Steven P. Treon, Shayna Sarosiek, Jorge J. Castillo

How we use Genomics and BTK-Inhibitors in the Treatment of Waldenstrom Macroglobulinemia.

  • Cell Biology
  • Hematology
  • Immunology
  • Biochemistry

Mutations in MYD88 (95-97%) and CXCR4 (30-40%) are common in Waldenstrom macroglobulinemia (WM). TP53 is also altered in 20-30% of WM patients, particularly those previously treated. Mutated MYD88 upregulates and activates HCK that drives BTK pro-survival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants such as CXCR4S338X show greater resistance to BTK-inhibitors. Covalent BTK-inhibitors (cBTK-i) produce major responses in 70-80% of WM patients. MYD88 and CXCR4 mutation status can impact time to major response, depth of response and/or progression-free survival (PFS) in WM patients treated with cBTK-i. The cBTK-i zanubrutinib shows greater response activity and/or improved PFS in wild-type MYD88, mutated CXCR4, or altered TP53 patients. Marked differences in adverse events have been observed between BTK-inhibitors in WM patients, including atrial fibrillation, bleeding diathesis and neutropenia. Intolerance is also common with c-BTKi, and dose reduction or switchover to another c-BTKi can be considered. For patients with acquired resistance to c-BTKi, newer options include the non-covalent BTK-inhibitor pirtobrutinib or the BCL2 antagonist venetoclax. Combinations of BTK-inhibitors with chemoimmunotherapy, CXCR4 and BCL2 antagonists have advanced and are discussed. Algorithms for positioning BTK-inhibitors in treatment-naïve and previously treated WM patients based on genomics, disease characteristics, and co-morbidities are presented.

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