Pooled Analysis of Safety Data from Clinical Trials Evaluating Acalabrutinib Monotherapy in Hematologic Malignancies

John C. Byrd, Roger Owen, Susan M. O'Brien, Jennifer R. Brown, Peter Hillmen, Bojena Bitman, Nataliya Chernyukhin, Ahmed Hamdy, Raquel Izumi, Priti Patel, Liat Schwartz-Sagi, Edwin Tucker, Nathan H. Fowler, Matthew J. Streetly, Adrian Wiestner, Simon Rule and Michael Wang


Background: Activation of Bruton tyrosine kinase (BTK) is implicated in the pathogenesis of various hematologic malignancies. The BTK inhibitor ibrutinib has activity against other kinases, including interleukin-2-inducible T-cell kinase (ITK), epidermal growth factor receptor (EGFR) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) (Sargiv-Barfi, 2015; Wang, 2016; Chen, 2016), which may contribute to some of its reported toxicities. Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK with minimal off-target activity. The safety profile of acalabrutinib monotherapy was evaluated using pooled safety data from 7 ongoing clinical studies in hematologic malignancies.

Methods: Safety data from all patients (pts) treated with ≥1 dose of acalabrutinib monotherapy in the studies listed in the Table were pooled for analysis. Acalabrutinib was administered at 100-400 mg daily. Safety data evaluated in the pooled analysis included pt incidence and severity of adverse events (AEs) and rates of treatment discontinuation and dose modifications.

Results: Safety data were pooled from 610 pts. The median age was 66 years (range 32.0-90.0). Baseline ECOG performance status was ≤1 in 95% of pts, and the median number of prior treatments was 1 (range 0-13). The median duration of exposure was 14.2 months (range 0.03-32.4), and the total exposure was 701.5 pt-years. AEs of any grade occurred in 603 (98.9%) pts and treatment-related AEs of any grade occurred in 445 (73%). The most common any-grade AEs (≥20%) were headache (42.3% any cause; 29.2% treatment related; 1.3% Grade ≥3), diarrhea (38.4%; 16.6%; 2.1%), fatigue (23.4%; 7.4%; 1.5%), nausea (23.1%; 9.3%; 1.5%) and contusion (21.6%; 13.4%; 0%). Less than half (n=295 [48.4%]) of all pts experienced Grade ≥3 AEs, the most frequent of which (≥3%) were neutropenia (9.3% any cause; 6.6% treatment related), anemia (7.0%; 1.5%), pneumonia (5.7%; 1.1%) and thrombocytopenia (3.6%; 1.5%). Serious AEs (SAEs) were reported in 218 (35.7%) pts and were considered related to study treatment in 58 pts (9.5%). Grade 5 AEs were reported in 22 (3.6%) pts, the most frequent was pneumonia, occurring in 6/22 pts; 3/22 were considered treatment related by the investigator: esophageal carcinoma, hepatic failure due to hepatitis B reactivation, and intracranial hematoma. Atrial fibrillation (AF) of any grade was reported in 14 (2.3%) pts, of which 6 events (1.0%) were Grade 3; there were no Grade 4 or 5 AF events. Most AF events (12/14) occurred in pts with known risk factors or contributing factors including concurrent infections/pneumonia (2/14), hypertension (4/14), pre-existing cardiovascular disease (4/14) and history of AF (2/14). Hemorrhage Grade ≥3, SAE and/or any grade or seriousness of central nervous system (CNS) hemorrhage was reported in 15 (2.5%) pts, most frequently in the gastrointestinal tract (5/15) and CNS (3/15). Six of these 15 events were SAEs; 4 were treatment related, 1 of which was fatal. Infection events of any grade were reported in 372 (61.0%) pts; Grade ≥3 infection occurred in 99 (16.2%) pts, with pneumonia as the most frequently reported event (n=35 [5.7%]). Opportunistic fungal infections were reported in 4 pts: Pneumocystis jirovecii pneumonia (Grade 2), aspergillosis (Grade 2 and Grade 5), and cryptococcal pneumonia (Grade 2). Five cases (0.8%) of tumor lysis syndrome were reported: 4 cases (1 Grade 4 [treatment related by investigator], 2 Grade 3 and 1 Grade 2) occurred after discontinuing treatment due to disease progression, and 1 case (Grade 3) occurred on day 7 and was considered treatment related by investigator, but did not lead to discontinuation. AEs led to treatment discontinuation in 37 (6.1%) pts. AEs leading to discontinuation in ≥2 pts included pneumonia (0.5%), thrombocytopenia (0.5%), anemia (0.3%), dyspnea (0.3%), glioblastoma multiforme (0.3%), and neutropenia (0.3%). Dose reductions (intake of less than the prescribed dose for ≥3 consecutive days) due to AEs occurred in 12 pts (2.0%). The median relative dose intensity was 98.5%.

Conclusions: Acalabrutinib monotherapy shows a tolerable safety profile across various hematologic malignancies. Of the most common AEs, the majority were low grade (Grades 1-2) and did not lead to treatment discontinuation.

Disclosures Byrd: Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Genentech: Research Funding. Owen: Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy, Honoraria, Other: Support to attend academic meetings; Celgene: Consultancy, Honoraria; Takeda: Honoraria, Other: Support to attend academic meetings. O'Brien: Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Acerta: Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Sunesis: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Alexion: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Janssen: Consultancy; Astellas: Consultancy; Vaniam Group LLC: Consultancy; AbbVie: Consultancy; Aptose Biosciences, Inc.: Consultancy; Amgen: Consultancy; GSK: Consultancy. Brown: Gilead: Consultancy, Research Funding; Janssen Oncology: Honoraria; Redx: Consultancy; Astellas Pharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Janssen: Consultancy; Infinity Pharmaceuticals: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy, Honoraria; Celgene: Consultancy; AstraZeneca: Consultancy; Sun BioPharma: Consultancy, Research Funding. Hillmen: Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Bitman: Astra Zeneca: Equity Ownership; Acerta Pharma: Employment. Chernyukhin: Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Hamdy: Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Izumi: Acerta Pharma: Employment, Equity Ownership. Patel: Acerta Pharma: Employment. Schwartz-Sagi: Acerta Pharma: Employment. Tucker: Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Wiestner: Acerta Pharma: Research Funding; Pharmacyclics: Research Funding. Rule: Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite: Consultancy; Napp: Consultancy; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Wang: Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Kite Pharma: Research Funding; Oncoceutics: Research Funding; BeiGene: Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Asana: Research Funding; Oncternal: Research Funding; Karus: Research Funding; Juno Therapeutic: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

  • * Asterisk with author names denotes non-ASH members.