Comparison of FLAG-Idarubicin to FLAG-Idarubicin Plus Venetoclax for Treatment of Newly Diagnosed AML in Patients Eligible for Intensive Induction. Analysis of 200 Consecutive Patients Treated at a Single Center

The combination of 3 days of anthracycline and 7 days of infusional cytarabine (3+7) has been the most-commonly aministered induction chemotherapy regimen for newly diagnosed patients eligible for intensive therapy over five decades. However, CR rates and long-term outcomes in non-favorable risk AML induced with 3+7 have been unsatisfactory. We previously demonstrated that initial remission induction therapy with the combination of three days of idarubicin with five days of fludarabine and intermediate dose cytarabine (FLAG-Ida) results in improved outcomes without added toxicity compared to 3+7 in non-favorable risk AML (Solh et al Leukemia Research 2020). The addition of venetoclax to FLAG-Ida (FLAG-Ida-Ven) was recently shown to be tolerable and efficacious (DiNardo et al Am J Hematol 2022) but has not been directly compared to FLAG-Ida. Starting in mid-2022 our center changed its preferred initial intensive induction regimen for AML from FLAG-Ida to FLAG-Ida-Ven. Venetoclax was administered without ramp-up for 14 consecutive days starting on d1 of the regimen. Here we compare patients induced with FLAG-Ida-Ven to those induced with FLAG-Ida over a five -year period at our center. All consecutive patients receiving initial induction for AML with either regimen from January 2019 to March 2024 (n=200) were included in the analysis (FLAG-Ida =154, FLAG-Ida-Ven=46). Diagnostic procedures, supportive care measures and response assessments were identical between patients treated with the two regimens. FLT-3 inhibitor therapy was added to all patients with a FLT-3 activating mutation and gemtuzumab ozogamicin (GO)was added to all patients with core-binding factor (CBF) AML during induction therapy. Patient characteristics, response and hematopoietic cell transplantation (HCT) data was extracted from our institutional database where they had been prospectively entered. Patient characteristics for patients treated with FLAG-Ida-Ven and FLAG-Ida respectively were well matched and not statistically different : Median age 55 vs 57; male 54% vs 54%; race -white 67% vs 71%, black 26% vs 20%; WBC at diagnosis 11.5 vs 19 x 10e9/L, median BM blasts 51% vs 60%, cytogenetic risk groups – favorable 15% vs 14%, intermediate 76% vs 71%, adverse 9% vs 15%; NCCN overall risk group – favorable 28% vs 32%, intermediate 20% vs 17%, adverse 52% vs 51%. Complete remission (CR) and Composite CR (CRc) rates following a single cycle of FLAG-Ida-Ven vs FLAG-Ida were 93% vs 83% (p=0.07) and 98% vs 88% (p=0.05) respectively. In NCCN poor/intermediate risk AML, CR rates were 91% vs 75% (p=0.06) and CRc rates were 97% vs 83% (p=0.047) respectively. Hospital length of stay for induction therapy was slightly shorter for FLAG-Ida-Ven than FLAG-Ida: median 23 vs 26 d (p=0.042) IQR 21-29 d vs 23-30. Deaths within 60 days of start of induction were 9% vs 4% (p=NS) and positive blood cultures during induction were seen in 30% vs 26% (p=NS). For patients with NCCN intermediate/poor risk AML 55% vs 59% (p=NS) of patients induced with FLAG-Ida-Ven and FLAG-Ida proceeded to HCT within 6 months of induction with no significant difference in type of donor or regimen used. Estimated K-M probabilities of one year leukemia-free survival (LFS) for FLAG-Ida-Ven vs FLAG-Ida were 75% vs 77% (p=NS). For patients undergoing HCT, one-year LFS post-transplant was 76% vs 80% (p=NS). This direct comparison of patients consecutively treated over 5 years at a single center suggests that addition of venetoclax to the FLAG-Ida regimen results in significantly higher composite CR rates in non-favorable risk AML without additional toxicity or prolongation of inpatient stay. A similar proportion of non-favorable risk AML treated with either regimen proceeded to HCT within 6 months. Analysis of LFS and post-transplant outcomes was limited by relatively short follow-up among the FLAG-Ida-Ven cohort and will benefit from later reassessment. FLAG-Ida-Ven should be considered a standard remission induction regimen for fit newly diagnosed AML patients especially for patients with non-favorable risk disease.