Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia

Abstract

Background: The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.

Methods: We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.

Results: Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.

Conclusions: 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. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

Figures

Figure 1. Response to Ibrutinib over Time

Panel A shows the median percent change from baseline in the absolute lymphocyte count (ALC) and the sum of the products of lymph-node diameters (SPD) in all patients. I bars denote distribution-free 95% confidence intervals. Panel B shows the curves for cumulative best response (complete response plus partial response, partial response with lymphocytosis, and stable disease).

Figure 2. Overall Response Rates (ORR) According to Subgroup

Rai stage 0 indicates low risk, stage I or II intermediate risk, and stage III or IV high risk. The dotted line shows the response rate for all 85 patients. IGHV denotes immunoglobulin variable-region heavy-chain gene.

Figure 3. Kaplan–Meier Curves for Progression-free Survival and Overall Survival

Panels A and B show the probability of progression-free survival and overall survival, respectively, for all 85 patients (top graphs) and according to status with respect to the 17p13.1 and 11q22.3 deletions (middle graphs) and IGHV mutation status (bottom graphs). Tick marks indicate censored data.