Venetoclax regimen improves outcomes in AML with IDH mutations
The addition of venetoclax to azacitidine benefited untreated patients with isocitrate dehydrogenase mutations ineligible for intensive chemotherapy, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The combination of venetoclax (Venclexta; AbbVie, Genentech) and azacitidine appeared associated with a higher response rate, longer duration of response and longer OS than azacitidine alone.
“[Patients with AML] with IDH mutations have even better responses to venetoclax-based regimens than IDH wild-type patients,” Daniel A. Pollyea, MD, MS, clinical director of leukemia services and Robert H. Allen chair in hematology research at University of Colorado Denver, told Healio. “No differences in toxicity were observed [between] IDH-positive and IDH wild-type patients treated with venetoclax.”
Approximately 20% of patients with AML have IDH mutations. They are more common among older patients.
Preclinical data showed venetoclax — which selectively binds and inhibits the BCL-2 protein — had activity against cells with IDH1/2 mutations. Clinical studies demonstrated patients with IDH1/2 mutations who received venetoclax and azacitidine achieved durable responses and longer median OS than those who received azacitidine alone.
Pollyea and colleagues aimed to evaluate the efficacy and safety of venetoclax and azacitidine for previously untreated patients with AML who had IDH1/2 mutations and were ineligible for intensive treatment due to age (75 years or older) or comorbidities, such as congestive heart failure requiring treatment or ejection fraction 50% or less, chronic stable angina, ECOG performance status 2 or 3, carbon monoxide diffusing capacity of 65% or less, or forced expiratory volume of 65% or less.
Researchers pooled data from two studies: the phase 3 VIALE-A trial, designed to compare venetoclax-azacitidine vs. placebo-azacitidine, and a phase 1B study in which all patients received venetoclax-azacitidine. In both studies, patients treated with the combination received venetoclax dosed at 400 mg orally daily, plus azacitidine dosed at 75 mg/m2 on days 1 to 7 of each 28-day cycle.
“The rationale was to accumulate as many IDH-positive patients treated with venetoclax plus azacitidine as possible and compare them with a group of IDH-positive patients who received azacitidine plus placebo to help better appreciate a trend we have noticed since the very first [study of venetoclax in AML] — that IDH-positive patients have better responses to venetoclax-based regimens,” Pollyea said.
Key endpoints for the pooled analysis included OS, complete response (CR), complete response with partial hematologic recovery (CRh), complete response with incomplete hematologic recovery (CRi) and safety.
Investigators isolated DNA from bone marrow aspirates collected from patients before they received the first dose of study drug. In the phase 3 study, samples were assessed with the Abbott RealTime IDH1 (Abbott) and Abbott RealTime IDH2 (Abbott) assays. In the phase 1B study, samples were assessed using the MyAML panel (Invivoscribe).
Patients with positive tests were classified as mutation “detected” and those with negative tests were classified as mutation “not detected.” Patients with missing specimens or inconclusive tests were excluded.
The biomarker pooled analysis included 433 evaluable patients, including 306 treated with venetoclax-azacitidine and 127 treated with placebo-azacitidine. Of these patients, 107 had detected IDH1/2 mutations and 326 did not.
Among those with detected IDH mutations, median age was comparable between the venetoclax-azacitidine and placebo-azacitidine groups (76 years vs. 78 years).
The majority of patients in each treatment group had de novo AML (73% vs. 86%), intermediate cytogenetic risk (79% vs. 68%), and ECOG performance status of 0 or 1 (56% vs. 68%).
Median number of treatment cycles among patients with IDH mutations was eight (range, 1-37) for those who received venetoclax-azacitidine and 2.5 (range, 1-18) for those who received placebo-azacitidine.
Among those with detected IDH1/2 mutations, a considerably higher percentage who received venetoclax-azacitidine than placebo-azacitidine achieved CR or CRh (72% vs. 7%).
Those who received venetoclax had shorter median time to CR/CRh (1 month vs. 2.6 months) and were more likely to achieve CR/CRh by the start of cycle 2 (51% vs. 0%). They also achieved longer median duration of response (29.5 months vs. 15.5 months) and longer median OS (24.5 months vs. 6.2 months).
Researchers observed similar trends based on specific mutation type.
In the venetoclax-azacitidine treatment group, patients with detected IDH1/2 mutations appeared more likely than those with no detected mutations to achieve CR/CRh (72% vs. 60%). They also achieved longer median duration of response (29.5 months vs. 17.5 months) and longer median OS (24.5 months vs. 12.3 months).
The venetoclax-azacitidine combination exhibited an acceptable safety profile, Pollyea said. Researchers observed no unexpected toxicities with the combination.
Among patients treated with venetoclax-azacitidine, rates of grade 3 or grade 4 hematologic adverse events were comparable between those with and without IDH1/2 mutations (81% vs. 74%). These included thrombocytopenia (46% vs. 34%), febrile neutropenia (43% vs. 41%), neutropenia (35% vs. 33%) and anemia (29% vs. 24%). However, there were no significant differences in pneumonia or sepsis between treatment groups.
The study results confirm the addition of venetoclax to azacitidine results in higher response rates and longer duration of responses among patients with IDH1 or IDH2 mutations, making it an effective first-line therapy option for patients with AML and IDH1 or IDH2 mutations who are ineligible for intensive chemotherapy, Pollyea said.
“The next step would be for the field to help identify why IDH mutations confer additional sensitivity [to] venetoclax so that [patients without IDH mutations] could also potentially derive this degree of benefit from this regimen,” Pollyea told Healio.
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Pollyea DA, et al. Abstract 461. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.