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Review
. 2022 Nov;97 Suppl 2(Suppl 2):S19-S25.
doi: 10.1002/ajh.26682.

Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare)

Julia H Aronson  1 , Sigrid S Skånland  2   3 , Lindsey E Roeker  1 , Meghan C Thompson  1 , Anthony R Mato  1
Affiliations
Review

Approach to a patient with "double refractory" chronic lymphocytic leukemia: "Double, double toil and trouble" (Shakespeare)

Julia H Aronson et al. Am J Hematol. 2022 Nov.

Abstract

As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the "double refractory" patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.

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Conflict of interest statement

S.S.S. has received honoraria from AbbVie and AstraZeneca, and research support from BeiGene and TG Therapeutics. L.E.R. has served as a consultant/advisor for AbbVie, AstraZeneca, Beigene, Janssen, Lockwood Group, Loxo Oncology, MJH, OncLive, Pharmacyclics, Pfizer, and TG Therapeutics, travel support from Loxo Oncology, holds minority ownership interest in Abbott Laboratories and has received research funding (paid to the institution) from Pfizer, Loxo Oncology, and Aptose Biosciences. M.C.T. has received an honorarium from MJH Life Sciences, Curio Science, VJHemOnc, Brazilian Association of Hematology and Hemotherapy (ABHH), and Massachusetts Medical Society. A.R.M. has served as a consultant advisory board/steering committee for Abbvie, AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Genentech, Laboratorios Pfizer Ltda., LOXO Oncology, Octopharma, Pharmacyclics LLC, Nurix, Genmab, TG Therapeutics; DSMB for Celgene, TG Therapeutics, member of Medical Advisory Board for CLL Society, CME speaker for Curio, consultant for DAVA, Medscape, and an ad hoc scientific advisor for the Lymphoma Research Foundation.

Figures

FIGURE 1
FIGURE 1
Defining the double refractory patient population. BTKi, Bruton’s tyrosine kinase inhibitors; CLL, chronic lymphocytic leukemia
FIGURE 2
FIGURE 2
Updated sequencing algorithm incorporating noncovalent Bruton’s tyrosine kinase inhibitors (ncBTKi). CAR-T, chimeric antigen receptor T cells; SCT, stem cell transplantation
See this image and copyright information in PMC

References

    1. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223. - PMC - PubMed
    1. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425–2437. - PMC - PubMed
    1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107–1120. - PubMed
    1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225–2236. - PubMed
    1. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007. - PMC - PubMed

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