The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Amyloidosis and Myeloma Unit Department of Hematology Hospital Clínic de Barcelona Barcelona Spain

BeiGene Co Ltd Shanghai China

BeiGene USA Inc San Mateo CA

Bing Center for Waldenstrom Macroglobulinemia Dana Farber Cancer Institute Boston MA

Centre for Waldenström's Macroglobulinemia and Associated Disorders University College London Hospital Foundation Trust London United Kingdom

Clinical Research Division Fred Hutchinson Cancer Center Seattle WA

Colorado Blood Cancer Institute Denver CO

Comprehensive Cancer Center Ulm Universitätsklinikum Ulm Ulm Baden Württemberg Germany

Department of Clinical Oncology Maria Sklodowska Curie National Institute of Oncology Krakow Poland

Department of Clinical Therapeutics National and Kapodistrian University of Athens Athens Greece

Department of Haematology Alfred Hospital and Centre for Blood Diseases Monash University Melbourne VIC Australia

Department of Haematology Flinders Medical Centre Adelaide SA Australia

Department of Haematology Monash Health and Monash University Clayton VIC Australia

Department of Haematology Princess Alexandra Hospital and University of Queensland Brisbane QLD Australia

Department of Haematology Royal Bournemouth and Christchurch Hospital Bournemouth United Kingdom

Department of Haematology Royal North Shore Hospital Sydney NSW Australia

Department of Haematology Sir Charles Gairdner Hospital University of Western Australia Perth WA Australia

Department of Hematology AO Spedali Civili di Brescia Lombardia Italy

Department of Hematology Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń Bydgoszcz Poland

Department of Hematology Concord Repatriation General Hospital Sydney NSW Australia

Department of Hematology Hematopoietic Cell Transplantation City of Hope National Medical Center Duarte CA

Department of Hematology Hospital Universitario de Salamanca Salamanca Spain

Department of Hematology Karolinska Universitetssjukhuset and Department of Medicine Huddinge Karolinska Institutet Stockholm Sweden

Department of Hematology Niguarda Cancer Center ASST Grande Ospedale Metropolitano Niguarda Milan Italy

Department of Hematology University Medical Center Utrecht Utrecht Netherlands

Department of Internal Medicine Haematology University Hospital and Faculty of Medicine Hradec Králové Czech Republic

Haematological Malignancy Diagnostic Service St James University Hospital Leeds United Kingdom

Service d'Hématologie Clinique Sorbonne University Pitié Salpêtrière Hospital Paris France

U O Ematologia Dipartimento Oncologia e Ematologia Ospedale Civile Santa Maria delle Croci AUSL Ravenna Italy

Všeobecná fakultní nemocnice Praha Prague Czechia

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