Treatment of Double-Refractory Chronic Lymphocytic Leukemia-An Unmet Clinical Need

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Feb 10

PMID 38338868

Authors

Przemyslaw Zygmunciak

Tadeusz Robak

Bartosz Pula

Affiliations

Soon will be listed here.

Abstract

Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton's kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter's transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL.

Citing Articles

Targeting Tumor Microenvironment Interactions in Chronic Lymphocytic Leukemia Using Leukotriene Inhibitors.

Sadeghi L, Merrien M, Bjorkholm M, Osterborg A, Sander B, Claesson H Int J Mol Sci. 2025; 26(5).

PMID: 40076826 PMC: 11899779. DOI: 10.3390/ijms26052209.

Efficacy and Effectiveness Outcomes of Treatments for Double-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review.

Zuber M, Akkala S, Li N, Veettil S, Tan C, Villa Zapata L Cancer Med. 2024; 13(18):e70258.

PMID: 39344587 PMC: 11440144. DOI: 10.1002/cam4.70258.

Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL).

McKeown J, Byrne A, Bright S, Charleton C, Kandwal S, cmelo I Pharmaceuticals (Basel). 2024; 17(8).

PMID: 39204139 PMC: 11359702. DOI: 10.3390/ph17081034.

Extramedullary and extranodal manifestations in chronic lymphocytic leukemia - an update.

Robak T, Pula A, Braun M, Robak E Ann Hematol. 2024; 103(9):3369-3383.

PMID: 39052034 PMC: 11358350. DOI: 10.1007/s00277-024-05854-1.

A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Wisniewski K, Pula B Int J Mol Sci. 2024; 25(10).

PMID: 38791284 PMC: 11120758. DOI: 10.3390/ijms25105246.

References

Cosson A, Chapiro E, Bougacha N, Lambert J, Herbi L, Cung H . Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1. Leukemia. 2017; 31(7):1625-1629. DOI: 10.1038/leu.2017.100. View

Woyach J, Bojnik E, Ruppert A, Stefanovski M, Goettl V, Smucker K . Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood. 2013; 123(8):1207-13. PMC: 3931190. DOI: 10.1182/blood-2013-07-515361. View

Woyach J, Furman R, Liu T, Ozer H, Zapatka M, Ruppert A . Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24):2286-94. PMC: 4144824. DOI: 10.1056/NEJMoa1400029. View

Geyer M, Riviere I, Senechal B, Wang X, Wang Y, Purdon T . Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight. 2019; 5. PMC: 6538317. DOI: 10.1172/jci.insight.122627. View

Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G . Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med. 2019; 380(22):2095-2103. PMC: 11827445. DOI: 10.1056/NEJMoa1900574. View

Liu T, Woyach J, Zhong Y, Lozanski A, Lozanski G, Dong S . Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood. 2015; 126(1):61-8. PMC: 4492196. DOI: 10.1182/blood-2015-02-626846. View

Kater A, Levin M, Dubois J, Kersting S, Enggaard L, Veldhuis G . Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022; 23(6):818-828. DOI: 10.1016/S1470-2045(22)00220-0. View

Alaggio R, Amador C, Anagnostopoulos I, Attygalle A, de Oliveira Araujo I, Berti E . The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022; 36(7):1720-1748. PMC: 9214472. DOI: 10.1038/s41375-022-01620-2. View

Siddiqi T, Maloney D, Kenderian S, Brander D, Dorritie K, Soumerai J . Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023; 402(10402):641-654. PMC: 11753452. DOI: 10.1016/S0140-6736(23)01052-8. View

10.

Timofeeva N, Gandhi V . Ibrutinib combinations in CLL therapy: scientific rationale and clinical results. Blood Cancer J. 2021; 11(4):79. PMC: 8085243. DOI: 10.1038/s41408-021-00467-7. View

11.

Roberts A, Davids M, Pagel J, Kahl B, Puvvada S, Gerecitano J . Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 374(4):311-22. PMC: 7107002. DOI: 10.1056/NEJMoa1513257. View

12.

Frey N, Gill S, Hexner E, Schuster S, Nasta S, Loren A . Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol. 2020; 38(25):2862-2871. PMC: 8265376. DOI: 10.1200/JCO.19.03237. View

13.

Peters F, Strefford J, Eldering E, Kater A . T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective. Haematologica. 2021; 106(5):1234-1243. PMC: 8586819. DOI: 10.3324/haematol.2020.267914. View

14.

Mohamed A, Yu L, Backesjo C, Vargas L, Faryal R, Aints A . Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009; 228(1):58-73. DOI: 10.1111/j.1600-065X.2008.00741.x. View

15.

Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B . The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2010; 117(2):563-74. PMC: 3031480. DOI: 10.1182/blood-2010-05-284984. View

16.

Mihalyova J, Hradska K, Jelinek T, Motais B, Celichowski P, Hajek R . Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders. Int J Mol Sci. 2021; 22(21). PMC: 8584080. DOI: 10.3390/ijms222111470. View

17.

Reiff S, Mantel R, Smith L, Greene J, Muhowski E, Fabian C . The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation. Cancer Discov. 2018; 8(10):1300-1315. PMC: 6261467. DOI: 10.1158/2159-8290.CD-17-1409. View

18.

Burger J, Landau D, Taylor-Weiner A, Bozic I, Zhang H, Sarosiek K . Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition. Nat Commun. 2016; 7:11589. PMC: 4876453. DOI: 10.1038/ncomms11589. View

19.

Walter H, Rule S, Dyer M, Karlin L, Jones C, Cazin B . A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2015; 127(4):411-9. PMC: 4731845. DOI: 10.1182/blood-2015-08-664086. View

20.

Siddiqi T, Soumerai J, Dorritie K, Stephens D, Riedell P, Arnason J . Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL. Blood. 2021; 139(12):1794-1806. PMC: 10652916. DOI: 10.1182/blood.2021011895. View