Venetoclax Plus Chemotherapy Improves OS in Patients With AML, MDS

Findings from the phase 2 CLIA study show the safety and activity of venetoclax when added to intensive chemotherapy in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS; Lancet Haematol. 2021 Aug; 8(8):e552-e561. doi: 10.1016/S2352-3026(21)00192-7.)

According to lead investigator Tapan M. Kadia, Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, Texas, and co-investigators, the addition of venetoclax, a BCL2 inhibitor, to lower intensity therapy has been shown to improve overall survival (OS) in older (aged 75+) and unfit patients with newly-diagnosed AML.

Thus, Dr Kadia et al aimed to investigate the activity of venetoclax plus cladribine, high-dose cytarabine, and idarubicin (CLIA) in patients aged 65 or younger with AML.

Between Feb 25, 2019 and March 23, 2021, a total of 50 patients with a new diagnosis of AML, mixed phenotype of acute leukemia, or high-risk MDS who received no curative therapy for leukemia, were enrolled in the study at MD Anderson Cancer Center. Patients received cladribine and cytarabine intravenously on days 1-5 and idarubicin intravenously on days 1-3. Consolidation was cladribine and cytarabine on days 1-3 and idarubicin on days 1-2. Venetoclax was given on days 2-8 with each course. Patients with a known FLT3-IDT or FLT3-TKD mutated received midostaurin or gilteritinib.

The primary outcome was composite complete response (CR). Secondary outcomes included overall response (OR), duration of response (DOR), event-free survival (EFS), overall survival (OS), and safety.

Overall, 47 patients had composite CR as well as an OR; 2 patients did not response; and 1 patient died during induction. Thirty-seven out of 45 patients had undetectable MRD. At the median follow-up of 13.5 months, the median DOR, EFS, and OS were not reached. At 12 months, the estimated DOR was 74%, EFS was 68%, and OS was 85%.

The most common adverse events of grade ≥3 included febrile neutropenia (84%), infection (12%), and alanine aminotransferase elevations (12%).

There was 1 death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor, and 2 patients died of infections complications while in CR in consolidation cycles, both of whom had a FLT3-mutated AML and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.

Researchers concluded that venetoclax added to CLIA is safe and active in patients with newly diagnosed AML or high-risk MDS, producing high-rates of durable MRD-negative remissions and encouraging EFS and OS.—Emily Bader