Venetoclax Shows Promising Efficacy in Relapsed or Refractory Acute Myelogenous Leukemia

Venetoclax (Venclexta) monotherapy has significant clinical activity in patients with acute myelogenous leukemia (AML) whose disease has relapsed or is resistant to chemotherapy and in those deemed unable to tolerate chemotherapy, according to a new study (Konopleva M, et al. Cancer Discov. 2016 Aug 12. Epub ahead of print). The overall response rate (ORR) for venetoclax in the phase 2 single-arm study was 19%, with complete remissions in some patients. This was the first study to examine venetoclax monotherapy in patients with relapsed or refractory AML or untreated AML who are unfit for intensive therapy.

Venetoclax is a highly selective, oral small-molecule inhibitor of B-cell lymphoma/lymphoma-2 (BCL-2). In April 2016, venetoclax was approved by the FDA for the treatment of patients with chronic lymphocytic leukemia with 17p deletion.

“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,” said Anthony Letai, MD, PhD, Associate Professor of Medicine, Harvard Medical School, Boston, and the study’s senior investigator, in a press release. “This could be accomplished by a single oral dose of venetoclax daily and demonstrated the potential clinical activity of BCL-2 inhibition in AML.”

Dr Letai and colleagues recruited 32 patients with AML (median age, 71 years) to evaluate oral venetoclax at a dosage of 800 mg daily. A total of 26 patients received at least 4 weeks of therapy.

Cytogenetic analysis, BH3 profiling, and next-generation sequencing revealed that 12 (38%) patients had iso­citrate dehydrogenase (IDH) gene mutations and 6 (19%) patients had a high BCL-2–sensitive protein index.

The ORR was 19%, with 2 (6%) patients achieving a complete response; 4 (13%) other patients had a complete response with incomplete blood count recovery. All responses were observed in patients who had previously received treatment for AML. For most patients, activity was observed at the first assessment at week 4. The median duration of therapy in responders was 144.5 days, and the median duration of complete response was 48 days. All patients discontinued therapy, including 29 as a result of progressive disease, 1 because of an adverse event, 1 withdrew consent, and 1 patient proceeded to allogeneic hematopoietic stem-cell transplant.

An additional 6 (19%) patients had antileukemic activity demonstrated by partial bone marrow response and incomplete hematologic recovery that did not meet the standard response criteria.

The median time to progression was 2.5 months. The 6-month overall survival estimate was 36%, and the median overall survival was 4.7 months.

The 4 patients with incomplete blood count recovery had mutations in IDH. The researchers remarked that previous investigations have found mutations in IDH1/2 are present in approximately 15% to 20% of patients with AML; in the current study, 12 (38%) patients had IDH1/2 mutations. In addition, 3 patients with IDH1/2 mutations also had FLT3-ITD mutations, which is an adverse prognostic factor; none of these patients achieved a response.

The response to venetoclax correlated with biomarker results, including indices of BCL-2 expression and BH3 profiling. “This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL-2,” Dr Letai noted. “Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics.”

Coinvestigator Marina Konopleva, MD, PhD, Professor, Departments of Leukemia and Stem Cell Transplantation, M.D. Anderson Cancer Center, Houston, added, “We believe that venetoclax will soon become an equal partner to standard-of-care chemotherapy in elderly patients with AML when used in combination with hypomethylating agents and other approaches.”

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