Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.
Author
Dimopoulos, Meletios
Sanz, Ramon Garcia
Lee, Hui-Peng
Trneny, Marek
Varettoni, Marzia
Opat, Stephen
D'Sa, Shirley
Owen, Roger G.
Cull, Gavin
Mulligan, Stephen
Czyz, Jaroslaw
Castillo, Jorge J.
Motta, Marina
Siddiqi, Tanya
Gironella Mesa, Mercedes
Granell Gorrochategui, Miquel
Talaulikar, Dipti
Zinzani, Pier Luigi
Askari, Elham
Grosicki, Sebastian
Oriol, Albert
Rule, Simon
Kloczko, Janusz
Tedeschi, Alessandra
Buske, Christian
Leblond, Veronique
Trotman, Judith
Chan, Wai Y.
Michel, Jan
Schneider, Jingjing
Tan, Ziwen
Cohen, Aileen
Huang, Jane
Tam, Constantine S.
Date
2020-12-08Journal
Blood advancesType
Journal ArticlePublisher
American Society of HematologyDOI
10.1182/bloodadvances.2020003010Rights
© 2020 by The American Society of Hematology.Metadata
Show full item recordAbstract
Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.