Double-Exposed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Clinical Approach and Management
DOI:
https://doi.org/10.58931/cht.2025.4s0676Abstract
Managing patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have been treated with both a covalent Bruton’s tyrosine kinase (BTK) and BCL2 inhibitor represents an increasingly common and complex clinical challenge. While some patients may be candidates for retreatment with a covalent BTK and/or BCL2 inhibitor, those who are refractory to both classes have limited therapeutic options beyond phosphoinositide 3-kinase (PI3K) inhibitors or allogeneic hematopoietic stem cell transplantation, which is typically feasible only for highly selected individuals. In this context, enrollment in clinical trials or compassionate access programs provides the best opportunity to access promising novel therapies, including next-generation BTK inhibitors and T-cell–directed immunotherapy approaches. This review provides a practical approach for assessing and managing double-exposed CLL/SLL in the current Canadian context.
References
Burger JA, Barr PM, Robak T, Owen C, Tedeschi A, Sarma A, et al. Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL. Blood. 2025; epub ahead of print. DOI: https://doi.org/10.1182/blood.2024028205
Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-35. DOI: https://doi.org/10.1182/blood.2024024631
Grainger BT, Thompson PA, Cheah CY. Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukemia. Blood. 2025;146(2):145-54. DOI: https://doi.org/10.1182/blood.2024024893
Aronson JH, Skånland SS, Roeker LE, Thompson MC, Mato AR. Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare). Am J Hematol. 2022;97 Suppl 2:S19-S25. DOI: https://doi.org/10.1002/ajh.26682
Yoon JT, Zhou Y, Mikhaleva M, Choi DS, Fernandes SM, Armand P, et al. Characteristics and outcomes of patients with double refractory and double exposed chronic lymphocytic leukemia. Blood Adv. 2025;9(11):2808-17. DOI: https://doi.org/10.1182/bloodadvances.2025016006
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-60. DOI: https://doi.org/10.1182/blood-2017-09-806398
Tam CS, Balendran S, Blombery P. Novel mechanisms of resistance in CLL: variant BTK mutations in second-generation and noncovalent BTK inhibitors. Blood. 2025;145(10):1005-9. DOI: https://doi.org/10.1182/blood.2024026672
Giné E, Martinez A, Villamor N, López-Guillermo A, Camos M, Martinez D, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95(9):1526-33. DOI: https://doi.org/10.3324/haematol.2010.022277
Eyre TA, Riches JC, Patten PEM, Walewska R, Marr H, Follows G, et al. Richter transformation of chronic lymphocytic leukaemia: a British Society for Haematology Good Practice Paper. Br J Haematol. 2022;196(4):864-70. DOI: https://doi.org/10.1111/bjh.17882
Lew TE, Lin VS, Cliff ER, Blombery P, Thompson ER, Handunnetti SM, et al. Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition. Blood Adv. 2021;5(20):4054-8. DOI: https://doi.org/10.1182/bloodadvances.2021005083
Puckrin R, Banerji V, Peters A, Bruins R, Noormohamed S, Bell K, et al. Treatment patterns and outcomes in CLL patients following cBTKi discontinuation. EHA Congress Library. 2025.
Mansour AG, Huang Y, Alsouqi A, Kittai AS, Byrd JC, Grever MR, et al. Outcomes of patients with chronic lymphocytic leukemia discontinuing Bruton tyrosine kinase inhibitors due to adverse effects. Blood. 2024;144:4629. DOI: https://doi.org/10.1182/blood-2024-199676
Rogers KA, Thompson PA, Allan JN, Coleman M, Sharman JP, Cheson BD, et al. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. 2021;106(9):2364-73. DOI: https://doi.org/10.3324/haematol.2020.272500
Shadman M, Flinn IW, Levy MY, Porter RF, Burke JM, Zafar SF, et al. Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study. Lancet Haematol. 2023;10(1):e35-e45. DOI: https://doi.org/10.1016/S2352-3026(22)00320-9
Shah NN, Wang M, Roeker LE, Patel K, Woyach JA, Wierda WG, et al. Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial. Haematologica. 2025;110(1):92-102.
