Combination of Venetoclax Plus FLAG-IDA Leads to High Response Rates in Newly Diagnosed AML

By DocWire News Editors - Last Updated: April 13, 2023

According to research presented during the 2021 ASH Annual Meeting, induction and consolidation therapy comprising venetoclax plus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) induced responses in 98% of patients with newly diagnosed acute myeloid leukemia (AML). However, this regimen may be associated with inferior outcomes in patients with TP53 mutations versus those with wild-type TP53, the investigators, led by Curtis Lachowiez, MD, reported.

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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. 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 overall response rate (ORR) was 98%, which included a complete remission (CR) rate of 73%, CR with partial recovery of peripheral blood counts (CRh) rate of 12%, CR with incomplete count recovery (CRi) rate of 2%, and morphologic leukemia-free state (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; p = 0.001) and ELN risk group (HR = 1.92; p = 0.008). In contrast, there was a decreased risk of mortality with FLAG-IDA plus venetoclax versus FIA (HR = 0.28; p = 0.02).

Post Tags:AML
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