Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia

Liu, Xu; Tsakmaklis, Nicholas; Yang, Guang; Chen, Jiaji G.; Liu, Xia; Demos, Maria; Kofides, Amanda; Patterson, Christopher J.; Meid, Kirsten; Gustine, Joshua; Dubeau, Toni; Palomba, M. Lia; Advani, Ranjana H.; Castillo, Jorge J.; Furman, Richard R.; Hunter, Zachary; Treon, Steven P.

doi:10.1182/blood-2017-01-761726

Cited by 120 publications

(93 citation statements)

References 25 publications

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“…This expands upon prior studies demonstrating CXCR4 mutations confer both in vitro and clinical resistance to ibrutinib . Acquired BTK C481S mutations are also strongly associated with CXCR4 mutations in the development of ibrutinib resistance . Importantly, 80% of patients deemed to be ibrutinib nonresponders in our cohort harbored a CXCR4 mutation, and all discontinued ibrutinib within 6 months of treatment initiation.…”

Section: Discussionsupporting

confidence: 79%

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

et al. 2018

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Ibrutinib is the first approved therapy for symptomatic patients with Waldenström macroglobulinemia (WM). The reasons for discontinuing ibrutinib and subsequent outcomes have not been previously evaluated in WM patients. We therefore conducted a retrospective review of 189 WM patients seen at our institution who received treatment with ibrutinib, of whom 51 (27%) have discontinued therapy. Reasons for discontinuation include: disease progression (n = 27; 14%), toxicity (n = 15; 8%), nonresponse (n = 5; 3%), and other unrelated reasons (n = 4; 2%). The cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months from treatment initiation was 22%, 26%, 35%, and 43%, respectively. A baseline platelet count ≤100 K/µL and presence of tumor CXCR4 mutations were independently associated with 4-fold increased odds of ibrutinib discontinuation. An IgM rebound (≥25% increase in serum IgM) was observed in 37 patients (73%) following ibrutinib discontinuation and occurred within 4 weeks for nearly half of patients. The response rate to salvage therapy was 71%; responses were higher in patients without an IgM rebound and when salvage therapy was initiated within 2 weeks of stopping ibrutinib. Patients who discontinued ibrutinib due to disease progression versus nonprogression events had significantly shorter overall survival (21 versus 32 months; P = .046). Response to salvage therapy was associated with an 82% reduction in the risk of death following ibrutinib discontinuation. WM patients who discontinue ibrutinib require close monitoring, and continuation of ibrutinib until the next therapy should be considered to maintain disease control.

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Section: Discussionsupporting

confidence: 79%

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

et al. 2018

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“…Supporting the conclusion that BTK and PLCG2 mutations are not necessary for ibrutinib resistance, studies in other B cell lymphomas have also identified resistance mechanisms that do not involve mutations in BTK or PLCG2. In Waldenstrom’s macroglobulinemia and mantle cell lymphoma (MCL), mutations in CARD11 have been reported in ibrutinib-resistant disease and some of these mutations can block sensitivity of MCL cell lines to ibrutinib in vitro [30, 31]. Activating mutations in CARD11 also predict primary resistance to ibrutinib in follicular lymphoma [32] and diffuse large B cell lymphoma [33].…”

Section: Btk and Plcg2 Mutations Are Not Necessary For Acquired Resismentioning

confidence: 99%

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Lampson

Brown

2018

Expert Review of Hematology

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Introduction: Ibrutinib is the first BTK inhibitor to show efficacy in chronic lymphocytic leukemia (CLL) and is also the first BTK inhibitor to which patients have developed resistance. Mutations in BTK and PLCG2 are found in ≈80% of CLL patients with acquired resistance to ibrutinib, but it remains unclear if these mutations are merely associated with disease relapse or directly cause it. Areas covered: Unique properties of both CLL and ibrutinib that complicate attempts to definitively conclude whether BTK/PLCG2 mutations are passengers or drivers of ibrutinib-resistant disease are reviewed. Characteristics of mutations that drive drug resistance are summarized and whether BTK/PLCG2 mutations possess these is discussed. These characteristics include (1) identification in multiple patients with acquired resistance, (2) in vitro validation of drug-resistant properties, (3) mutual exclusivity with one another, (4) increasing frequency over time on drug, and (5) high frequency at the time and site of clinical relapse. Expert Commentary: While BTK/PLCG2 mutations have characteristics suggesting that they can drive ibrutinib resistance, this conclusion remains formally unproven until specific inhibition of such mutations is shown to cause regression of ibrutinib-resistant CLL. Data suggest that alternative mechanisms of resistance do exist in some patients.

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“…Whilst TP53 may not be the contributing factor to therapy resistance, it may be an indicator of genomic instability. This suggests that additional mutation testing may be required for BTK and PLCG2 , both of which have been shown to drive resistance to BTKi therapy in WM (Xu et al , ).…”

Section: Summary Of Wm Patients (N = 14) and Samples (N = 58)mentioning

confidence: 99%

Importance of sequential analysis of TP53 variation in patients with Waldenström Macroglobulinaemia

et al. 2019

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Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia

Abstract: Key Points BTKCys481 mutations, including multiple mutated variants within individual patients are common in ibrutinib-progressing WM patients. BTKCys481 mutations were associated with mutated CXCR4 in WM patients progressing on ibrutinib.

Cited by 120 publications

References 25 publications

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

Ibrutinib discontinuation in Waldenström macroglobulinemia: Etiologies, outcomes, and IgM rebound

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

Importance of sequential analysis of TP53 variation in patients with Waldenström Macroglobulinaemia

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