This article is more than 5 years old. Information may no longer be current.
Single-agent venetoclax shows promise in relapsed, refractory AML
Click Here to Manage Email Alerts
Venetoclax exhibited promising clinical activity and an acceptable safety profile in patients with relapsed or refractory acute myelogenous leukemia, according to results of a single-arm phase 2 study.
The agent also showed promise in patients with AML who are unable to receive intensive chemotherapy.
Anthony G. Letai
Venetoclax (Venclexta; AbbVie, Genentech) received FDA approval in April 2016 for the treatment of chronic lymphocytic leukemia. The drug functions as a highly selective, small molecule inhibitor of B-cell leukemia/lymphoma-2 (BCL-2).
“AML is a disease in which new therapies are desperately needed, and based on published preclinical work, this type of cancer seemed to be an excellent target for the BCL-2 inhibitor venetoclax,” Anthony G. Letai, MD, PhD, associate professor of medicine at Harvard Medical School and staff physician at Dana-Farber Cancer Institute, said in a press release. “In this clinical trial, we found that even among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL-2 inhibition, even to the point of complete remissions.”
The analysis included data from 32 patients (median age, 71 years; range, 19-84) with high-risk relapsed or refractory disease, or who were deemed unfit for intensive chemotherapy.
Patients receive an 800 mg daily course of oral venetoclax. All patients received at least one therapeutic dose, and 26 patients completed at least 4 weeks of therapy.
The entire cohort had an overall response rate of 19% (n = 6), which included two complete responses and four complete responses with incomplete platelet recovery.
All responding patients had prior therapy with hypomethylating agents, and three responders had antecedent hematologic disorders.
An additional six patients (19%) displayed antileukemic activity, such as partial bone marrow response and incomplete hematologic recovery, but failed to meet International Working Group criteria for response.
Four of 12 patients who harbored IDH1 or IDH2 mutations responded to therapy.
The median time on study for responding patients was 144.5 days (range, 83-256), with a median response duration of 48 days.
The median time to progression was 2.5 months (range, 1-3). Ten percent (95% CI, 2.5-23.3) of patients achieved 6-month leukemia-free survival.
The researchers estimated a 6-month OS of 36% (95% CI, 20-53) and a median OS of 4.7 months (range, 2.3-6).
All but one patient had available peripheral blood samples, which the researchers used to conduct biomarker studies.
Twenty-two patients were evaluated for BCL-2 family protein expression, of whom six had a BCL-2 family sensitivity protein index. One patient in this cohort achieved a complete remission with incomplete platelet recovery, and three patients exhibited antileukemic activity.
Patients with a BCL-2 family sensitivity protein index remained on venetoclax for a longer duration than those without (P = .0381).
The researchers also used BH3 profiling, which identified potential resistance mechanisms and correlated with on-target BCL-2 inhibition.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL-2,” Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
All patients experienced treatment-related adverse events, the most common of which included any-grade nausea, diarrhea, hypokalemia, vomiting and headache.
Eighty-four percent (n = 27) of patients experienced a serious adverse event, the most common of which was febrile neutropenia (31%; n = 10).
No patients required a dose reduction due to adverse events, although eight patients temporarily interrupted treatment.
All patients discontinued therapy, mostly due to progressive disease (n = 29). One patient each discontinued due to adverse events, consent withdrawal, or in order to proceed to hematopoietic stem cell transplantation.
The researchers acknowledged limitations of their study. The majority of the cohort did not achieve a clinical response, and those who did experienced short-lived responses. Additionally, biomarker analyses were conducted retrospectively.
“We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combinations with hypomethylating agents and other approaches,” Letai said. “Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.” – by Cameron Kelsall
Disclosure: AbbVie and Genentech provided funding for this study. Letai reports research support from and a consultant role with AbbVie. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to Top
Henry Fung
It is astonishing that gemtuzumab ozogamicin (Mylotarg, Pfizer) was the last drug approved by the FDA for treatment of acute myelogenous leukemia (non–acute promyelocytic leukemia). It was approved in 2000, and Pfizer voluntarily withdrew it from the market in 2010.
Anthony G. Letai , MD, PhD, and colleagues have reported early results from a study investigating the small molecule venetoclax (Venclexta; AbbVie, Genentech) in patients with relapsed or refractory AML. It was impressive that complete remission could be achieved with a single agent in patients with advanced leukemia, although duration of response was very brief (median, 48 days) and the overall response rate was only 19%. More importantly, response correlated with BCL-2 protein expression and BH3 profiling.
It is very unlikely that a single agent can significantly alter the natural history of the disease. I am almost certain that future studies will focus on incorporating venetoclax into existing induction or consolidation regimens and include all patients with AML. It is arguable that venetoclax in combination with conventional chemotherapy may benefit more patients, even with poor response as a single agent. However, in the era of precision medicine, it is time to treat different AML differently, and BCL-2 expression and BH3 profiling may be helpful for patient selection.
Click Here to Manage Email Alerts