Vol 55, No 3 (2024)
Guidelines / Expert consensus
Published online: 2024-06-20

open access

Page views 115
Article views/downloads 52
Get Citation

Connect on Social Media

Connect on Social Media

Expert opinion on use of acalabrutinib for chronic lymphocytic leukemia treatment

Bartosz Puła1, Elżbieta Iskierka-Jażdżewska2, Krzysztof Jamroziak3, Krzysztof Giannopoulos4, Tomasz Wróbel5, Tadeusz Robak26, Iwona Hus7
DOI: 10.5603/ahp.100523
Acta Haematol Pol 2024;55(3):130-136.


Bruton’s tyrosine kinase inhibitors (BTKis) have become one of the most vital drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). BTKis are currently a well-established therapy for treatment-naïve, as well as relapsed or refractory, cases. BTKis have been shown to be crucial in the treatment of high-risk CLL patients bearing TP53 aberrations or characterized by the unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib was the first-in-class BTK inhibitor; however, despite its therapeutic potential, it is also characterized by specific adverse events, including hypertension, increased bleeding risk, cardiac toxicity, and skin changes. Although the next generation of BTKis was shown to be more specific, this adverse event profile is regarded currently as class-specific. In this review, we discuss the current status of acalabrutinib, a second-generation BTKi.

Article available in PDF format

View PDF Download PDF file


  1. Hus I, Giannopoulos K, Jamroziak K, et al. Diagnostic and therapeutic recommendations of the Polish Society of Haematologists and Transfusiologists, and Polish Adult Leukemia Group-CLL for chronic lymphocytic leukemia in 2023. Acta Haematologica Polonica. 2023; 54(6): 342–371.
  2. Hallek M, Al‐Sawaf O, Hallek M, et al. Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures. American Journal of Hematology. 2021; 96(12): 1679–1705.
  3. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2021; 32(1): 23–33.
  4. Szmit S. Recommendations on cardiac safety during ibrutinib therapy. Acta Haem Pol. 2023; 54(1): 3–5.
  5. Barr P, Owen C, Robak T, et al. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia . Blood Advances. 2022; 6(11): 3440–3450.
  6. Munir T, Brown J, O'Brien S, et al. Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol . 2019; 94(12): 1353–1363.
  7. Sharman J, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of elevate-TN. Blood. 2023; 142(Supplement 1): 636–636.
  8. Wolska-Washer A, Robak T, Wolska-Washer A, et al. Acalabrutinib: a bruton tyrosine kinase inhibitor for the treatment of chronic lymphocytic leukemia. Expert Review of Hematology. 2022; 15(3): 183–194.
  9. Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: Final ASCEND trial results. HemaSphere. 2022; 6(12): e801.
  10. Seymour J, Byrd J, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023; 142(8): 687–699.
  11. Byrd J, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021; 39(31): 3441–3452.
  12. Tam C, Brown J, Kahl B, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022; 23(8): 1031–1043.
  13. Shadman M, Munir T, Roback T, et al. Zanubrutinib (zanu) versus bendamustine + rituximab (br) in patients (pts) with treatment‐naïve (TN) CLL/SLL: extended follow‐up of the sequoia study. Hematol Oncol. 2023; 41(S2): 235–238.
  14. Tam C, Robak T, Ghia P, et al. Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion. Haematologica. 2020; 106(9): 2354–2363.
  15. Brown J, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023; 388(4): 319–332.
  16. Mato A, Samp J, Gauthier G, et al. Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies. Cancer Biol Ther . 2018; 19(7): 636–643.
  17. Awan F, Schuh A, Brown J, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019; 3(9): 1553–1562.
  18. Shadman M, Flinn I, Levy M, et al. Phase 2 study of zanubrutinib in BTK inhibitor-intolerant patients (Pts) with relapsed/refractory B-cell malignancies. Blood. 2021; 138(Supplement 1): 1410–1410.
  19. Byrd J, Wierda W, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020; 135(15): 1204–1213.
  20. Wu J, Liu C, Tsui S, et al. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016; 9(1).
  21. Wu J, Zhang M, Liu D, et al. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016; 9(1).
  22. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. Pharmacol Exp Ther. 2017; 363(2): 240–252.
  23. Kaptein A, Bruin Gde, Hoek MEv, et al. Potency and selectivity of BTK inhibitors in clinical development for B-cell malignancies. Blood. 2018; 132(Supplement 1): 1871–1871.
  24. Xiao L, Salem JE, Clauss S, et al. Ibrutinib-mediated atrial fibrillation attributable to inhibition of C-terminal Src kinase. Circulation. 2020; 142(25): 2443–2455.
  25. Covey T, Barf T, Gulrajani M, et al. Abstract 2596: ACP-196: a novel covalent Bruton's tyrosine kinase (Btk) inhibitor with improved selectivity and in vivo target coverage in chronic lymphocytic leukemia (CLL) patients. Cancer Research. 2015; 75(15_Supplement): 2596–2596.
  26. Ghia P, Pluta A, Wach M, et al. ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020; 38(25): 2849–2861.
  27. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res. 2017; 23(14): 3734–3743.
  28. Rogers K, Thompson P, Allan J, et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021; 106(9): 2364–2373.
  29. Yazdy M, Mato A, Roeker L, et al. Toxicities and outcomes of acalabrutinib-treated patients with chronic lymphocytic leukemia: a retrospective analysis of real world patients. Blood. 2019; 134(Supplement_1): 4311–4311.
  30. Sharman J, Ghia P, Miranda P, et al. Analysis of ventricular arrhythmias and sudden death from prospective, randomized clinical trials of acalabrutinib. Br J Haemato. 2024.
  31. Zygmunciak P, Robak T, Puła B, et al. Treatment of double-refractory chronic lymphocytic leukemia — an unmet clinical need. Int J Mol Sci. 2024; 25(3): 1589.
  32. Allan J, Kittai A, James D, et al. A matching-adjusted indirect comparison of acalabrutinib with and without obinutuzumab versus zanubrutinib in treatment-naïve chronic lymphocytic leukemia. Blood. 2023; 142(Supplement 1): 6563–6563.
  33. Kittai A, Skarbnik A, Miranda M, et al. A matching‐adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia. Am J Hematol. 2023; 98(12).
  34. Awan F, Addison D, Alfraih F, et al. International consensus statement on the management of cardiovascular risk of Bruton’s tyrosine kinase inhibitors in CLL. Blood Adv. 2022; 6(18): 5516–5525.
  35. Roeker L, DerSarkissian M, Ryan K, et al. Real-world comparative effectiveness of acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia. Blood Adv. 2023; 7(16): 4291–4301.
  36. Brown J, Byrd J, Ghia P, et al. Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients. Haematologica. 2021; 107(6): 1335–1346.
  37. O’Brien S, Brown J, Byrd J, et al. Monitoring and managing BTK inhibitor treatment-related adverse events in clinical practice. Front Oncol. 2021; 11: 720704.
  38. Davids M, Lampson B, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021; 22(10): 1391–1402.
  39. Cramer P, Fürstenau M, Robrecht S, et al. Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial. Lancet Haematol. 2022; 9(10): e745–e755.
  40. Ryan C, Davids M, Hermann R, et al. MAJIC: A phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022; 18(33): 3689–3699.
  41. Wiśniewski K, Puła B, Wiśniewski K, et al. A review of resistance mechanisms to Bruton’s kinase inhibitors in chronic lymphocytic leukemia. Int J Mol Sci. 2024; 25(10): 5246.