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
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
Hospital Universitario de Salamanca, Salamanca, Spain.
Blood Adv. 2020 Dec 8;4(23):6009-6018. doi: 10.1182/bloodadvances.2020003010.
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-naïve) 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.
缺乏MYD88基因激活突变（MYD88WT）的华氏巨球蛋白血症（WM）患者对伊布替尼单药治疗的预后相对较差，在一项2期关键研究中未报告有主要反应。泽布替尼是一种新型的选择性布鲁顿酪氨酸激酶（BTK）抑制剂，旨在最大程度地提高BTK占有率并最小化脱靶活性。ASPEN研究包括对泽布替尼和伊布替尼在携带MYD88突变的WM患者中的疗效和安全性进行随机比较，以及一个单独的队列，该队列中的患者没有MYD88突变（MYD88WT）或突变状态未知，他们接受了泽布替尼治疗。本文报告了后一个单臂队列的结果。疗效终点包括总缓解率、主要缓解率和完全缓解（CR）或非常好的部分缓解（VGPR）率、无进展生存期（PFS）、缓解持续时间（DOR）和总生存期（OS）。入组了28例患者（23例复发/难治性患者；5例初治患者），其中26例经中心确认患有MYD88WT疾病，2例MYD88突变状态未知。在中位随访17.9个月时，26例MYD88WT患者中有7例（27%）达到了VGPR，50%达到了主要缓解（部分缓解或更好）；无CR病例。在18个月时，估计的PFS率和OS率分别为68%和88%，而中位DOR尚未达到。2例患者因不良事件停用泽布替尼。分别有3例、1例和2例患者报告了治疗中出现的高血压、房颤和大出血（包括1例与依诺肝素治疗同时发生）。该亚组研究结果表明，泽布替尼单药治疗可在MYD88WT WM患者中诱导高质量的缓解。该试验已在www.clinicaltrials.gov上注册，注册号为NCT #03053440。
