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The addition of the BCL-2 inhibitor venetoclax (Venclexta) to intensive chemotherapy was safe and active in patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes, researchers reported.

Of the 50 patients who participated in the study, 94% had a composite complete response to the regimen, while 82% had undetectable measurable residual disease (MRD), said Tapan M. Kadia, MD, and colleagues from MD Anderson Cancer Center in Houston.

As they explained in , the 7+3 regimen (7 days of standard-dose cytarabine [Cytosar-U] and 3 days of anthracyclines) has long been the standard of care for initial induction treatment for younger and fit patients with newly diagnosed AML, and there have been multiple attempts over the years to improve on this regimen in order to extend long-term overall survival (OS).

Venetoclax in combination with lower-intensity therapy has become a part of standard of care for older and unfit patients with newly diagnosed AML. After positive results from the and trials venetoclax was granted full for use in combination with azacitidine, decitabine, or low-dose cytarabine for adults ages 75 or older with newly diagnosed AML, or in those who have comorbidities that prevent intensive induction chemotherapy.

With the idea of further optimizing frontline therapy for younger and fit patients, Kadia's team evaluated venetoclax combined with intensive chemotherapy in newly diagnosed younger (ages 65 and under) and fit patients with AML.

The phase II cohort study, conducted at MD Anderson, enrolled 50 patients (median age of 48) with a new diagnosis of AML, mixed phenotype acute leukemia, or high-risk myelodysplastic syndromes, with no previous potentially curative therapy for leukemia.

Participants 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 (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin (Rydapt) or gilteritinib (Xospata).

Of the 50 patients, 42 had a complete response and five had a complete response with incomplete blood count recovery. Two patients did not respond, and a third died during induction therapy.

Of the 45 patients available for MRD assessment, 37 had undetectable MRD while on the study, the investigators reported.

At a median follow-up of 13.5 months, median OS was not reached, while the estimated 12-month OS rate was 85%. Median event-free survival was also not reached, and the estimated 12-month event-free survival rate was 68%.

Kadia and colleagues noted that the regimen's activity was observed across all risk groups, with an estimated 12-month OS rate of 78% among the favorable European LeukemiaNet (ELN) risk group, 93% among the intermediate ELN risk group, and 81% among the adverse ELN risk group.

The most common grade 3 or higher adverse events were febrile neutropenia (84% of patients), infection (12%), and alanine aminotransferase elevations (12%).

The authors noted that the patient who died during induction had received a concomitant FLT3 inhibitor, and had bacteremia and sepsis before count recovery. Two other patients died while in complete response in consolidation cycles, both of whom had FLT3-mutated AML and were receiving combination therapy with an FLT3 inhibitor.

No deaths were considered to be treatment related, the researchers said.

They wrote that while this was a single-center, single-arm study with no comparator or control groups, it can nonetheless "provide the basis for future randomized comparisons to help confirm the benefit in increasing long-term overall survival."

In an , Prachi Jain, MBBS, and Alice Mims, MD, both of Ohio State University in Columbus, agreed that a randomized, multicenter study is needed to more fully evaluate the benefits of adding venetoclax to intensive chemotherapy, and also raised the issue of which therapies will be optimal in combination with venetoclax.

"The question remains whether more intensive chemotherapy is needed as the backbone for venetoclax or whether a comparison of hypomethylating agents plus venetoclax would show similar results in regards to outcomes, including MRD negativity, with less toxicity and potentially better quality of life," Jain and Mims wrote.

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