IDH inhibitors or chemotherapy in relapsed or refractory IDHmut acute myeloid leukemia.
Authors: Murray Graeme , Bouligny Ian Michael , Patel Tilak , Doyel Michael , Boron Josh , Tran Valerie , Gor Juhi , Hang Yiwei , Ho Thuy , Zacholski Kyle , Venn Chad Michael , Alnimer Yanal Mufeed , Wages Nolan , Grant Steven , Maher Keri Renee ,   LCRT
Published: June 2023

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.