Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia

Kerry A Rogers, Philip A Thompson, John N Allan, Morton Coleman, Jeff P Sharman, Bruce D Cheson, Daniel Jones, Raquel Izumi, Melanie M Frigault, Cheng Quah, Rakesh K Raman, Priti Patel, Min Hui Wang, Thomas J Kipps, Kerry A Rogers, Philip A Thompson, John N Allan, Morton Coleman, Jeff P Sharman, Bruce D Cheson, Daniel Jones, Raquel Izumi, Melanie M Frigault, Cheng Quah, Rakesh K Raman, Priti Patel, Min Hui Wang, Thomas J Kipps

Abstract

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.

Trial registration: ClinicalTrials.gov NCT02717611.

Figures

Figure 1.
Figure 1.
Trial profile. AE: adverse events.
Figure 2.
Figure 2.
Response to acalabrutinib. Patients who discontinued study treatment before evaluation for response (n=6) or who were not available for response assessment (n=2) were classified as not evaluable. CR: complete remission; Cri: CR with incomplete bone marrow recovery; ORR: overall response rate; PD: progressive disease; PR: partial remission; PRL: partial remission with lymphocytosis; SD: stable disease.
Figure 3.
Figure 3.
Duration of response to acalabrutinib. (A, B) The median duration of response was not reached when patients with partial remission with lymphocytosis were excluded (A) or when they were included (B). CI: confidence interval; DOR: duration of response; PR: partial remission; PRL: partial remission with lymphocytosis.
Figure 4.
Figure 4.
Progression-free survival and overall survival with acalabrutinib. (A, B) The medians were not reached for progression-free survival (A) or overall survival (B). CI: confidence interval; OS: overall survival; PFS: progression-free survival.

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