With great power comes great responsibility: Managing side effects of novel treatments in chronic lymphocytic leukemia (CLL)
DOI:
https://doi.org/10.58931/cht.2022.1215Abstract
The treatment paradigm shift in CLL has uprooted many clinicians’ standard practices. Previously, treatment largely depended on age, organ function and “fitness” based on clinical trials which used CIRS (cumulative illness rating scale) scores. Today, as a hematologist who mainly treats patients with CLL, treatment strategies are more complex and multi-factorial. Treatments are based on molecular profiling, which aids in the identification of lower-risk patients for time-limited treatment options versus higher-risk patients (IGVH unmutated, del 17p or TP534 ) who benefit from continuous therapies. The highest-risk patients can be identified using a staging system for CLL known as the CLL-International Prognostic Index (CLL-IPI). However, increased CIRS scores are prognostic for poor outcomes independent of the CLL-IPI. As a result, selecting the right treatment for the right individual has never been more important, especially in the era of novel therapeutics. This treatment selection decision pathway includes understanding both patient factors and medical factors that may influence patient outcomes.
References
Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008 Oct 1;56(10)1926-31. doi:10.1111/j.1532-5415.2008.01935.x DOI: https://doi.org/10.1111/j.1532-5415.2008.01935.x
Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Sept;21(9):1188-200. doi:10.1016/S1470-2045(20)30443-5 DOI: https://doi.org/10.1016/S1470-2045(20)30443-5
Crombie J, Davids MS. IGHV mutational status testing in chronic lymphocytic leukemia. Am J Hematol. 2017 Jun 7;92(12):1393-7. doi:10.1002/ajh.24808 DOI: https://doi.org/10.1002/ajh.24808
Te Raa GD, Kater AP. TP53 dysfunction in CLL: Implications for prognosis and treatment. Best Pract Res Clin Haematol. 2016 Mar;29(1):90-99. doi:10.1016/j.beha.2016.08.002 DOI: https://doi.org/10.1016/j.beha.2016.08.002
Byrd JC, Furman RR, Coutre SE, Flinn IW, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369:32-42. doi:10.1056/NEJMoa1215637 DOI: https://doi.org/10.1056/NEJMoa1215637
Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-91. doi:10.1016/S0140-6736(20)30262-2 DOI: https://doi.org/10.1016/S0140-6736(20)30262-2
Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018 Oct 3;8:93. doi:10.1038/s41408-018-0131-2 DOI: https://doi.org/10.1038/s41408-018-0131-2
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 Jun;17(6):779-90. doi:10.1016/S1470-2045(16)30029-8 DOI: https://doi.org/10.1016/S1470-2045(16)30029-8
Molica S, Shanafelt TD, Giannarelli D, Gentile M, Mirabelli R, et al. The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016 Nov;91(11):1090-5. doi:10.1002/ajh.24493 DOI: https://doi.org/10.1002/ajh.24493
Gentile M, Shanafelt TD, Rossi D, Laurenti L, Mauro FR, et al. Validation of the CLL-IPI and comparison with the MDACC prognostic index in newly diagnosed patients. Blood. 2016 Oct 20;128(16)2093-5. doi:10.1182/blood-2016-07-728261 DOI: https://doi.org/10.1182/blood-2016-07-728261
Rigolin GM, Cavallari M, Quaglia FM, Formigaro L, Lista E, et al. In CLL, comorbidities and the complex karyotype are associated with an inferior outcome independently of CLL-IPI. Blood. 2017 Jun 29;129(26):3495-8. doi:10.1182/blood-2017-03-772285 DOI: https://doi.org/10.1182/blood-2017-03-772285
Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, et al. Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol. 2019 Feb 1;37(4)269-77. doi:10.1200/JCO.18.01580 DOI: https://doi.org/10.1200/JCO.18.01580
Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. doi:10.1016/S1470-2045(16)30019-5 DOI: https://doi.org/10.1016/S1470-2045(16)30019-5
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370:1101-1110. doi:10.1056/NEJMoa1313984 DOI: https://doi.org/10.1056/NEJMoa1313984
Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. doi:10.1038/leu.2015.14 DOI: https://doi.org/10.1038/leu.2015.14
Panovska A, Nemcova L, Nekvindova L, Spacek M, Simkovic M, et al. Real-world data on efficacy and safety of obinutuzumab plus chlorambucil, rituximab plus chlorambucil, and rituximab plus bendamustine in the frontline treatment of chronic lymphocytic leukemia: The GO-CLLEAR Study by the Czech CLL Study Group. Hematol Oncol. 2020 May 13;38(4):509-16. doi:10.1002/hon.2744 DOI: https://doi.org/10.1002/hon.2744
Bourrier N, Landego I, Bucher O, Squires M, Streu E, et al. Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia. BMC Cancer. 2022 Feb 6;22:148. doi:10.1186/s12885-022-09256-2 DOI: https://doi.org/10.1186/s12885-022-09256-2
Fischer K, Al-Sawaf O, Hallek M. Preventing and monitoring for tumor lysis syndrome and other toxicities of venetoclax during treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1)357-362. doi:10.1182/hematology.2020000120 DOI: https://doi.org/10.1182/hematology.2020000120
