Results of a phase 2 trial suggest the BCL2 inhibitor venetoclax can produce responses in patients with acute myelogenous leukemia (AML) who do not respond to or cannot tolerate chemotherapy.
However, the overall response rate in this trial was low, and responses were not durable.
All of the patients studied discontinued venetoclax, most due to disease progression.
The study was published in Cancer Discovery. It was funded by AbbVie in collaboration with Genentech/Roche.
The trial included 32 patients with AML and a median age of 71 (range, 19–84). Thirteen patients had an antecedent hematologic disorder or myeloproliferative neoplasm, and 4 had therapy-related AML with complex cytogenetics.
Twelve patients had mutations in IDH genes, and 6 had a high BCL2-sensitive protein index.
Thirty patients had received at least 1 prior therapy, and 13 had received at least 3 prior treatment regimens. Two patients were considered unfit for intensive chemotherapy and were treatment-naive at study entry.
The patients received venetoclax at 800 mg daily. All 32 patients received at least 1 dose, and 26 patients received at least 4 weeks of therapy.
Efficacy
The overall response rate was 19%. Two patients had a complete response (CR), and 4 had a CR with incomplete blood count recovery. Three of the 6 responders had an antecedent hematologic disorder.
“[E]ven among pretreated patients whose AML was refractory to intensive chemotherapy, there was evidence of exceptional sensitivity to selective BCL2 inhibition, even to the point of complete remissions,” said study author Anthony Letai, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days.
The 4 patients who had CRs with incomplete count recovery had IDH mutations. Response to the drug correlated with biomarker results, including indices of BCL2 protein expression and BH3 profiling.
“This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL2,” Dr Letai said. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”
Safety and discontinuation
All of the patients discontinued therapy—29 due to progressive disease and 1 due to an adverse event (terminal ileitis). One patient withdrew consent, and 1 proceeded to allogeneic transplant after achieving stable disease.
All of the patients experienced treatment-emergent adverse events. The most common were nausea (59%), diarrhea (56%), hypokalemia (41%), vomiting (41%), fatigue (34%), headache (34%), hypomagnesemia (34%), febrile neutropenia (31%), and hypophosphatemia (31%).
Serious adverse events occurred in 84% of patients. These included febrile neutropenia (28%), pneumonia (16%), abdominal pain (6%), acute renal failure (6%), failure to thrive (6%), hypotension (6%), sepsis (6%), and urinary tract infection (6%).
Based on the results of this trial, the researchers concluded that venetoclax may be a viable treatment option for AML patients when used in combination with other therapies.
“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,” said study author Marina Konopleva, MD, PhD, of MD Anderson Cancer Center in Houston, Texas.
“Planned studies will test the hypothesis that venetoclax may likewise improve outcomes in younger AML patients when combined with high-dose chemotherapy.”
