Zanubrutinib Monotherapy for Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pooled Analysis of Three Studies.
CLL/SLL
Overall response rate
Post hoc analysis
Zanubrutinib
Journal
Advances in therapy
ISSN: 1865-8652
Titre abrégé: Adv Ther
Pays: United States
ID NLM: 8611864
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
23
05
2022
accepted:
20
06
2022
pubmed:
29
7
2022
medline:
27
8
2022
entrez:
28
7
2022
Statut:
ppublish
Résumé
Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). This post hoc analysis pooled patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL/SLL receiving zanubrutinib monotherapy from three phase 1/2 studies (BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205). A total of 211 patients with CLL/SLL (TN 19, R/R 192) were included. After weighting (TN 19, R/R 24), the overall response rate (ORR) was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001). ORR was also significantly higher in the TN group than in the one prior line of therapy group (100 vs. 98.9%, p < 0.0001). Among those with R/R disease, the ORR was 97.8% in patients with one prior line of therapy (n = 79) and 90.7% in those with > 1 prior lines of therapy (n = 85; p = 0.080). The median follow-up times were 50.1, 35.7, and 45.9 months for TN, R/R and all cohorts, respectively. Progression-free survival and overall survival were significantly longer in the TN group and only one prior line of therapy group compared with the > 1 prior lines of therapy group (all p < 0.05) and were similar in the TN group compared with the one prior line therapy group. Efficacy was similar regardless of the presence of genomic aberrations. Most frequent grade ≥ 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). Atrial fibrillation occurred in only 1.9% of patients. With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. Clinical Trials.gov identifiers, NCT03189524, NCT02343120 (retrospectively registered), and NCT03206918 (retrospectively registered).
Identifiants
pubmed: 35900694
doi: 10.1007/s12325-022-02238-7
pii: 10.1007/s12325-022-02238-7
doi:
Substances chimiques
Piperidines
0
Pyrazoles
0
Pyrimidines
0
zanubrutinib
AG9MHG098Z
Banques de données
ClinicalTrials.gov
['NCT03189524', 'NCT03206918', 'NCT02343120']
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
4250-4265Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.
Références
Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118:4313–20.
doi: 10.1182/blood-2011-06-338855
Niemann CU, Wiestner A. B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol. 2013;23:410–21.
doi: 10.1016/j.semcancer.2013.09.001
Herman SE, Mustafa RZ, Gyamfi JA, et al. Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123:3286–95.
doi: 10.1182/blood-2014-02-548610
Ponader S, Chen SS, Buggy JJ, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182–9.
doi: 10.1182/blood-2011-10-386417
de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119:2590–4.
doi: 10.1182/blood-2011-11-390989
Ponader S, Burger JA. Bruton’s tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol. 2014;32:1830–9.
doi: 10.1200/JCO.2013.53.1046
Hillmen P, Eichhorst B, Brown J, et al., editors. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. In: Proceedings of the 2021 European hematology association virtual congress; 2021.
NMPA. Zanubrutinib Label in CDE (CXHS2000037). https://www.cde.org.cn/main/xxgk/postmarketpage?acceptidCODE=5b25b17659c2ce6026869f57909e2053 .
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA. 2010;107:13075–80.
doi: 10.1073/pnas.1004594107
Tam CS, Trotman J. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134:851–9.
doi: 10.1182/blood.2019001160
Xu W, Yang S, Zhou K, et al. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with the BTK inhibitor zanubrutinib: phase 2, single-arm, multicenter study. J Hematol Oncol. 2020;13:48.
doi: 10.1186/s13045-020-00884-4
Zhu J, Li J, Zhou J, et al. BGB-3111, a highly specific BTK inhibitor, is well tolerated and highly active in Chinese patients with relapsed/refractory B-cell malignancies: initial report of a phase 1 trial in China. Washington DC: American Society of Hematology; 2017.
Ou YC, Tang Z, Novotny W, et al. Rationale for once-daily or twice-daily dosing of zanubrutinib in patients with mantle cell lymphoma. Leuk Lymphoma. 2021;62:2612–24.
doi: 10.1080/10428194.2021.1929961
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–56.
doi: 10.1182/blood-2007-06-093906
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68.
doi: 10.1200/JCO.2013.54.8800
Yang D, Dalton JE, editors. A unified approach to measuring the effect size between two groups using SAS
Austin PC. Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research. Commun Stat Simul Comput. 2009;38:1228–34.
doi: 10.1080/03610910902859574
Zhou K, Zou D, Zhou J, et al. Zanubrutinib monotherapy in relapsed/refractory mantle cell lymphoma: a pooled analysis of two clinical trials. J Hematol Oncol. 2021;14:167.
doi: 10.1186/s13045-021-01174-3
Ahn IE, Tian X. Prediction of outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: development and validation of a four-factor prognostic model. J Clin Oncol. 2021;39:576–85.
doi: 10.1200/JCO.20.00979
O’Brien SM, Byrd JC, Hillmen P, et al. Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis. Am J Hematol. 2019;94:554–62.
doi: 10.1002/ajh.25436
Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127:2122–30.
doi: 10.1182/blood-2015-07-659144
Ahn IE, Farooqui MZH, Tian X, et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131:2357–66.
doi: 10.1182/blood-2017-12-820910
O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131:1910–9.
doi: 10.1182/blood-2017-10-810044
Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019;133:1298–307.
doi: 10.1182/blood-2018-11-846808
Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136:2038–50.
doi: 10.1182/blood.2020006844
Byrd JC, Hillmen P. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39:3441–52.
doi: 10.1200/JCO.21.01210