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

Abstract

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies

“…The spectrum of TEAEs reported is generally consistent with that observed in previous studies of zanubrutinib and other BTK inhibitors. 11,[13][14][15][16]18 Infections (particularly of the respiratory tract) were the most common category of TEAEs and likely the greatest source of morbidity and mortality; [4][5][6][7][8][9][10]19 41% of all grade 5 TEAEs (16/39) and 31% (25/80) of treatment discontinuations were infection related. Contributions to the risk of infection from BTK inhibitors include neutropenia (an on-target effect of BTK inhibition) and depletion/dysfunction of normal B-cells.…”

Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review

“…The first results have been reported only for the nonrandomized Cohort C, enrolling 109 patients with del(17p) treated with zanubrutinib. The ORR was 94.5%, and the estimated 18-month PFS rate was 88.6% [ 59 ]. Follow-ups for Cohorts A and B have not been reported to date, as well as the results of Cohort D, which is studying zanubrutinib in combination with venetoclax.…”

Targeting Bruton’s Tyrosine Kinase in CLL

“…TP53 aberration, referring to a mutation of the TP53 tumor suppressor gene or deletion of chromosome 17p where TP53 is encoded, is a strong negative prognostic marker in CLL ( 58 ). First-line treatment with an intensive chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR) reported median PFS of 15 months for patients with TP53 aberration as opposed to nearly 5 years for those without the aberration ( 48 , 54 ). Treatment with BTKis substantially extended the survival of patients with TP53 aberration ( 48 , 59 ) with the observed rates of 5-year PFS and OS being 70% and 85%, respectively, when ibrutinib was first-line therapy ( 47 ).…”