ASPEN: Long-Term Follow-Up Results of a Phase 3 Randomized Trial of Zanubrutinib vs Ibrutinib in Patients With Waldenström Macroglobulinemia

Jorge J. Castillo, Constantine S. Tam, Ramon Garcia-Sanz, Stephen Opat, Shirley D'Sa, Wojciech Jurczak, Hui Peng Lee, Gavin Cull, Roger G. Owen, Paula Marlton, Bjorn E. Wahlin, Alessandra Tedeschi, Tanya Siddiqi, Christian Buske, Veronique Leblond, Wai Y. Chan, Jingjing Schneider, Aileen Cohen, Meletios Dimopoulos

Research output: Contribution to journalMeeting Abstractpeer-review


Context: ASPEN is a randomized, open-label, phase 3 study comparing zanubrutinib, a potent and selective Bruton tyrosine kinase inhibitor (BTKi), with the first-generation BTKi, ibrutinib, in Waldenström macroglobulinemia (WM). Data with a median follow-up of 43 months are presented. Design: In cohort 1, patients with MYD88 mutations were randomized 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily; stratifications were CXCR4 mutations and prior lines of therapy. In cohort 2, patients without MYD88 mutations received zanubrutinib 160 mg twice daily. Main Outcome Measures: The primary endpoint was the proportion of patients with complete response/very good partial response (CR+VGPR). Results: In cohorts 1 and 2, 201 (zanubrutinib=102; ibrutinib=99) and 28 patients were enrolled, respectively. More cohort 1 patients in the zanubrutinib versus ibrutinib arm had CXCR4 mutations (32% [33/98] vs 20% [20/92] with next-generation sequencing data) and were aged >75 years (33% vs 22%). With median treatment durations of 42 (zanubrutinib) and 41 (ibrutinib) months, 67% and 58% remain on treatment, respectively. Investigator-assessed CR+VGPR rate was 36% versus 22% (zanubrutinib vs ibrutinib; P=0.02) and 31% in cohort 2 (1 CR). CR+VGPR rates for wild-type CXCR4 were 45% versus 28% (zanubrutinib vs ibrutinib; P=0.04) and were 21% versus 5% (P=0.15) for mutated CXCR4. Median progression-free survival and overall survival were not yet reached. Rates of atrial fibrillation, diarrhea, hypertension, localized infection, hemorrhage, muscle spasms, pneumonia, grade ≥3 infection, and adverse events leading to discontinuation/death were lower for zanubrutinib versus ibrutinib, as were exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension (0.2 vs 0.8 and 0.5 vs 1.0 persons/100 person-months; P<0.05); neutropenia rate was higher. Zanubrutinib safety outcomes were similar between cohorts. Conclusions: ASPEN is the largest phase 3 WM trial with head-to-head BTKi comparison. At a median follow-up of 43 months, zanubrutinib had higher CR+VGPR rates and clinically meaningful advantages in long-term safety/tolerability versus ibrutinib.

Original languageEnglish
Article numberIBCL-117
Pages (from-to)S385
Number of pages1
JournalClinical Lymphoma, Myeloma and Leukemia
Publication statusPublished - Oct 2022
EventSociety of Hematologic Oncology Annual Meeting 2022 - Houston, United States of America
Duration: 28 Sept 20221 Oct 2022
Conference number: 10th


  • BTK inhibitor
  • IBCL
  • Phase III
  • Waldenström macroglobulinemia
  • zanubrutinib

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