Role for Ibrutinib Confirmed in Relapsed/Refractory 17p Deletion CLL

September 29, 2016

Phase II data provide further evidence that patients with relapsed/refractory chronic lymphocytic leukemia with 17p deletion have a new treatment option with ibrutinib.

Data from the phase II RESONATE-17 study provide further evidence that patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion (del17p) have a new treatment option with oral ibrutinib. The study was published in Lancet Oncology.

“Alongside data from other emerging treatments, ibrutinib might contribute to a reassessment of the role and timing of stem cell transplantation by changing the choice and sequence of treatments used for management of high-risk CLL,” wrote Susan O’Brien, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues. “These data mark an era of targeted therapeutics that is changing historical treatment algorithms for patients with del17p CLL or small lymphocytic lymphoma [SLL], the most difficult subset of patients to treat.”

Ibrutinib is currently approved by the US Food and Drug Administration for patients with CLL with del17p, and recommended in National Comprehensive Cancer Network treatment guidelines as a standard of care for first-line and relapsed/refractory del17p CLL.

In RESONATE-17, O’Brien and colleagues tested ibrutinib 420 mg once daily in 144 patients with del17p CLL or SLL from 40 international study sites. The primary endpoint was overall response rate in all-treated population per International Workshop on Chronic Lymphocytic Leukemia 2008 response criteria modified for treatment-related lymphocytosis.

“Since RESONATE-17 is a single-arm, non-randomized study that used an independent review committee only through primary analysis of activity, we also reported investigator-assessed responses,” the researchers wrote.

At the prespecified primary analysis time of 11.5 months follow-up, the overall response rate was 64% according to independent review, and 83% according to investigator assessment. An extended analysis that followed patients for a median of 27.6 months showed an investigator-assessed overall response rate of 83%; 8% of patients had a complete response, 2% had complete response with incomplete bone marrow recovery, 64% had a partial response, 7% had partial response with lymphocytosis, and 2% had nodular partial response. The 24-month progression-free survival rate was 63% (95% CI, 54%–70%) and the 24-month overall survival rate was 75% (95% CI, 67%–81%).

“These results substantiate findings from a cohort of patients with relapsed or refractory del17p CLL (n = 34) from a post-hoc subgroup analysis of the phase Ib/II ibrutinib study that reported an overall response of 79% (6% complete response, 65% partial response, and 9% partial response with lymphocytosis) and a median progression-free survival of 28 months,” the researchers wrote.

The researchers conducted a subgroup analysis of patients achieving an overall response to identify prognostic variables. They found that response was similar for all subgroups examined. No clinically relevant changes were found from baseline to 6 months or 24 months for immunoglobulin A, G, or M concentrations.

“The safety profile of ibrutinib-treated patients in this study was consistent with previous reports, with most adverse events being mild to moderate in severity,” the researchers noted.

The most common reason for treatment discontinuation was disease progression (24%); treatment was also discontinued due to adverse events, unacceptable toxicity, or death in 17% of patients. In addition, 9% of patients experienced major bleeding.

Thirty percent of patients had grade 3 or worse infections, including 13% of patients who had pneumonia. With the extended follow-up, 38 patients died, including 18 as a result of adverse events.

“Overall, these results suggest that treatment with ibrutinib in patients with ultra-high-risk CLL is associated with a favorable risk:benefit profile,” the researchers concluded.