Zanubrutinib for high-risk Waldenström macroglobulinemia with complex karyotype and hyperleukocytosis: A case report and literature review.

To report the management and outcome of an elderly, high-risk lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patient presenting with severe symptomatic anemia, marked hyperleukocytosis, a complex karyotype, dual MYD88/CXCR4 mutations, and significant comorbidities, highlighting the therapeutic challenges and the efficacy of targeted therapy after chemoimmunotherapy intolerance. This case report details a 78-year-old male diagnosed with high-risk lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (MYD88 L265P⁺, pathogenic CXCR4 ⁺, complex karyotype: 46,X,-Y,add(6)(q224),+18/47,XY,+18/47,X,Y,+4,+18/48,XY,+4,+18/48,XY,+3,+18/46,XY) and significant comorbidities including hypertension and suspected cardiac amyloidosis. Initial treatment with bendamustine-rituximab was administered but led to significant toxicity. Subsequently, therapy was switched to the second-generation Bruton's tyrosine kinase inhibitor, zanubrutinib. Clinical progress, hematologic response, and adverse events were monitored. Initial treatment with bendamustine-rituximab was discontinued due to severe toxicity, including a grade 3 infusion reaction and subsequent neutropenic fever. Following the switch to zanubrutinib, he achieved a sustained partial hematologic response and clinical improvement. Disease-related complications (hyperviscosity retinopathy) and treatment-related adverse events (neutropenia) occurred but were managed appropriately while continuing zanubrutinib. Zanubrutinib demonstrated efficacy and manageable toxicity in an elderly, high-risk lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patient with a complex karyotype, dual MYD88/CXCR4 mutations, hyperleukocytosis, and significant comorbidities, following intolerance to standard chemoimmunotherapy. This case supports the use of targeted Bruton's tyrosine kinase inhibition in achieving favorable outcomes in complex lymphoplasmacytic lymphoma/Waldenström macroglobulinemia presentations and contributes to understanding the significance of complex karyotypes in the era of novel therapies.