Koenig KL, Huang Y, Dotson EK, Sheredy S, Bhat SA, et al. Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists. Blood Adv. 2020 Oct 13;4(19):4860-4863. doi:10.1182/bloodadvances.2020002593 DOI: https://doi.org/10.1182/bloodadvances.2020002593
Cooper JP, Khajaviyan S, Smith SD, et al. Outcomes of Patients With Therapy-Related MDS After Chemoimmunotherapy for Chronic Lymphocytic Leukemia Compared With Patients With De Novo MDS: A Single-Institution Experience. Clin Lymphoma Myeloma Leuk. 2019 Jun;19(6):390-5. doi:10.1016/j.clml.2019.03.003 DOI: https://doi.org/10.1016/j.clml.2019.03.003
Tambaro FP, Garcia-Manero G, O'Brien SM, Faderl SH, Burger JA, et al. Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome. Leukemia. 2015 Aug 20;30:325-30. doi:10.1038/leu.2015.227 DOI: https://doi.org/10.1038/leu.2015.227
Mato AR, Thompson M, Allan JN, Brander DM, Pagel JM, et al. Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States. Haematologica. 2018 Sept;103(9):1511-7. doi:10.3324/haematol.2018.193615 DOI: https://doi.org/10.3324/haematol.2018.193615
Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, 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 Dec;94(12)1353-63. doi:10.1002/ajh.25638 DOI: https://doi.org/10.1002/ajh.25638
Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-28. doi:10.1056/NEJMoa1812836 DOI: https://doi.org/10.1056/NEJMoa1812836
Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, et al. Long-term Outcomes for Ibrutinib-Rituximab and Chemoimmunotherapy in CLL: Updated Results of the E1912 Trial. Blood. 2022 Jul 14;140(2):112-120. doi:10.1182/blood.2021014960 DOI: https://doi.org/10.1182/blood.2021014960
Shanafelt TD, et. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. doi:10.1056/NEJMoa1817073 DOI: https://doi.org/10.1056/NEJMoa1817073
Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):336-345. doi:10.1182/hematology.2020000118 DOI: https://doi.org/10.1182/hematology.2020000118
Uminski K, Brown K, Bucher O, Hibbert I, Dhaliwal DH, et al. Descriptive analysis of dosing and outcomes for patients with ibrutinib-treated relapsed or refractory chronic lymphocytic leukemia in a Canadian centre. Curr Oncol. 2019 Oct;26(5):e610-e617. doi:10.3747/co.26.4957 DOI: https://doi.org/10.3747/co.26.4957
O’Brien SM, Brown JR, Byrd JC, Furman RR, Ghia P, et al. Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice. Front Oncol. 2021 Nov 8;11:720704. doi:10.3389/fonc.2021.720704 DOI: https://doi.org/10.3389/fonc.2021.720704
Rhodes JM, Lo Re VA, Mato AR, et al. Ibrutinib-associated Arthralgias/Myalgias in Patients With Chronic Lymphocytic Leukemia: Incidence and Impact on Clinical Outcomes. Clin Lymphoma Myeloma Leuk. 2020 Jul;20(7):438-444.e1. doi:10.1016/j.clml.2020.02.001 DOI: https://doi.org/10.1016/j.clml.2020.02.001
Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017 May 4;129(18):2581-2584. doi:10.1182/blood-2016-10-742437 DOI: https://doi.org/10.1182/blood-2016-10-742437
Bose P, Gandhi V. Recent therapeutic advances in chronic lymphocytic leukemia. F1000Res. 2017 Oct 31;6:1924. doi:10.12688/f1000research.11618.1 DOI: https://doi.org/10.12688/f1000research.11618.1
Bose P, Chen LS, Gandhi V. Ibrutinib dose and clinical outcome in chronic lymphocytic leukemia – learning from the ‘real world’. Leuk Lymphoma. 2019 Jul;60(7):1603-1605. doi:10.1080/10428194.2019.1571207 DOI: https://doi.org/10.1080/10428194.2019.1571207
Parikh SA, Achenbach SJ, Call TC, Rabe KG, Ding W et al. The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice. Cancer Med. 2020 May;9(10):3390-9. doi:10.1002/cam4.2998 DOI: https://doi.org/10.1002/cam4.2998
Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-52. doi:10.1200/JCO.21.01210 DOI: https://doi.org/10.1200/JCO.21.01210
Brown JR, Byrd JC, Ghia P, Sharman JP, Hillmen P, et al. Cardiovascular adverse events in patients with chronic lymphocytic leukemia receiving acalabrutinib monotherapy: pooled analysis of 762 patients. Haematologica. 2022 Jun 1;107(6):1335-46. doi:10.3324/haematol.2021.278901 DOI: https://doi.org/10.3324/haematol.2021.278901
Hillmen P, Brown JR, Eichhorst BF, Lamanna N, O'Brien SM, et al. ALPINE: zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2020 Apr;16(10):517-23. doi:10.2217/fon-2019-0844 DOI: https://doi.org/10.2217/fon-2019-0844
Awan FT, Schuh A, Brown JR, Furman RR, Pagel JM, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019 May 14;3(9):1553-62. doi:10.1182/bloodadvances.2018030007 DOI: https://doi.org/10.1182/bloodadvances.2018030007
Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5 DOI: https://doi.org/10.1016/S0140-6736(21)00224-5
Lamanna N. The emerging role of pirtobrutinib in chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2022 Apr;20(4):212-4.
