BCL-2 Inhibitor Venetoclax Demonstrates Activity in Pretreated AML

Marina Konopleva, MD, PhD

Some patients with heavily treated acute myelogenous leukemia (AML) benefited from treatment with the BCL-2 inhibitor venetoclax (ABT-199), according to a phase II clinical study presented at the 2014 ASH Annual Meeting.

Six of 32 patients had objective responses (two complete) and two others had stable disease. Some patients achieved independence from transfusion and substantial reductions in blast counts. The most frequently reported adverse events in the 32-patient safety population included nausea, diarrhea, vomiting, pneumonia, hypomagnesemia, and fatigue. A majority of patients had grade 3/4 adverse events, including febrile neutropenia, pneumonia, hypokalemia, and hypotension.

“This preliminary efficacy demonstrates clinical activity in heavily pretreated AML patients with limited available treatment options,” Marina Y. Konopleva, MD, PhD, associate professor of Leukemia and Stem Cell Transplantation at the University of Texas MD Anderson Cancer Center, said during the meeting. “Biologic activity observed included objective responses, transfusion independence, and blast reductions.”

“Venetoclax monotherapy has an acceptable safety profile in patients with relapsed and refractory AML and those unfit for chemotherapy,” she added.

BCL-2 has been associated with drug resistance and poor prognosis in AML. Patients with relapsed/refractory AML have a poor prognosis and few treatment options. Venetoclax is a selective, oral, small-molecule inhibitor of BCL-2.

Konopleva reported findings from a phase II, multicenter, open-label trial to evaluate venetoclax’s efficacy in patients with relapsed/refractory AML or as first-line therapy for patients unfit for chemotherapy. Treatment began with a venetoclax dose of 20 mg per day, escalating to 800 mg daily by day 6.

The trial had a primary endpoint of preliminary efficacy. Secondary objectives included preliminary safety and pharmacokinetics/pharmacodynamics. Additionally, investigators performed an exploratory evaluation of potential biomarkers that could serve as surrogates for clinical endpoints, Konopleva said.

Investigators enrolled 32 patients, who were a median age of 71 years. All but two of the patients had relapsed/refractory AML. Fourteen patients had received three or more prior regimens for AML, 24 had received hypomethylating agents, and four had undergone allogeneic stem cell transplant. Two patients had received no prior therapy.

Thirteen patients had a history of myeloid disorders, consisting of myelodysplastic syndrome in 11 patients and myeloproliferative neoplasm in two.

An analysis of molecular markers showed that 11 of 32 patients had IDH mutations, six had FLT3-ITD mutations, and four had NPM1 mutations, followed by smaller numbers of several other mutations.

Two patients had confirmed complete responses, and four others had complete responses with incomplete blood count recovery. Additionally, six patients had anti-leukemic activity that did not meet criteria for partial response. Of those, two patients each had ≥50% blast reduction with two-cell-line recovery and transfusion independence, ≥50% blast reduction with one-cell-line recovery, and ≥50% blast reduction with no hematologic recovery.

Four of the six objective responses, including both complete responses, occurred in the subgroup of patients with IDH mutations. Two of the11 patients with IDH mutations had stable disease, four had progressive disease, and one had marrow aplasia.

“Five out of six patients who achieved complete responses or responses with incomplete cell recovery occurred at the first evaluation at week 4,” Konopleva said. “From those, four out of five had IDH-1 or IDH-2 mutations.”

Analysis of the association between biomarkers and clinical activity showed that tumors in which a majority of leukemia cells did not express BCL-2 or had low-level expression of BCL-X_L (a known marker of resistance to venetoclax) were categorized as resistant. Patients with this profile had little or no antitumor activity in response to treatment with venetoclax.

Tumors in which a majority of leukemia cells expressed BCL-2 and had low-level expression of BCL-X_L were categorized as sensitive. Patients in this category stayed on therapy longer and were more likely to have anti-leukemic activity, Konopleva said.

Investigators also performed BH3 profile studies, which measured dependence on anti-apoptotic proteins. The studies demonstrated an inverse correlation between anti-apoptotic protein levels and a reduction in blast count.

“This agent is being evaluated in AML, in combination with hypomethylating agents and chemotherapy, while exploring predictive biomarkers,” Konopleva said.

Konopleva M, Pollyea DA, Potluri J, et al. A phase 2 study of ABT-199 (GDC-1099) in patients with acute myelogenous leukemia. Presented at: the 56^th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 118.

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