Results from a phase 2 study of 3 oral targeted agents for chronic lymphocytic leukemia (CLL) showed that patients achieved deep remissions after a limited-time duration treatment. The study, published in the Journal of Clinical Oncology, included both treatment-naive patients and those with recurrent/relapsed disease.1 The regimen worked well enough that phase 3 studies are underway.
Patients in this trial (ClinicalTrials.gov Identifier: NCT02427451) received a combination regimen of obinutuzumab, ibrutinib, and venetoclax.2 The 3 agents have different mechanisms of action, and are thought to combine well against CLL. Obinutuzumab, an anti-CD20 monoclonal antibody, is given first, followed by ibrutinib, which inhibits the B-cell signaling protein Bruton tyrosine kinase (BTK). Venetoclax, a BCL-2 inhibitor, comes last.
“We took the 3 most highly effective nonchemotherapy drugs that we had in CLL, put them in this regimen, and dosed them so they’re started sequentially,” said the study’s lead investigator Kerry Rogers, MD, hematologist with The Ohio State University Comprehensive Cancer Center’s Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.
Staggering the doses helps to avoid tumor lysis syndrome (TLS), a potentially deadly side effect that can occur when too many cancer cells die simultaneously, releasing their contents into the bloodstream. Because it works so rapidly, venetoclax has been known to cause TLS, but the risk can be reduced by starting with a low dose and gradually escalating. Also, pretreating with obinutuzumab has been shown to lessen the risk of TLS.
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The study designers took note of these considerations. The trial included 14 cycles of 28 days each. In cycle 1, the patients received obinutuzumab only. Cycle 2 added ibrutinib. Finally, on day 1 of cycle 3, venetoclax was started at 20 mg daily, increasing every 7 days until the target dose of 400 mg was reached. The protocol also allowed single-agent ibrutinib to be continued after completing cycle 14.
Of 50 patients enrolled, 25 were treatment naive (TN) and the other 25 had relapsed or refractory (RR) disease, with a median of 1 prior line of therapy. The primary endpoint was complete remission with no detectable minimal residual disease (MRD) in either the blood or the bone marrow, and this was achieved in 28% of patients in both groups.
The overall response rate was 84% among TN patients and 88% among RR patients, and by the end of the treatment period, 67% of TN patients and 50% of RR patients had undetectable MRD, although not all had achieved complete remission.
“The overall response rate was very promising,” said Meghan Thompson, MD, hematologist at Memorial Sloan Kettering Cancer Center in New York City.
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September 21, 2020 at 07:00PM
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Triple Therapy for CLL Shows Promise in Phase 2 Trial - Cancer Therapy Advisor
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