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Vadastuximab talirine appears safe, effective when combined with 7 + 3 chemotherapy for AML induction
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SAN DIEGO — Vadastuximab talirine was safely combined with 7 + 3 chemotherapy for the induction treatment of patients with acute myeloid leukemia, according to results of a dose-escalation study presented at the ASH Annual Meeting and Exposition.
The combination also conferred a high remission rate, the majority of which were minimal residual disease–negative remissions, after the first induction cycle.
Standard induction treatment for patients aged younger than 65 years with AML includes continuous infusion of cytarabine for 7 days with an anthracycline for 3 days, also known as 7 + 3 chemotherapy.
This regimen confers complete response in the majority of patients; however, some patients require a second induction because they are primarily resistant to treatment, or because they achieve a morphologic complete response but have flow cytometric or molecular evidence of minimal residual disease.
“Nothing has been shown to be superior to 7 + 3 chemotherapy, despite 4 decades of research,”
Harry P. Erba, MD, PhD, professor of medicine and director of the hematologic malignancy program at University of Alabama at Birmingham, said during a press conference. “What we’ve learned more recently is the depth of remission after that initial treatment, by using very sensitive tests, may predict for better outcome.
“This led to the hypothesis that if we can change in some way the induction therapy to get a deeper remission, or a minimal residual disease–negative state, this may ultimately lead to improved outcomes for patients,” Erba added.
Vadastuximab talirine (SGN-CD33A, Seattle Genetics) is an antibody directed at CD33, which is a cell surface antigen expressed in nearly 90% of AML patients.
Erba and colleagues evaluated whether the addition of vadastuximab talirine to 7 + 3 chemotherapy could enhance and deepen remission from induction treatment, leading to a reduction in relapse and greater OS.
The analysis included 42 patients (median age, 45.5 years; range, 18-65 years; 36% men) who received vadastuximab talirine in 10 + 10–mcg/kg (n = 4) or 20 + 10–mcg/kg (n = 38) doses on days 1 and 4 concomitantly with 7 + 3 induction therapy (100 mg/m2 cytarabine plus 60 mg/m2 daunorubicin).
Fifty percent of patients had intermediate cytogenetic risk and 36% had adverse cytogenetic risk per Medical Research Council criteria. Seventeen percent of patients had secondary AML.
Researchers conducted response assessments on days 15 and 28; bone marrow examination using a multi-parametric flow cytometric assay determined minimal residual disease status.
B est response included complete response 60% of patients , or complete response with flow cytometric or molecular evidence of minimal residual disease in 17%.
Thus, the overall response rate was 76%; 94% of these responses occurred after cycle 1 of induction therapy.
“Overall, the response rate of 76% is not too dissimilar from what we would see in a well-chosen population of patients who are fit for a clinical trial,” Erba said. “So why are we getting excited about this? There was a hint from a study that this might add benefit. The first hint was that 30 out of the 32 patients only required one round of chemotherapy to achieve that remission. Just that fact might not lead to FDA approval, but it is really important for a patient who cares about the difference of being in the hospital for 4 weeks vs. 6 to 8 weeks. It also suggested, though, that we might be getting deeper remissions.”
Using a sensitive assay, researchers found 25 of the 32 patients (78%) attained minimal residual disease–negative status.
Among patients who achieved a complete response or complete response with flow cytometric or molecular evidence of minimal residual disease, estimated median time to neutrophil recovery was 33 days and to platelet recovery was 35 days.
Three dose-limiting toxicities — including lack of platelet and absolute neutrophil count recovery by day 42 — occurred at the 20 + 10–mcg/kg dose level, which researchers determined was the maximum tolerated dose.
All patients experienced grade 4 myelosuppression.
Grade 1 or grade 2 nonhematologic adverse events that occurred in more than 15% of patients included nausea (55%), diarrhea (33%), constipation (31%) decreased appetite (19%), fatigue (19%) and vomiting (17%).
Researchers reported no infusion-related reactions, veno-occlusive disease or significant hepatotoxicity.
Mortality rates were 0% at 30 days and 7% at 60 days.
Median OS had not been reached at the time of the analysis. Thirty-six patients were alive and six (14%) were still on treatment.
“We are hoping these deep remissions will translate into a real benefit for patients, which obviously we’ll only be able to test in a setting of a randomized trial, which is planned to start in the first quarter of 2017,” Erba said. – by Alexandra Todak
Reference: Erba HP, et al. Abstract 211. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
Disclosure: Erba reports research funding from Seattle Genetics, as well as additional financial relationships with various pharmaceutical companies. Please see the abstract for a list of all researchers’ relevant financial disclosures.
Perspective
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Mikkael Sekeres, MD, MS
This study seeks to improve OS and overall relapse rates for patients with acute myeloid leukemia, a cancer of the bone marrow. Leukemia can be deadly and even with the best available therapy, just over a quarter of patients survive 5 years after their diagnosis. In a clinical trial, the experimental drug vadastuximab talirine — or 33A, a monoclonal antibody designed to specifically target AML cells — was demonstrated safe when combined with a standard chemotherapy regimen, and effective, with three quarters of patients achieving remission.
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