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Haematologica 2021 Volume 106(9):2364-2373
Phase II study of acalabrutinib in ibrutinib- intolerant patients with relapsed/refractory chronic lymphocytic leukemia
Kerry A. Rogers,1 Philip A. Thompson,2 John N. Allan,3 Morton Coleman,3 Jeff P. Sharman,4 Bruce D. Cheson,5 Daniel Jones,1 Raquel Izumi,6 Melanie M. Frigault,6 Cheng Quah,6 Rakesh K. Raman,6 Priti Patel,6
Min Hui Wang6 and Thomas J. Kipps7
1The Ohio State University, Columbus, OH; 2MD Anderson Cancer Center, Houston, TX; 3Weill Cornell Medicine, New York, NY; 4Willamette Valley Cancer Institute, Eugene, OR; 5Georgetown University Hospital, Washington, DC; 6AstraZeneca, South San Francisco, CA; and 7UC San Diego Moores Cancer Center, San Diego, CA, USA
ABSTRACT
B-cell receptor signaling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia. The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better toler- ated by patients who are intolerant to ibrutinib. A phase II study of acal- abrutinib was conducted in patients with relapsed/refractory chronic lymphocytic leukemia who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events or persistent/recurrent grade 2 adverse events despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intol- erance. Sixty patients were treated. The overall response rate to acal- abrutinib was 73% and three patients (5%) achieved complete remis- sion. At a median follow-up of 35 months, the median progression-free and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent adverse events with acalabru- tinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). The most common reasons for acalabrutinib discontinuation were progres- sive disease (23%) and adverse events (17%). Most patients with base- line samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effec- tive and tolerable in most patients with relapsed/refractory chronic lym- phocytic leukemia who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant. ClinicalTrials.gov identifier: NCT02717611.
Introduction
Targeted Bruton tyrosine kinase (BTK) inhibitors are highly effective for the treatment of chronic lymphocytic leukemia (CLL).1 These agents block signaling by inhibiting BTK, a key kinase in the B-cell receptor signaling pathway.2-4 The effi- cacy of BTK inhibition in CLL was demonstrated by ibrutinib, the first BTK inhibitor approved for treatment of CLL.5
Ibrutinib is not always tolerated by patients with CLL. In a large, retrospective study of ibrutinib-treated CLL, toxicity was the most common reason for treat- ment discontinuation, accounting for 63.1% of discontinuations in the front-line setting and 50.2% of discontinuations among patients with relapsed/refractory CLL.6 The most common toxicities leading to discontinuation were arthralgia (41.6%), atrial fibrillation (25.0%), and rash (16.7%) in the front-line setting and atrial fibrillation (12.3%), infection (10.7%), and pneumonitis (9.9%) in relapsed/refractory CLL. These toxicities may be due to BTK inhibition or off-tar-
Chronic Lymphocytic Leukemia
Correspondence:
KERRY A. ROGERS
kerry.rogers@osumc.edu
Received: September 25, 2020. Accepted: February 19, 2021. Pre-published: March 18, 2021.
https://doi.org/10.3324/haematol.2020.272500 ©2021 Ferrata Storti Foundation
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