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Ibrutinib yields encouraging outcomes in CLL

Ibrutinib was associated with OS of more than 80% at 26 months follow-up in a cohort of individuals with chronic lymphocytic leukemia, according to results of a multicenter study.

Ibrutinib is an oral covalent Bruton’s tyrosine kinase inhibitor with the capacity to treat B-cell malignancies (PCI-32765, Pharmacyclics).

 

John C. Byrd

John C. Byrd, MD, the D. Warren Brown chair of leukemia research at the Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, and colleagues conducted the phase 1b-2 study to investigate the safety, efficacy, pharmacokinetics and pharmacodynamics of ibrutinib.

The analysis included 85 individuals with relapsed or refractory CLL or small lymphocytic lymphoma. Most of the cohort had high-risk disease.

Treatment regimens included a once-daily dose of 420 mg (n=51) and a once-daily dose of 840 mg (n=34).

Few hematologic toxic adverse events occurred across the cohort. Grade 1 or 2 transient diarrhea, fatigue and upper respiratory tract infections were the most frequently occurring events.

Researchers reported a 71% overall response rate in both treatment groups. In addition, partial response with lymphocytosis occurred in 20% of the 420 mg cohort and 15% of the 840 mg cohort.

Responses were independent of clinical and genomic risk factors observed before treatment initiation. These risk factors included advanced-stage disease, number of previous therapies and 17p13.1 deletion.

The estimated PFS at 26 months was 75%. The estimated OS at this point was 83%.

“We demonstrated that it is possible to administer a targeted therapy — ibrutinib — orally for an extended period of time, without significant side effects,” Byrd told HemOnc Today.

Byrd emphasized the response rates occurred regardless of dose strength or previous risk factors.

“But remission duration is the most important endpoint of the study,” Byrd said. “For perspective, with standard therapy, we would expect a PFS of 3 to 6 months. These survival outcomes are not matched by anything else in CLL.”

In an editorial accompanying the paper, Robin Foa, MD, and Anna Guarini, PhD, of the department of hematology at Sapienza University in Rome, wrote that the complete remission rate associated with ibrutinib may be low.

“The activity of this agent will need to be assessed in patients who have received less previous treatment,” they wrote. “Will ibrutinib alone be adequate for patients with more aggressive disease, such as those with 17p13.1 deletion and p53 disruption?”

Foa and Guarini raised other questions, including whether aggressive treatment is optimal for all patients with CLL, whether controlling the disease with less toxic compounds might be effective, and whether CLL should be subdivided into treatment categories.

That said, Foa and Guarini noted the results “are a further advancement in the ever-changing management of hematologic cancers, which is shifting from a chemotherapy-based approach to treatments aimed at the underlying biologic mechanisms of disease occurrence and progression.”

“BTK inhibitors certainly represent an important step forward and a potential turning point in the treatment of CLL,” they added. “The challenges today are to define their effectiveness as front-line treatment both alone and in combination with other agents, as well as their long-term effects.”

Disclosure: The researchers report funding support from Pharmacyclics and Janssen, as well as grants from the Leukemia and Lymphoma Society, the D. Warren Brown Foundation, the Harry T. Mangurian Jr. Foundation and the NIH.