Alternating Venetoclax Regimens Strategy for Newly Diagnosed AML

Cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax showed high rates of complete remission (CR), CR with incomplete count recovery (CRi), and measurable residual disease (MRD) negativity in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy or aged 60 years and older, according to a phase II prospective trial.

“The responses yielded favorable long-term overall survival (OS) and event-free survival (EFS) profiles in this population,” said Alexandre Bazinet, MD, of The University of Texas MD Anderson Cancer Center, while presenting at the 66th American Society of Hematology Annual Meeting & Exposition.

The analysis included 141 patients with a median age of 68 years (range, 47–84). Mutations included DNMT3A in 30% of patients, NPM1 in 23%, N/KRAS in 21%, TET2 in 20%, TP53 in 17%, and FLIT3-ITD in 4%.

The composite CR rate was 85% (n=120) including 73% of patients with a CR and 12% with a CRi. Among these patients, 78% achieved MRD negativity based on flow cytometry. The median number of cycles given was two (range, 1–18), and 62 patients (44%) went on to receive allogeneic hematopoietic stem cell transplant during CR.

According to the report, complex karyotype (hazard ratio [HR], 2.97; 95% C I, 1.55-5.67; P<.001) and NPM1 mutation (HR, 0.38; 95% CI, 0.17-0.86; P=.02) were independent prognostic factors for OS.

The researchers also generated a risk model to predict the most influential variables for OS, which categorized patients with NPM1 or DDX41 mutations as very good risk; patients without risk-defining genetic abnormalities as good risk; patients with N/KRAS without NPM1 mutations as intermediate risk; and patients with complex karyotype or multihit TP53 mutation as poor risk.

This model stratified patients according to survival with better performance than European LeukemiaNet 2022 criteria, the researchers said.

“Benefit was seen across most genomically defined subgroups, including those with RAS mutations, where a hypomethylating agent plus venetoclax alone approach is associated with a median OS of 12 months,” noted Dr. Bazinet.

 

Reference

Bataller A, Kantarjian HM, Bazinet A, et al. Phase II study of cladribine with low dose cytarabine and venetoclax alternating with azacytidine and venetoclax for newly diagnosed acute myeloid leukemia. Abstract #56. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.