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Building on the Success of BCL-2 Inhibition in AML

Published Online:3:56 PM, Mon September 18, 2017

Daniel Pollyea, MD, MS
Understanding of the role of BCL-2 in acute myeloid leukemia (AML) continues to evolve, even as BCL-2–targeted therapy improves outcomes in the disease, an AML specialist said at the 2017 Society of Hematologic Oncology Annual Meeting in Houston, Texas.

Originally discovered in follicular lymphoma, BCL-2 overexpression occurs almost universally in many types of B-cell lymphoma. Rather than induce proliferation, BCL-2 overexpression leads to impaired cell death (apoptosis).

Investigation of BCL-2 has demonstrated that the gene protein BCL-2 is involved in functions “critical to control apoptosis,” said Daniel Pollyea, MD, MS, assistant professor of medicine, and clinical director of Leukemia Services at the University of Colorado School of Medicine in Aurora, Colorado.

Describing the rationale for targeting BCL-2 in AML, Pollyea said, “There is plenty of evidence to suggest that apoptosis is deranged in AML. BCL-2 overexpression is a poor-risk factor in AML and is associated with poor response to intensive and conventional chemotherapy. But we also know that, unlike in B-cell lymphomas, BCL-2 is not universally overexpressed in AML.”

Another potential rationale for targeting BCL-2 in AML emerged from studies of leukemia stem cells, Pollyea continued. The laboratory studies showed that BCL-2 inhibition was associated with preferential toxicity to the leukemia stem cell compartment, whereas cytarabine was not. Other preclinical work showed that BCL-2 inhibition preferentially reduced the leukemia stem cell population.

The preclinical studies provided the basis for development of clinical BCL-2 inhibitors. Two early members of the therapeutic class were oblimersen, an antisense oligonucleotide, and obatoclax, a BH3 mimetic exhibiting pan BCL-2 inhibition.

In phase I/II studies, oblimersen demonstrated activity in relapsed/refractory AML and in older patients with untreated or relapsed/refractory AML. The best results occurred in a study of older patients with untreated AML. Oblimersen plus conventional 7+3 therapy led to complete responses in 14 of 29 patients. Subsequently, a phase III randomized trial of chemotherapy plus or minus oblimersen showed no difference in complete response rate or overall survival.

In several phase I/II trials, obatoclax demonstrated minimal activity in patients with AML or myelodysplastic syndromes.
The clinical development of venetoclax (Venclexta), a more specific and potent inhibitor as compared with predecessors, established BCL-2 inhibition as an effective strategy for AML. A preliminary clinical study showed relatively modest single-agent activity in a population of patients with relapsed/refractory AML: complete responses in 19% of patients and overall activity of 38%.

A study of leukemia stem cells in untreated versus relapsed AML provided an impetus for the continued investigation of venetoclax, said Pollyea. Analysis of paired specimens before initial treatment and at relapse showed a dramatic increase in the number and heterogeneity of leukemia stem cells at recurrence.

“It was quite humbling to think that any stem cell-directed therapy could be effective in the relapsed setting, given the treatment’s impact on stem cells,” said Pollyea. “It was much more encouraging to think about moving it into the upfront setting, and fortunately, that is what happened with venetoclax.”

A subsequent clinical trial involving older patients with newly diagnosed AML confirmed the hypothesis about BCL-2 inhibition in the upfront setting. Paired with a hypomethylating agent, venetoclax therapy led to a complete response rate (with or without complete hematologic recovery) of 68%, which was slightly better when the BCL-2 inhibitor was combined with decitabine (Dacogen) than with azacytidine (Vidaza).
Preliminary analyses of the data suggested durability of responses and a 12-month overall survival of 70%.

Pollyea’s center contributed 33 patients to the venetoclax-azacitidine arm of the trial. The regimen led to complete responses in 85% and an overall response rate of 91%.

“We had a tremendous response rate,” he said. “Truly, all but one patient who completed a cycle of therapy had a very significant reduction in blast count.”

Four patients subsequently had progressive disease, but only one occurred during ongoing treatment, after a 13-month remission, he added.
Looking ahead, Pollyea identified 5 areas of investigation for the future to elucidate information that will help optimize the use of venetoclax and other BCL-2 inhibitors in AML.
  • Identifying the factors that influence the potency of venetoclax plus a hypomethylator
  • Continuing to search for potential mechanism of action beyond induction of apoptosis
  • Identifying drivers of resistance to the therapy
  • Extrapolating the results to other patient populations (such as younger patients and those with MDS)
  • Determining whether a role exists for other BCL-2 inhibitors

 
Reference:
Pratz K, Pollyea DA, Jonas BA, et al. Safety and efficacy of venetoclax (VEN) in combination with decitabine or azacytidine in treatment-naïve, elderly patients (≥65 years) with acute myeloid leukemia (AML). Presented at: 2017 EHA Annual Meeting; June 22-25, 2017; Madrid, Spain. Abstract S472.


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