About 10 percent of patients with chronic lymphocytic leukemia (CLL) discontinued therapy with the Bruton tyrosine kinase (BTK) inhibitor drug ibrutinib because of disease progression during clinical trials, according to a study published online in JAMA Oncology.
CLL is the most prevalent leukemia in adults and it is not considered curable without an allogeneic (donor) stem cell transplant. However, advances in therapy have been made, notably the emergence of kinase inhibitors for patients whose disease relapsed, according to the study background.
The drug ibrutinib (marketed as Imbruvica) is the first drug designed to target Bruton's tyrosine kinase (BTK), a protein essential for CLL-cell survival and proliferation. The drug is approved by U.S. Food and Drug Administration in chronic lymphocytic leukemia and mantle cell lymphoma. Much of the clinical and basic-science research that led to the approval of ibrutinib for CLL was performed by scientists at The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC -- James).
Hematologists Kami Maddocks, MD, Jennifer Woyach, MD, and colleagues have now described the characteristics of patients who discontinued ibrutinib therapy and their outcomes in a group of 308 patients participating in four trials at The OSUCCC -- James.
The study results show that with a median (midpoint) follow-up of 20 months, 232 patients (75 percent) remained on therapy, 31 (10 percent) discontinued because of disease progression and 45 discontinued for other reasons (including 28 because of infection, eight for other adverse events and nine due to other medical events).
Disease progression included Richter's transformation (when the cancer becomes an aggressive lymphoma) or progressive CLL. Richter's transformation appeared to occur early and CLL progression later. Median survival after Richter's transformation was 3.5 months and 17.6 months following CLL progression, the results indicate.
"These data enhance our understanding of how patients do on ibrutinib long-term and who is likely to relapse. We know that many patients will have very durable remissions with ibrutinib, and understanding which patients are at higher risk helps us select who might benefit from clinical trials investigating other new agents and combination therapies rather than starting ibrutinib treatment by itself," says Woyach, senior author of the study. "We have confirmed that specific gene mutations are seen in patients who relapse, which gives us an idea of other drugs that might be effective in these circumstances."
OSUCCC -- James researchers conclude that this data confirms ibrutinib as an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation.
"Outcomes data show poor prognosis after discontinuation, especially for those patients with Richter's transformation. Patients with either progressive CLL or Richter's tend to require therapy quickly after ibrutinib is stopped, so having a plan in place for alternative therapy is necessary. This sub-segment of patients who relapse on ibrutinib remains a high research priority to identify new targets and new therapies, and we have multiple studies ongoing at the James to try to help these patients," adds Maddocks.
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Reasons for ibrutinib therapy discontinuation in CLL