Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study

Abstract

Background: Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods: The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee. Results: Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction. Conclusion: Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile.

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…However, the emergence of novel agents, such as Bruton tyrosine kinase (BTK) inhibitor ibrutinib, acalabrutinib and zanubrutinib, the phosphoinositide 3-kinase (PI3K) inhibitor idelalisib, the BCL-2 inhibitor venetovlax and other novel agents targeting different pathways, revolutionized the treatment and prognosis [105][106][107]. Targeting the promising biomarker EZH2, tazemetostat (EPZ-6438) shows antitumor activity in patients with refractory B-cell non-Hodgkin lymphoma [33,108,109].…”

Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion

“…20 Activity of zanubrutinib was also observed in a separate phase 2 trial of 91 R/R CLL/SLL patients in China, including in a subset of 17 patients with del(17p) who achieved a 88.2% ORR. 21 Zanubrutinib has recently received accelerated approval in the United States for adult patients with mantle cell lymphoma who have received at least one prior therapy 22 and is currently undergoing further clinical testing in several prospective, multicenter, randomized phase 3 trials in CLL/SLL. The SEQUOIA trial (NCT03336333) is an open-label, multicenter, randomized phase 3 study of TN patients with CLL/SLL.…”

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia

“…Median PFS was not reached, and 12-month PFS was 100%. 36 This trial determined the recommended Phase 2 dose of 160 mg twice daily and demonstrated a well-tolerated safety profile. ORR was high and was similar in patients with high-risk genetic features.…”

“…A phase 2 study of zanubrutinib conducted in China enrolled 91 patients with relapsed/refractory CLL who received 160 mg of zanubrutinib twice daily. 36 The median age was 61 years old and patients had received standard chemoimmunotherapy (fludarabine or chlorambucil-based), with a median of 1 prior line of therapy (range 1–9). Forty-five percent of patients had received at least 2 prior lines of therapy.…”