Zanubrutinib for the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N = 301; n = 132, treatment-naive [TN]; n = 169, relapsed/refractory [R/R]), data from SEQUOIA (phase 3; TN; zanubrutinib; NCT03336333), ALPINE (phase 3; R/R; zanubrutinib vs ibrutinib; NCT03734016), and AU-003 (NCT02343120) (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n = 127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n = 75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among patients treated with zanubrutinib and 38.5% among those treated with ibrutinib, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n = 24; median follow-up, 69.6 months), 10 of 24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% confidence interval [CI], 95.2-98.8), and in ALPINE was 89.3% (95% CI, 80.1-95.3) with zanubrutinib vs 76.0% (95% CI, 64.7-85.1) with ibrutinib. Responses deepened over time in both TN and R/R populations. The most frequent nonhematologic treatment-emergent adverse events occurring in >20% of patients treated with zanubrutinib with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea, and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and R/R settings.