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News in Brief

Venetoclax Yields Strong Responses in CLL

DOI: 10.1158/2159-8290.CD-NB2015-180 Published February 2016
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Results from an international phase II trial show that the investigational drug venetoclax (ABT-199/GDC-0199; AbbVie/Genentech) is effective in patients with chronic lymphocytic leukemia (CLL) who lack part of chromosome 17 (17p deletion), which contains TP53, and are refractory to standard treatment. The data were presented by Stephan Stilgenbauer, MD, of the University of Ulm in Germany, at the annual meeting of the American Society of Hematology in Orlando, FL, held December 5–8.

Figure1

Stephen Stilgenbauer presents the findings of a phase II trial of venetoclax for the treatment of chronic lymphocytic leukemia in patients with a 17p deletion. These patients have a particularly poor prognosis.

Up to 10% of patients newly diagnosed with CLL have the 17p aberration, which also occurs in 30% to 50% of patients with relapsed, refractory disease. Their prognosis is “most dismal,” Stilgenbauer said, because they respond poorly to standard chemo-immunotherapy, with a median progression-free survival (PFS) of less than 12 months. Venetoclax targets the antiapoptotic protein BCL2, which is overexpressed in CLL cells. By binding to and inhibiting BCL2, “this agent can drive cells toward death despite the lack of TP53,” Stilgenbauer explained.

The study enrolled 107 patients with treatment-resistant CLL, all harboring the 17p deletion. The overall response rate was 79.4%, with eight patients experiencing complete remissions, and 84.7% maintaining their response at 12 months. Minimal residual disease—small numbers of leukemic cells that remain in patients even during remission, a major cause of relapse—was undetectable in over 20% of responders. The median PFS and overall survival have not been reached.

Venetoclax's toxicity profile was acceptable, Stilgenbauer said, and its main side effects, neutropenia and upper respiratory tract infections, “were lower than seen with front-line chemo-immunotherapy.”

To mitigate the risk of a common, potentially fatal complication called tumor lysis syndrome—metabolic abnormalities that can occur when dying cells release their contents into the bloodstream—patients received venetoclax in a stepwise dosing schedule. “The goal was 400 mg, but we were already seeing tumor-cell destruction when we started with 20 mg,” Stilgenbauer said. “This highlights venetoclax's dramatic efficacy; there aren't many other therapeutic agents that can achieve a response at only 5% of the target dose.”

“These results will change the treatment landscape for a high-risk patient population,” said Robert Hromas, MD, chair of medicine at the University of Florida in Gainesville. “It's an enormously exciting time to be working in the blood cancer field. When Rudolf Virchow coined the word ‘leukemia’ 150 years ago, his principle was ‘as the cell goes, so goes the disease, so goes the patient.’ Today, it's really ‘as the gene goes, so goes the cell, so goes the disease’—we have the ability to define and selectively target molecular defects, and I think that, for the first time, we can begin talking about curing CLL.”

Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, noted the “completely different, accelerated pace” of drug approvals for CLL, with four therapies in the last 2 years: obinutuzumab (Gazyva; Genentech), ofatumumab (Arzerra; GlaxoSmithKline), ibrutinib (Imbruvica; Pharmacyclics/Janssen), and idelalisib (Zydelig; Gilead Sciences). Venetoclax has been designated a Breakthrough Therapy by the FDA, and Zelenetz thinks it will “almost certainly be approved” in 2016.

“The challenge now will be figuring out how to use these therapies in novel, creative ways that reduce toxicity, shorten treatment durations, and ultimately eliminate this disease,” he said. –Alissa Poh

Notes

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

  • ©2016 American Association for Cancer Research.
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Cancer Discovery: 6 (2)
February 2016
Volume 6, Issue 2
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Venetoclax Yields Strong Responses in CLL
Cancer Discov February 1 2016 (6) (2) 113-114; DOI: 10.1158/2159-8290.CD-NB2015-180

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Venetoclax Yields Strong Responses in CLL
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