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Title: | Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: A substudy of the phase 3 ASPEN trial. | Authors: | Trotman J.;Rule S.;Kloczko J.;Tedeschi A.;Buske C.;Leblond V.;Chan W.Y.;Michel J.;Schneider J.;Tan Z.;Cohen A.;Huang J.;Tam C.S.;Opat S. ;Dimopoulos M.;Sanz R.G.;Lee H.-P.;Trneny M.;Varettoni M.;D'Sa S.;Owen R.G.;Cull G.;Mulligan S.;Czyz J.;Castillo J.J.;Motta M.;Siddiqi T.;Mesa M.G.;Gorrochategui M.G.;Talaulikar D.;Zinzani P.L.;Askari E.;Grosicki S.;Oriol A. | Institution: | (Dimopoulos) Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece (Sanz) Hospital Universitario de Salamanca, Salamanca, Spain (Lee) Department of Haematology, Flinders Medical Centre, Adelaide, SA, Australia (Trneny) 1st Department of Medicine, Faculty of Medicine 1, Charles University, General Hospital, Prague, Czechia (Varettoni) Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy (Opat) Monash Health, Monash University, Clayton, VIC, Australia (Opat) Department of Hematology, School of Clinical Sciences, Monash University, Clayton, VIC, Australia (D'Sa) University College London Hospital Foundation Trust, London, United Kingdom (Owen) St James University Hospital, Leeds, United Kingdom (Cull) Sir Charles Gairdner Hospital, Perth, WA, Australia (Cull) Pathology and Laboratory Medicine, University of Western Australia, Perth, WA, Australia (Mulligan) Royal North Shore Hospital, Sydney, NSW, Australia (Czyz) Szpital Uniwersytecki nr 2, Dr Jana Biziela, Kujawsko-pomorskie, Bydgoszcz, Poland (Czyz) Department of Hematology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland (Castillo) Bing Center for Waldenstrom Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, United States (Castillo) Medical Oncology, Harvard Medical School, Boston, MA, United States (Motta) AO Spedali Civili di Brescia, Lombardia, Italy (Siddiqi) City of Hope National Medical Center, Duarte, CA, United States (Mesa) Hospital Universitario Vall d'Hebron, Barcelona, Spain (Gorrochategui) Hospital de La Santa Creu i Sant Pau, Barcelona, Spain (Talaulikar) John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia (Zinzani) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (Zinzani) Istituto di Ematologia "Seragnoli, Dipartimento diMedicina Specialistica, Diagnostica e Sperimentale Universita degli Studi, Bologna, Italy (Askari) Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain (Grosicki) Department ofHematology and Cancer Prevention, Health Sciences Faculty, Medical University of Silesia, Katowice, Poland (Oriol) Institut Catala d'Oncologia, Hospital Universitari Germans Trias iPujol, Barcelona, Spain (Rule) Plymouth Hospitals National Health Service (NHS) Trust, Derriford Hospital, Devon, United Kingdom (Kloczko) Uniwersytecki Szpital Kliniczny w Bialymstoku, Podlaskie, Poland (Tedeschi) ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy (Buske) Comprehensive Cancer Center (CCC) Ulm, Universitatsklinikum Ulm, Baden-Wurttemberg, Germany (Leblond) Clinical Hematology Department, Sorbonne University, Pitie Salpetriere Hospital, Paris, France (Trotman) Concord Repatriation General Hospital, Sydney, Concord, NSW, Australia (Trotman) Concord Repatriation General Hospital, Department of Haematology, University of Sydney, Concord, NSW, Australia (Chan, Schneider, Cohen, Huang) BeiGene USA, Inc., San Mateo, CA, United States (Michel) BeiGeneSwitzerland GmbH, Basel, Switzerland (Tan) BeiGene (Beijing) Co., Ltd, Beijing, China (Tam) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (Tam) St Vincent's Hospital, Fitzroy, VIC, Australia (Tam) Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia (Tam) Royal Melbourne Hospital, Parkville, VIC, Australia | Issue Date: | 2-Jan-2021 | Copyright year: | 2020 | Publisher: | American Society of Hematology | Place of publication: | United States | Publication information: | Blood Advances. 