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CHRONIC LYMPHOCYTIC LEUKEMIA

Evaluation of bleeding events in patients receiving acalabrutinib therapy

Leukemia (2023)Cite this article

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Abstract

Acalabrutinib is a next-generation, more selective, covalent Bruton tyrosine kinase inhibitor (BTKi), designed to have less toxicity, including bleeding, than the first-generation covalent BTKi ibrutinib. We performed a retrospective medical record review of 289 patients with B-cell malignancies treated with acalabrutinib to evaluate and describe bleeding events. Median acalabrutinib exposure was 40.8 months (range 0–81.6) with 83% of patients experiencing at least one bleeding event. Of these patients, 59%, 35%, and 6% had a clinically non-relevant minor, clinically relevant minor, or major bleed as their first, most severe event per ISTH criteria, respectively. For all bleed events, 24% were clinically relevant minor/major and 2.5% were CTCAE grade ≥3. Age >65, prior bleed history, and longer time on acalabrutinib therapy were found to be independent risk factors for clinically relevant minor/major bleeds. Additionally, 1263 procedures were identified, and the incidence of clinically non-relevant and clinically relevant minor/major bleeds related to procedures was 0.95% and 1.3%, respectively. In conclusion, with a long median exposure time, most bleeds were clinically non-relevant per ISTH criteria and CTCAE grade <3 for patients with B-cell malignancies treated with acalabrutinib.

Acalabrutinib is a Bruton’s tyrosine kinase inhibitor (BTKi), approved for the treatment of chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) [1]. Acalabrutinib is more selective for BTK with less off-target activity on other kinases than the first-generation BTKi ibrutinib [2]. This selectivity was meant to decrease toxicities, such as bleeding and cardiovascular events, seen with ibrutinib [3]. Unlike ibrutinib, acalabrutinib does not inhibit the Src family kinases which have an important role in platelet adhesion to collagen, which should decrease rates of bleeding [4]. In the phase 3 trial ELEVATE-RR, acalabrutinib had significantly lower incidence of contusions, as well as bleeding events compared to ibrutinib. However, the frequency of major bleeding was comparable [5]. Rates of bleeding events on clinical trials using acalabrutinib are similar, with the majority being grade 1–2 cutaneous bleeds; however, major hemorrhage has been observed with rates ranging between 2–5% [5,6,7,8,9].

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The Biostatistics Shared Resource (BSR) at The Ohio State University Comprehensive Cancer Center, Columbus, OH for biostatistical support of this study. Research reported in this publication was supported by The Ohio State University Comprehensive Cancer Center. ASK is a recipient of the Conquer Cancer, the ASCO Foundation, Career Development Award. KAR and JAW are Scholars in Clinical Research of The Leukemia & Lymphoma Society.

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Authors and Affiliations

  1. The Ohio State University, Department of Pharmacy, Columbus, OH, USA

    Pooja S. Kumar, Tracy Wiczer & Lindsay Rosen

  2. The Ohio State College of Pharmacy, Columbus, OH, USA

    Arthur J. Pollauf & Amy Zheng

  3. The Ohio State University, Department of Biomedical Informatics, Center for Biostatistics, Columbus, OH, USA

    Marilly Palettas

  4. Driscoll Children’s Hospital, Corpus Christi, TX, USA

    Leylah Azali

  5. The Ohio State University, Department of Internal Medicine, Division of Hematology, Columbus, OH, USA

    Seema A. Bhat, Michael R. Grever, Kerry A. Rogers, Jennifer A. Woyach & Adam S. Kittai

  6. University of Cincinnati, Department of Internal Medicine, Cincinnati, OH, USA

    John C. Byrd

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  1. Pooja S. Kumar
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Contributions

PSK, AJP, AZ, and LA collected data. PSK, TW, MP, and ASK interpreted data and were involved in the conception and design of the study. PSK and ASK wrote the manuscript, and all authors analyzed the data, edited, and revised the manuscript, provided critical intellectual content, provided patient care, and approved the manuscript.

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Correspondence to Adam S. Kittai.

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Competing interests

PSK, TW, LR, AJP, AZ, MP, LA have no conflicts to disclose. SAB receives research funding from AstraZeneca, and has consulted for Pharmacyclics, Janssen, Beigene, and AstraZeneca, and has received honorarium from OncLive, and has received travel funding from Arqule. JCB has consulted for Syndax, Trillium, AstraZeneca, Novartis, Newave and Kronos, and is the chair of the scientific advisory board and a major stockholder in Vincerx Pharma. MRG receives research funding from the Hairy Cell Leukemia Foundation for Patient Data Registry, has consulted AstraZeneca, Pharmacyclics, Ascerta (participant in long-term follow-up Data Safety Monitoring Committee), Axio, Inc; Serono/Merck, has received travel expenses from the Hairy Cell Leukemia Foundation, is the scientific board chair for the Hairy Cell Leukemia Foundation Scientific Board (no reimbursement), and has received scientific honorarium from the University of Pittsburgh. KAR receives research funding from Genentech, AbbVie, Janssen, and Novartis, consults for AbbVie, AstraZeneca, Genentech, Pharmacyclics, Innate Pharma, and Beigene, and received travel funding from AstraZeneca. JAW has received research funding from Janssen, Morphosys, and Schrodinger and has consulted for Abbvie, AstraZeneca, Beigene, Genentech, Janssen, Loxo, Newave, and Pharmacyclics. ASK has received research funding from AstraZeneca, and has consulted for Abbvie, AstraZeneca, Beigene, KITE, and Janssen.

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Kumar, P.S., Wiczer, T., Rosen, L. et al. Evaluation of bleeding events in patients receiving acalabrutinib therapy. Leukemia (2023). https://doi.org/10.1038/s41375-023-01869-1

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