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Venetoclax Plus FLAG-IDA Shows Promising Responses in Newly Diagnosed AML

January 13, 2022

Mid-January 2022

Induction and consolidation therapy comprising venetoclax plus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) was highly effective for the treatment of newly diagnosed acute myeloid leukemia (AML), according to research presented during the 2021 ASH Annual Meeting. However, patients with AML harboring TP53 mutations had an inferior survival versus those with wild-type TP53 when treated with the combination, reported lead author Curtis Lachowiez, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In the study, Dr. Lachowiez and colleagues investigated the overall activity of the FLAG-IDA plus venetoclax regimen in 41 patients with newly diagnosed AML. Activity of the treatment was assessed by the overall response rate (ORR), defined by complete remission (CR), CR with incomplete count recovery (CRi), CR with partial recovery of peripheral blood counts (CRh), morphologic leukemia-free state (MLFS), and partial response (PR). The researchers also assessed overall survival (OS), event-free survival (EFS), duration of response (DOR), and biomarkers predictive of venetoclax sensitivity in the patient population.

The cohort comprised patients with de novo AML (n=29), secondary AML (sAML; n=7), and treatment-related AML (tAML; n=5). The median age of the overall cohort was 44 years (range = 20-65). European LeukemiaNet (ELN) risk statuses were favorable in 20%, intermediate in 37%, and adverse in 44% of patients. The most common mutations were NRAS (29%), IDH2 (17%), RUNX1 (15%), and NPM1 (15%). At time of diagnosis, TP53 mutations were identified in 10% of patients, while KMT2A rearrangements were reported in 12% of patients.

Patients received a median of two treatment cycles (range = 1-6). According to the investigators, the ORR was 98%, which included a CR rate of 73%, CRh rate of 12%, CRi rate of 2%, and MLFS rate of 10%. Measurable residual disease negativity was achieved in 92% of patients with CR, CRh, and CRi.

The median time to best response was 29 days; however, patients achieved best response by as few as 22 days, the authors noted. After a median of 3.8 months, a total of 27 patients (66%) transitioned to allogeneic hematopoietic cell transplantation (HCT).

Patients did not reach the median DOR. The median length of cycles 1 and 2 were 31 and 41 days, respectively. Additionally, the median duration between treatment initiation and count recovery, which was defined as absolute neutrophil count 500 cells/mm3 and platelet count 50×109/L, was significantly longer after cycle 2 versus cycle 1 (47 vs. 32 days, respectively; p<0.001).

The most frequently reported adverse events in the study were febrile neutropenia (39%), pneumonia (24%), and bacteremia (19%). The researchers reported no 30- or 60-day mortality events. Nine patients experienced disease relapse, including in all four patients with TP53 mutations and one patient with inv(3) at baseline.

During the median follow-up period of 16 months, the median OS and EFS rates were not reached. The estimated one-year OS was 96%, while the one-year EFS was 77%. An 18-month survival of 100% was reported in patients with KMT2A rearrangements (n=5) as well as NPM1, IDH1, and/or IDH2 mutations (n=13). A significantly inferior OS was observed in patients who had TP53 mutations at diagnosis versus those with wild-type TP53 (24 months vs. not reached, respectively; p=0.03). In addition, those with TP53 mutations at diagnosis had an inferior median EFS (8 months vs. not reached; p<0.001) compared with wild-type TP53 patients.

In a propensity score-matched analysis that compared patients with a historical cohort treated with frontline FIA (fludarabine, idarubicin, cytarabine) induction, treatment with FLAG-IDA plus venetoclax led to significantly longer median OS (not reached vs. 47 months; p=0.022) as well as a trend toward improved median OS (24 vs. 19 months; p=0.09) and EFS (not reached vs. 8 months; p=0.064) rates in patients who did not undergo HCT.

A multivariate analysis showed a significant association between increased risk of mortality and advanced age (hazard ratio [HR] = 1.05; 95% CI 1.02-1.09; p=0.001) and ELN risk group (HR=1.92; 95% CI 1.185-3.11; p=0.008). In contrast, there was a decreased risk of mortality with FLAG-IDA plus venetoclax versus FIA (HR=0.28; 95% CI 0.096-0.84; p=0.02).

While promising, the authors noted that these results need to be confirmed in prospective randomized trials.

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Lachowiez C, DiNardo CD, Takahashi K, et al. Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia. Abstract #701. Presented at the 2021 American Society of Hematology Annual Meeting, December 13, 2021.

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