Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator's choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator's choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P < 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.

AstraZeneca South San Francisco CA USA

Barwon Health University Hospital Geelong VIC Australia

City Clinical Hospital No 4 DCC Dnipro Ukraine

Department of Hemato Oncology and Bone Marrow Transplantation Medical University of Lublin Poland

Department of Hematological Oncology Oncology Specialist Hospital Brzozow Poland

Division of Hematology Department of Internal Medicine Faculty of Medicine University of Debrecen Hungary

Fakultní Nemocnice Plzen Pilsen Czech Republic

Gachon University Gil Medical Center Incheon Republic of Korea

Hospital Universitario 12 de Octubre Madrid Spain

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Meldola Italy

Maria Sklodowska Curie National Institute of Oncology Krakow Poland

National Cancer Institute Kyiv Ukraine

Nebraska Hematology Oncology Lincoln NE USA

Saint John Regional Hospital University of New Brunswick Canada

The Royal Wolverhampton NHS Trust Wolverhampton United Kingdom

Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele Milano Italy

University Hospital Hradec Kralove Charles University Hradec Kralove Czech Republic

Zobrazit více v PubMed

Wen T, Wang J, Shi Y, et al. . Inhibitors targeting Bruton’s tyrosine kinase in cancers: drug development advances. Leukemia. 2021;35:312–332. PubMed PMC

Imbruvica [package insert]. Sunnyvale, CA, Horsham, PA: Pharmacyclics, Janssen Biotech, Inc.2022.

Munir T, Brown JR, O’Brien S, et al. . Final analysis from RESONATE: up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94:1353–1363. PubMed PMC

Archibald WJ, Rabe KG, Kabat BF, et al. . Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes. Ann Hematol. 2021;100:143–155. PubMed PMC

Pellegrini L, Novak U, Andres M, et al. . Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;159:103238. PubMed

Caldeira D, Alves D, Costa J, et al. . Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PLoS One. 2019;14:e0211228. PubMed PMC

Barf T, Covey T, Izumi R, et al. . Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363:240–252. PubMed

Estupiñán HY, Berglöf A, Zain R, et al. . Comparative analysis of BTK inhibitors and mechanisms underlying adverse effects. Frontiers Cell Develop Biol. 2021;9:630942. PubMed PMC

Byrd JC, Hillmen P, Ghia P, et al. . Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase 3 trial. J Clin Oncol. 2021;39:3441–3452. PubMed PMC

Calquence [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2022.

Ghia P, Pluta A, Wach M, et al. . ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38:2849–2861. PubMed

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;111:5446–5456. PubMed PMC

Byrd JC, Hillmen P, O’Brien S, et al. . Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133:2031–2042. PubMed PMC

Cull G, Burger JA, Opat S, et al. . Zanubrutinib for treatment-naïve and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study. Br J Haematol. 2022;196:1209–1218. PubMed PMC

Seymour JF, Kipps TJ, Eichhorst B, et al. . Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107–1120. PubMed

Kater AP, Wu JQ, Kipps T, et al. . Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38:4042–4054. PubMed PMC

Byrd JC, Wierda WG, Schuh A, et al. . Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020;135:1204–1213. PubMed PMC

Gentile M, Martino EA, Visentin A, et al. . Validation of a survival-risk score (SRS) in relapsed/refractory CLL patients treated with idelalisib-rituximab. Blood Cancer J. 2020;10:92. PubMed PMC

ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-2024 update