Experience of using acalabrutinib therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Introduction. Thanks to scientific advances and discoveries in the study of tumor cell biology, new effective drugs for the treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma have emerged. Currently, there are drugs with different application points at the molecular level. One such drug is acalabrutinib, which is a selective second-generation inhibitors of Bruton tyrosine kinase and has a more favorable toxicity profile.

Objective. To evaluate the efficacy of acalabrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Materials and methods. Since February 2020 acalabrutinib (100 mg 2 p/day orally) has been administered to 7 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (mean age 64 years) at the Hematology Research Center. Six patients received acalabrutinib in 1st-line therapy and one patient received acalabrutinib in 2nd-line therapy. The mean comorbidity index (CIRS) of the patients was 10 points (range, 8 to 14). Most patients had at least one of the adverse prognostic factors - IGHV nonmutated gene status, TP53 gene aberration (del17p13 and/or TP53 gene mutation), complex karyotype disorders.

Results. All patients achieved partial remission of the disease (overall response 100% in the form of regression of B-symptoms, lymphocytic leukocytosis, splenomegaly) at the control period of treatment with acalabrutinib +12 months. The most frequent adverse events when taking acalabrutinib were the occurrence of headache in the first month of taking the drug, spontaneous subcutaneous hematomas. No hematologic toxicity, infectious complications, or cardiac complications were noted. At a median follow-up of 34 months, no patient showed disease progression.

Conclusions. The selective Bruton tyrosine kinase inhibitor acalabrutinib has demonstrated high efficacy in patients with adverse risk factors, good tolerability and minimal toxicity, including in comorbid patients.

1. Jemal A., Siegel R., Ward E., Murray T., Xu J., Thun M.J. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66. https://doi.org/10.3322/canjclin.57.1.43.

2. Rozman C., Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333(16):1052-1057. https://doi.org/10.1056/NEJM199510193331606.

3. Chiorazzi N., Rai K.R., Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804-815. https://doi.org/10.1056/NEJMra041720.

4. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. https://doi.org/10.1016/S1470-2045(16)30029-8.

5. Mayr C., Speicher M.R., Kofler D.M., Buhmann R., Strehl J., Busch R. et al. Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia. Blood. 2006;107(2):742-751. https://doi.org/10.1182/blood-2005-05-2093.

6. Hallek M., Fischer K., Fingerle-Rowson G., Fink A.M., Busch R., Mayer J. et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174. https://doi.org/10.1016/S0140-6736(10)61381-5.

7. Fischer K., Bahlo J., Fink A.M., Goede V., Herling C.D., Cramer P. et al. Longterm remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215. https://doi.org/10.1182/blood-2015-06-651125.

8. Eichhorst B., Fink A.M., Bahlo J., Busch R., Kovacs G., Maurer C. et al. First-line rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942. https://doi.org/10.1016/S1470-2045(16)30051-1.

9. Kil L.P., de Bruijn M.J., van Hulst J.A., Langerak A.W., Yuvaraj S., Hendriks R.W. Bruton's tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3(1):71-83. Available at: https://pubmed.ncbi.nlm.nih.gov/23359016/.

10. Burger J.A. Treatment of Chronic Lymphocytic Leukemia. N Engl J Med. 2020;383(5):460-473. https://doi.org/10.1056/NEJMra1908213.

11. Burger J.A., Barr P.M., Robak T., Owen C., Ghia P., Tedeschi A. et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. https://doi.org/10.1038/s41375-019-0602-x.

12. Shanafelt T.D., Wang X.V., Kay N.E., Hanson C.A., O'Brien S., Barrientos J. et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):432-443. https://doi.org/10.1056/NEJMoa1817073.

13. Byrd J.C., Hillmen P., O'Brien S., Barrientos J.C., Reddy N.M., Coutre S. et al. Longterm follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-2042. https://doi.org/10.1182/blood-2018-08-870238.

14. Ahn I.E., Farooqui M.Z.H., Tian X., Valdez J., Sun C., Soto S. et al. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood. 2018;131(21):2357-2366. https://doi.org/10.1182/blood-2017-12-820910.

15. Woyach J.A., Ruppert A.S., Heerema N.A., Zhao W., Booth A.M., Ding W. et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018;379(26):2517-2528. https://doi.org/10.1056/NEJMoa1812836.

16. McMullen J.R., Boey E.J., Ooi J.Y., Seymour J.F., Keating M.J., Tam C.S. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829-3830. https://doi.org/10.1182/blood-2014-10-604272.

17. Barf T., Covey T., Izumi R., van de Kar B., Gulrajani M., van Lith B. et al. Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. J Pharmacol Exp Ther. 2017;363(2):240-252. https://doi.org/10.1124/jpet.117.242909.

18. Byrd J.C., Hillmen P., Ghia P., Kater A.P., Chanan-Khan A., Furman R.R. 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. https://doi.org/10.1200/JCO.21.01210.

19. Rogers K.A., Thompson P.A., Allan J.N., Coleman M., Sharman J.P., Cheson B.D. et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021;106(9):2364-2373. https://doi.org/10.3324/haematol.2020.272500.

20. Byrd J.C., Woyach J.A., Furman R.R., Martin P., O'Brien S., Brown J.R. et al. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021;137(24):3327-3338. https://doi.org/10.1182/blood.2020009617.

21. Hallek M., Cheson B.D., Catovsky D., Caligaris-Cappio F., Dighiero G., Dohner H. et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer InstituteWorking Group 1996 guidelines. Blood. 2008;111(12):5446-5456. https://doi.org/10.1182/blood-2007-06-093906.

22. Byrd J.C., Furman R.R., Coutre S.E., Burger J.A., Blum K.A., Coleman M. et al. Three-year follow-up of treatment-naive and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506. https://doi.org/10.1182/blood-2014-10-606038.

23. Brown J.R., Moslehi J., O'Brien S., Ghia P., Hillmen P., Cymbalista F. et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796-1805. https://doi.org/10.3324/haematol.2017.171041.

24. Shanafelt T.D., Parikh S.A., Noseworthy P.A., Goede V., Chaffee K.G., Bahlo J. et al. Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2017;58(7):1630-1639. https://doi.org/10.1080/10428194.2016.1257795.

25. Caldeira D., Alves D., Costa J., Ferreira J.J., Pinto F.J. Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis. PLoS One. 2019;14(2):e0211228. https://doi.org/10.1371/journal.pone.0211228.

26. Dickerson T., Wiczer T., Waller A., Philippon J., Porter K., Haddad D. et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019;134(22):1919-1928. https://doi.org/10.1182/blood.2019000840.