Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib

Abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib improves patient outcomes in chronic lymphocytic leukemia (CLL); however, some patients experience adverse events (AEs) leading to discontinuation. Acalabrutinib is a potent, covalent BTK inhibitor with greater selectivity than ibrutinib. We evaluated the safety and efficacy of 100 mg of acalabrutinib twice daily or 200 mg once daily in patients with CLL who discontinued ibrutinib because of intolerance as determined by the investigators. Among 33 treated patients (61% men; median age, 64 years; range, 50-82 years), median duration of prior ibrutinib treatment was 11.6 months (range, 1-62 months); median time from ibrutinib discontinuation to acalabrutinib start was 47 days (range, 3-331 days). After a median of 19.0 months (range, 0.2-30.6 months), 23 patients remained on acalabrutinib; 10 had discontinued (progressive disease, n = 4; AEs, n = 3). No acalabrutinib dose reductions occurred. During acalabrutinib treatment, the most frequent AEs included diarrhea (58%), headache (39%), and cough (33%). Grade 3/4 AEs occurred in 58%, most commonly neutropenia (12%) and thrombocytopenia (9%). Of 61 ibrutinib-related AEs associated with intolerance, 72% did not recur and 13% recurred at a lower grade with acalabrutinib. Overall response rate was 76%, including 1 complete and 19 partial responses and 5 partial responses with lymphocytosis. Among 25 responders, median duration of response was not reached. Median progression-free survival (PFS) was not reached; 1-year PFS was 83.4% (95% confidence interval, 64.5%-92.7%). Acalabrutinib was well tolerated with a high response rate in patients who were previously intolerant to ibrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Conflict of interest statement

Conflict-of-interest disclosure: F.T.A. has been a consultant for AbbVie, Janssen, Gilead, Sunesis, AstraZeneca, Genentech, and Pharmacyclics, received research funding from Innate Pharma and Pharmacyclics, and served on speakers’ bureaus for AstraZeneca and AbbVie. A.S. has been a consultant for and has received honoraria from AbbVie, Gilead, GlaxoSmithKline, Janssen, Novartis, and Roche. J.R.B. has been a consultant for AbbVie, Astellas Pharma, AstraZeneca, Celgene, Gilead, Verastem Pharmaceuticals, Janssen, Pfizer, Pharmacyclics, Redx, Roche/Genentech, and Sun BioPharma. R.R.F. has been a consultant for AbbVie, Acerta Pharma, Genentech, Gilead, Incyte, Janssen, Loxo Oncology, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem. J.M.P. has been a consultant for Gilead and Pharmacyclics and has equity ownership in and received research funding from Actinium Pharmaceuticals. P.H. has been a consultant for AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen, has received honoraria from AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen, and has received research funding from AbbVie, Gilead, Janssen, GlaxoSmithKline, Pharmacyclics, and Roche. D.M.S. has received research funding from the Lymphoma Research Foundation. J.W. has been a consultant for Janssen and received research funding from Acerta, AbbVie, Karyopharm, and Morphosys. P.C. is an employee of Acerta Pharma. M.M.F. is an employee of and holds stock in AstraZeneca. B.L. is an employee of AstraZeneca. A.H. and R.I. are patent holders and employees of Acerta Pharma and have equity ownership. E.B., M.H.W., and P.P. are employees of Acerta Pharma and have equity ownership. J.C.B. has received research funding from Acerta Pharma, Genentech, Janssen, and Pharmacyclics.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Patient flow through the study. CNS, central nervous system.

Figure 2.

Change in ibrutinib-related AEs during acalabrutinib treatment. *An additional 6 events of unknown grade (rash, diarrhea, hemorrhage, decreased appetite, dyspnea, and weight decreased) did not recur.

Figure 3.

PFS.

Figure 4.

Acalabrutinib pharmacodynamics in ibrutinib-intolerant patients. (A) BTK occupancy for ibrutinib-intolerant patients with day-1 (D1) predose (Pre) signal/noise ratio ≥5 (n = 4 patients excluded for this reason). For the box plots, the horizontal line in the center of the box shows the median, and the upper and lower edges of the box show the 25th and 75th percentiles, respectively. The I bars (whiskers) represent 1.5× the interquartile range, with symbols showing outliers according to the Tukey method. (B) BCR-induced BTK phosphorylation (p) shown as fold over D1 predose plus exogenous acalabrutinib control. Filtered on D1 predose fold change >1.5 (n = 15 patients excluded for this reason; n = 2 patients had insufficient cells to perform the assay). Significance was determined using a paired, 2-tailed, parametric Student t test comparing time points with D1 predose. ***P < .001, ****P < .0001. C, cycle; Post, postdose; SD, standard deviation.