Venetoclax/HMA combo still safe, effective for elderly with AML

In patients aged 65 years and older with acute myeloid leukemia (AML), the combination of venetoclax (Venclexta) and a hypomethylating agent had good efficacy and was well tolerated, according to updated results from a phase 1b dose-escalation and expansion trial.

Dr. Courtney DiNardo

At a median of 8.9 months of study, the overall response rate (ORR) among all treated patients was 68%, with a median duration of complete remission (CR) plus CR with incomplete count recovery (CRi) of 11.3 months, reported Courtney DiNardo, MD, from the University of Texas MD Anderson Center in Houston and her colleagues.

“Venetoclax in combination with azacitidine or decitabine was well tolerated, with similar safety profiles within all arms of the dose escalation and expansion phases in elderly patients with previously untreated AML ineligible for standard induction therapy,” they wrote in a paper published in Blood.

At the 2017 European Hematology Association Congress, the investigators reported that the combined rate of complete remission CR and CRi was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the drug combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).

In this, the most recent analysis, Dr. DiNardo and her colleagues reported on follow-up of 145 patients aged 65 and older with treatment-naive AML who were not eligible for intensive chemotherapy regimens used for younger adults. The median age was 74 years. Approximately half of all patients (49%) had poor-risk cytogenetics.

The patients were treated with either decitabine or azacitidine plus venetoclax at a dose of either 400 mg or 800 mg. Decitabine was dosed at 20 mg/m² intravenously on days 1-5 of a 28-day cycle. Azacitidine was dosed at 75 mg/m² subcutaneously on days 1-7 of every cycle.

The median time on study was 8.9 months. Among all patients treated at all doses, 67% had either a CR or CRi. The combined CR/CRi rate in patients treated at the 400 mg dose of venetoclax was 73%.

The CR/CRi rate for patients with poor-risk cytogenetics was 60%, and the rate for patients aged 75 years and older was 65%.

Among all patients, the median duration of CR/CRi was 11.3 months, and median overall survival was 17.5 months. In the 400 mg venetoclax cohort, the median duration of CR/CRi was 12.5 months, with the median OS not reached at the time of data cutoff.

Adverse events occurring in 30% or more of patients included constipation, diarrhea, vomiting, nausea, fatigue, febrile neutropenia, hypokalemia, decreased appetite, and decreased white blood cell count. There were no reported cases of the tumor lysis syndrome, a known complication of venetoclax therapy.

Venetoclax plus decitabine or azacitidine was effective in high-risk subgroups, including patients aged 75 years and older, those with poor cytogenetic risk, and those with secondary AML, the investigators noted.

“Though these observations are drawn from a relatively small subset of patients, the remission rates achieved by our low-intensity regimen are encouraging in light of the traditionally lower remission rates in the elderly AML population (40%-50%) compared with young patients receiving chemotherapy (60%-70%) and the relatively short duration of these remissions,” Dr. DiNardo and her colleagues wrote.

A phase 3 trial is currently underway comparing venetoclax at the 400 mg dose plus azacitidine with azacitidine alone in treatment-naive patients with AML who are ineligible for standard induction therapy.

The trial was supported by AbbVie and Genentech. Dr. DiNardo and multiple coauthors disclosed relationships with AbbVie, Genentech, and other companies.

SOURCE: DiNardo C et al. Blood. 2018 Oct 25. doi: 10.1182/blood-2018-08-868752.