpreted with caution, given the limitations of retrospective studies and significantly elevated comorbidities in the venetoclax cohort. Prospective trial designs are needed to provide further evidence for optimal therapeutic sequencing.