Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

1st Department of Medicine 1st Faculty of Medicine Charles University General Hospital Prague Czech Republic

4th Department of Internal Medicine Haematology Charles University Hospital and Faculty of Medicine Hradec Králové Czech Republic

Amyloidosis and Myeloma Unit Department of Hematology Hospital Clinic of Barcelona August Pi i Sunyer Biomedical Research Institute Barcelona Spain

ASST Grande Ospedale Metropolitano Niguarda Milan Italy

ASST Spedali Civili di Brescia Lombardia Italy

BeiGene USA Inc San Mateo CA; and

Bing Center for Waldenstrom Macroglobulinemia Dana Farber Cancer Institute Boston MA

City of Hope National Medical Center Duarte CA

Clinical Haematology Unit Monash University Clayton VIC Australia

Colorado Blood Cancer Institute Denver CO

Comprehensive Cancer Center Ulm Universitätsklinikum Ulm Ulm Germany

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

Department of Haematology Concord Repatriation General Hospital Sydney Concord NSW Australia

Department of Haematology Princess Alexandra Hospital Brisbane QLD Australia

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

Department of Lymphoma Myeloma University of Western Australia Perth WA Australia

Department of Medicine Harvard Medical School Boston MA

Department of Medicine University of Melbourne Parkville VIC Australia

Department of Medicine University of Washington and the Seattle Cancer Care Alliance Seattle WA

Flinders Medical Centre Adelaide SA Australia

Haematology Department University of Sydney Concord NSW Australia

Hospital Universitario de Salamanca Salamanca Spain

Maria Sklodowska Curie National Institute of Oncology Krakow Poland

Monash Health Clayton VIC Australia

Ospedale Civile S Maria delle Croci Azienda Unità Sanitaria Locale Ravenna Italy

Peter MacCallum Cancer Centre Melbourne VIC Australia

Royal Bournemouth and Christchurch Hospital Bournemouth United Kingdom

Royal Melbourne Hospital Parkville VIC Australia

Royal North Shore Hospital Sydney NSW Australia

School of Medicine University of Queensland Brisbane QLD Australia

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

Sir Charles Gairdner Hospital Perth WA Australia

St James's University Hospital Leeds United Kingdom

St Vincent's Hospital Fitzroy VIC Australia

Szpital Uniwersytecki No 2 im Dr Jana Biziela Bydgoszcz Poland

Unit of Hematology Department of Medicine Karolinska Universitetssjukhuset Karolinska Institutet Stockholm Sweden

University College London Hospital Foundation Trust London United Kingdom

University Medical Center Utrecht Utrecht The Netherlands

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