High Rate of Durable Remissions with BTK Inhibitor Ibrutinib in Patients with Relapsed Chronic Lymphocytic Leukemia
Durable remissions are uncommon with current treatments for relapsed chronic lymphocytic leukemia (CLL). Bruton’s tyrosine kinase (BTK) is an essential component of B-cell receptor signaling that mediates interactions with the tumor microenvironment and promotes survival and proliferation of CLL cells. Ibrutinib is a first-in-class oral covalent inhibitor of BTK designed for treatment of B-cell cancers. As reported in The New England Journal of Medicine, John C. Byrd, MD, of Ohio State University, and colleagues found that ibrutinib treatment produced high rates of durable responses in patients with relapsed or refractory CLL or small lymphocytic lymphoma.
Study Details
In a phase IB/II multicenter study, 85 patients with relapsed or refractory CLL (n = 82) or small lymphocytic lymphoma received ibrutinib once daily at 420 mg (n = 51) or 840 mg (n = 34). Patients had a median age of 66 years, 76% were male, and the median number of prior therapies was four. Most patients (65%) had high-risk disease (Rai stage III or IV). Interphase cytogenetic abnormalities consisted of 17p13.1 deletion in 33% and 11q22.3 deletion in 36%.
High Response Rates, Improved Survival
The overall response rate was 71% (2 complete responses and 34 partial responses) in the 420-mg group and 71% (24 partial responses) in the 840-mg group. Ten additional patients (20%) in the 420-mg group and five (15%) in the 840-mg group had a partial response with persistent lymphocytosis. Response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, number of previous therapies, and the 17p13.1 deletion.
At 26 months, the estimated progression-free survival rate was 75% and the overall survival rate was 83%. Among the patients with 17p13.1deletion, estimated 26-month progression-free survival was 57% and overall survival was 70%. At a median follow-up of 20.9 months (range, 0.7-26.7 months), 64% of patients were still receiving treatment.
Favorable Toxicity Profile
Toxic effects were predominantly grade 1 or 2. The most common adverse events of any grade were diarrhea (49%), upper respiratory tract infection (33%), fatigue (32%), and cough (31%). Grade 3 or 4 hematologic toxic effects consisted of neutropenia in 15% of patients, anemia in 6%, and thrombocytopenia in 6%. Neutropenia did not require treatment discontinuation and was managed with growth factor treatment in 5 of 13 patients. Bleeding events of grade 3 or higher occurred in four patients. A total of eight patients died within 30 days after receiving the last dose of ibrutinib: three due to pneumonia, one from systemic inflammatory response, one from sarcoma, and three from CLL progression.
As concluded by the authors, “Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions.” They further noted, “Ibrutinib has a favorable therapeutic index, which may facilitate its use in combination with other agents for the treatment of CLL. However, the durable remissions obtained thus far suggest that many patients may be treated successfully with monotherapy. Randomized clinical trials of ibrutinib in patients with CLL or small lymphocytic lymphoma are ongoing.”
The study was supported Pharmacyclics, Janssen, and others. For full disclosures of the study authors, visit www.nejm.org.
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