Ghia P, Barr PM, Allan JN, Siddiqi T, Tedeschi A, Kipps TJ, et al. Final analysis of fixed‐duration ibrutinib+ venetoclax for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the phase 2 captivate study. Hematological Oncology. 2025;43(p.e71_70093.). Thompson MC, Harrup RA, Coombs CC, Roeker LE, Pu JJ, Choi MY, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Adv. 2022;6(15):4553-7. DOI: https://doi.org/10.1002/hon.70093_71
van Gelder M, de Wreede LC, Bornhäuser M, Niederwieser D, Karas M, Anderson NS, et al. Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2017;52(3):372-80. DOI: https://doi.org/10.1038/bmt.2016.282
Kim HT, Shaughnessy CJ, Rai SC, Reynolds C, Ho VT, Cutler C, et al. Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia. Blood Adv. 2020;4(17):4113-23. DOI: https://doi.org/10.1182/bloodadvances.2020002184
Roeker LE, Dreger P, Brown JR, Lahoud OB, Eyre TA, Brander DM, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977-89. DOI: https://doi.org/10.1182/bloodadvances.2020001956
Puckrin R, Shafey M, Storek J. The role of allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: A review. Front Oncol. 2022;12:1105779. DOI: https://doi.org/10.3389/fonc.2022.1105779
Mato AR, Roeker LE, Jacobs R, Hill BT, Lamanna N, Brander D, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-96. DOI: https://doi.org/10.1158/1078-0432.CCR-19-3815
Sharman JP, Munir T, Grosicki S, Roeker LE, Burke JM, Chen CI, et al. Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol. 2025;43(22):2538-49. DOI: https://doi.org/10.1200/JCO-25-00166
Thompson MC, Roeker LE, Coombs CC, Jensen JL, Kamdar M, Skarbnik A, et al. Addressing a new challenge in chronic lymphocytic leukemia: outcomes of therapies after exposure to both a covalent Bruton's tyrosine kinase inhibitor and venetoclax. Blood. 2021;138:2628. DOI: https://doi.org/10.1182/blood-2021-150751
Mato AR, Woyach JA, Brown JR, Ghia P, Patel K, Eyre TA, et al. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med. 2023;389(1):33-44. DOI: https://doi.org/10.1056/NEJMoa2300696
Woyach J, Flinn IW, Awan F, Eradat H, Brander DM, Tees M, Pet al. P628: Updated analysis of BELLWAVE-001: a phase 1/2 open-label dose-expansion study of the efficacy and safety of nemtabrutinib for the treatment of B-cell malignancies. Hemasphere. 2023;7(S3):e7809236. DOI: https://doi.org/10.1097/01.HS9.0000969416.78092.36
Thompson MC, Parrondo RD, Frustaci AM, Allan JN, Ghia P, Mocanu I, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic Leukemia/Small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. Blood. 2024;144:885. DOI: https://doi.org/10.1182/blood-2024-199116
Shah NN, Omer Z, Collins GP, Forconi F, Danilov A, Byrd JC, Eet al. Efficacy and safety of the Bruton's tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/b study. Blood. 2025;144:884. DOI: https://doi.org/10.1182/blood-2024-194839
Woyach JA, Stephens DM, Brander DM, Kittai AS, Hu B, Sitlinger A, et al. Initial results of a phase 1 dose escalation study of LP-168, a novel covalent and non-covalent next-generation inhibitor of Bruton's tyrosine kinase. Blood. 2023;142:328. DOI: https://doi.org/10.1182/blood-2023-186432
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725-33. DOI: https://doi.org/10.1056/NEJMoa1103849
Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, et al. Decade-long leukaemia remissions with persistence of CD4. Nature. 2022;602(7897):503-9. DOI: https://doi.org/10.1038/s41586-021-04390-6
Liang EC, Albittar A, Huang JJ, Hirayama AV, Kimble EL, Portuguese AJ, et al. Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL. Blood Adv. 2023;7(22):6990-7005. DOI: https://doi.org/10.1182/bloodadvances.2023011399
Siddiqi T, Gauthier J, Kenderian SS, Brander DM, Dorritie K, Soumerai JD, et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): updated follow-up of Transcend CLL 004. Blood. 2024;144:4633. DOI: https://doi.org/10.1182/blood-2024-200840
Wierda W, Maloney DG, and Kenderian SS. Characteristics associated with response to lisocabtagene maraleucel (liso-cel) in patients (pts) with R/R CLL/SLL: exploratory analyses from TRANSCEND CLL 004. European Hematology Association. 2024. DOI: https://doi.org/10.1016/S2152-2650(24)00572-X
Wierda WG, Dorritie K, Gauthier J, Nath R, Kipps TJ, Riedell PA, et al. Lisocabtagene maraleucel (liso-cel) combined with ibrutinib (ibr) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): primary results from the open-label, phase 1/2 transcend CLL 004 study. Blood. 2024;144:887. DOI: https://doi.org/10.1182/blood-2024-200339
Fakhri B, Danilov A, Awan FT, Bentzen HH, Eradat H, Niemann CU, et al. Epcoritamab monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: clinical and translational results from EPCORE CLL‐1. Hematol Oncol. 2025;43:p.e216_70094. DOI: https://doi.org/10.1002/hon.70094_216
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