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Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia

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Abstract

Purpose of Review

The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM.

Recent Findings

Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi.

Summary

Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

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Data Availability

No datasets were generated or analysed during the current study.  P.K is the principal investigator of trials for which Mayo Clinic has received research funding from Amgen, Regeneron, Bristol Myers Squibb, Loxo Pharmaceuticals, Ichnos, Karyopharm, Sanofi, AbbVie and GlaxoSmithKline. Prashant Kapoor has served on the Advisory Boards of BeiGene, Mustang Bio, Pharmacyclics, X4 Pharmaceuticals, AstraZeneca, Kite, Oncopeptides, Angitia Bio, GlaxoSmithKline, AbbVie and Sanofi. 

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Authors and Affiliations

  1. Department of Hematology-Oncology, Mayo Clinic, Jacksonville, FL, USA

    Reema K. Tawfiq

  2. Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Jithma P. Abeykoon & Prashant Kapoor

  3. Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

    Jithma P. Abeykoon & Prashant Kapoor

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  1. Reema K. Tawfiq
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RKT, JPA and PK collected the data. RKT wrote the initial draft and prepared the tables. JPA edited the manuscript. PK revised the manuscript and the tables. All authors reviewed and approved the final manuscript.

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Correspondence to Prashant Kapoor.

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RKT and JPA  declare no competing interests. P.K is the principal investigator of trials for which Mayo Clinic has received research funding from Amgen, Regeneron, Bristol Myers Squibb, Loxo Pharmaceuticals, Ichnos, Karyopharm, Sanofi, AbbVie and GlaxoSmithKline. Prashant Kapoor has served on the Advisory Boards of BeiGene, Mustang Bio, Pharmacyclics, X4 Pharmaceuticals, AstraZeneca, Kite, Oncopeptides, Angitia Bio, GlaxoSmithKline, AbbVie and Sanofi.

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Tawfiq, R.K., Abeykoon, J.P. & Kapoor, P. Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia. Curr Hematol Malig Rep (2024). https://doi.org/10.1007/s11899-024-00731-0

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