Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial

被引：58

作者：

Dimopoulos, Meletios ^{[1
]}

Garcia Sanz, Ramon ^{[2
]}

Lee, Hui-Peng ^{[3
]}

Trneny, Marek ^{[4
]}

Varettoni, Marzia ^{[5
]}

Opat, Stephen ^{[6
,7
]}

D'Sa, Shirley ^{[8
]}

Owen, Roger G. ^{[9
]}

Cull, Gavin ^{[10
,11
]}

Mulligan, Stephen ^{[12
]}

Czyz, Jaroslaw ^{[13
,14
]}

Castillo, Jorge J. ^{[15
,16
]}

Motta, Marina ^{[17
]}

Siddiqi, Tanya ^{[18
]}

Gironella Mesa, Mercedes ^{[19
]}

Granell Gorrochategui, Miquel ^{[20
]}

Talaulikar, Dipti ^{[21
]}

Zinzani, Pier Luigi ^{[22
,23
]}

Askari, Elham ^{[24
]}

Grosicki, Sebastian ^{[25
]}

Oriol, Albert ^{[26
]}

Rule, Simon ^{[27
]}

Kloczko, Janusz ^{[28
]}

Tedeschi, Alessandra ^{[29
]}

Buske, Christian ^{[30
]}

Leblond, Veronique ^{[31
]}

Trotman, Judith ^{[32
,33
]}

Chan, Wai Y. ^{[34
]}

Michel, Jan ^{[35
]}

Schneider, Jingjing ^{[34
]}

Tan, Ziwen ^{[36
]}

Cohen, Aileen ^{[34
]}

Huang, Jane ^{[34
]}

Tam, Constantine S. ^{[37
,38
,39
,40
]}

机构：

[1] Natl & Kapodistrian Univ Athens, Dept Clin Therapeut, Athens, Greece

[2] Hosp Univ Salamanca, Salamanca, Spain

[3] Flinders Med Ctr, Dept Haematol, Adelaide, SA, Australia

[4] Charles Univ Prague, Gen Hosp, Dept Med 1, Fac Med 1, Prague, Czech Republic

[5] Fdn Ist Ricovero & Cura Carattere Sci IRCCS Polic, Pavia, Italy

[6] Monash Univ, Monash Hlth, Clayton, Vic, Australia

[7] Monash Univ, Sch Clin Sci, Dept Hematol, Clayton, Vic, Australia

[8] Univ Coll London Hosp Fdn Trust, London, England

[9] St James Univ Hosp, Leeds, W Yorkshire, England

[10] Sir Charles Gairdner Hosp, Perth, WA, Australia

[11] Univ Western Australia, Pathol & Lab Med, Perth, WA, Australia

[12] Royal North Shore Hosp, Sydney, NSW, Australia

[13] Szpital Uniwersytecki 2 Dr Jana Biziela, Kujawsko Pomorskie, Bydgoszcz, Poland

[14] Nicolaus Copernicus Univ Torun, Coll Med Bydgoszcz, Dept Hematol, Bydgoszcz, Poland

[15] Dana Farber Canc Inst, Bing Ctr Waldenstrom Macroglobulinemia, Boston, MA 02115 USA

[16] Harvard Med Sch, Med Oncol, Boston, MA 02115 USA

[17] AO Spedali Civili Brescia, Lombardia, Italy

[18] City Hope Natl Med Ctr, 1500 E Duarte Rd, Duarte, CA 91010 USA

[19] Hosp Univ Vall dHebron, Barcelona, Spain

[20] Hosp Santa Creu & Sant Pau, Barcelona, Spain

[21] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT, Australia

[22] Azienda Osped Univ Bologna, Bologna, Italy

[23] Univ Bologna, Dipartimento Med Specialist Diagnost & Sperimenta, Ist Ematol Seragnoli, Bologna, Italy

[24] Hosp Univ Fdn Jimenez Diaz, Madrid, Spain

[25] Med Univ Silesia, Hlth Sci Fac, Dept Hematol & Canc Prevent, Katowice, Poland

[26] Hosp Badalona Germans Trias & Pujol, Inst Catala Oncol, Barcelona, Spain

[27] Plymouth Hosp Natl Hlth Serv NHS Trust, Derriford Hosp, Plymouth, Devon, England

[28] Uniwersytecki Szpital Klini Bialymstoku, Podlaskie, Poland

[29] ASST Grande Osped Metropolitano Niguarda, Milan, Italy

[30] Univ Klinikum Ulm, Comprehens Canc Ctr CCC Ulm, Baden Baden, Germany

[31] Sorbonne Univ, Pitie Salpetriere Hosp, Clin Hematol Dept, Paris, France

[32] Concord Repatriat Gen Hosp, Concord, NSW, Australia

[33] Univ Sydney, Concord Repatriat Gen Hosp, Dept Haematol, Concord, NSW, Australia

[34] BeiGene USA Inc, San Mateo, CA USA

[35] BeiGene Switzerland GmbH, Basel, Switzerland

[36] BeiGene Beijing Co Ltd, Beijing, Peoples R China

[37] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[38] St Vincents Hosp, Fitzroy, Vic, Australia

[39] Univ Melbourne, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia

[40] Royal Melbourne Hosp, Parkville, Vic, Australia

来源：

BLOOD ADVANCES | 2020年 / 4卷 / 23期

关键词：

GENOMIC LANDSCAPE; MUTATIONS; RITUXIMAB; SURVIVAL; IBRUTINIB; RECOMMENDATIONS; BENDAMUSTINE; MULTICENTER; CXCR4;

D O I：

10.1182/bloodadvances.2020003010

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88(WT)) 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 withWMwho have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88(WT)) 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 MYD88(WT) disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88(WT) 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 MYD88(WT) WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

引用

页码：6009 / 6018

页数：10