4 (23) (pp 6009-6018), 2020. Date of Publication: 08 Dec 2020. | Journal: | Blood Advances | Abstract: | Patients with Waldenstrom 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.Copyright © 2020 by The American Society of Hematology | DOI: | http://monash.idm.oclc.org/login?url= http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1182/bloodadvances.2020003010 |
PubMed URL: | 33284944 [http://www.ncbi.nlm.nih.gov/pubmed/?term=33284944] | ISSN: | 2473-9529 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/28760 | Type: | Article | Subjects: | pruritus/si [Side Effect] randomized controlled trial (topic) rash/si [Side Effect] respiratory tract infection/si [Side Effect] second cancer/si [Side Effect] skin cancer/si [Side Effect] splenomegaly subdural hematoma/si [Side Effect] thrombocytopenia/si [Side Effect] upper respiratory tract infection/si [Side Effect] urinary tract infection/si [Side Effect] very elderly *Waldenstroem macroglobulinemia/dt [Drug Therapy] bendamustine/dt [Drug Therapy] chlorambucil/dt [Drug Therapy] cisplatin/dt [Drug Therapy] cyclophosphamide/dt [Drug Therapy] dexamethasone/dt [Drug Therapy] enoxaparin/cb [Drug Combination] hemoglobin/ec [Endogenous Compound] hydrocortisone/dt [Drug Therapy] ifosfamide/dt [Drug Therapy] immunoglobulin M/ec [Endogenous Compound] lomustine/dt [Drug Therapy] melphalan/dt [Drug Therapy] methylprednisolone/dt [Drug Therapy] *myeloid differentiation factor 88/ec [Endogenous Compound] ofatumumab/dt [Drug Therapy] prednisolone/dt [Drug Therapy] prednisone/dt [Drug Therapy] rituximab/dt [Drug Therapy] *zanubrutinib/ae [Adverse Drug Reaction] *zanubrutinib/cb [Drug Combination] *zanubrutinib/dt [Drug Therapy] *zanubrutinib/tm [Unexpected Outcome of Drug Treatment] *MYD88 gene *zanubrutinib/pv [Special Situation for Pharmacovigilance] adult aged anemia/si [Side Effect] arthralgia/si [Side Effect] article atrial fibrillation/si [Side Effect] backache/si [Side Effect] basal cell carcinoma/si [Side Effect] bleeding/si [Side Effect] cellulitis/si [Side Effect] clinical article constipation/si [Side Effect] contusion/si [Side Effect] coughing/si [Side Effect] decreased appetite/si [Side Effect] diarrhea/si [Side Effect] drug dose reduction drug efficacy drug safety drug withdrawal fatigue/si [Side Effect] female fever/si [Side Effect] gene mutation headache/si [Side Effect] hemoptysis/si [Side Effect] herpes zoster/si [Side Effect] human hypertension/si [Side Effect] hyponatremia/si [Side Effect] infection/si [Side Effect] laceration/si [Side Effect] lymphadenopathy male monotherapy multicenter study (topic) muscle spasm/si [Side Effect] neutropenia/si [Side Effect] opportunistic infection/si [Side Effect] overall survival peripheral edema/si [Side Effect] phase 3 clinical trial (topic) pneumonia/si [Side Effect] priority journal progression free survival constipation / side effect contusion / side effect coughing / side effect decreased appetite / side effect diarrhea / side effect drug dose reduction drug efficacy drug safety drug withdrawal fatigue / side effect female fever / side effect gene mutation headache / side effect hemoptysis / side effect herpes zoster / side effect human hypertension / side effect hyponatremia / side effect infection / side effect laceration / side effect lymphadenopathy male monotherapy multicenter study (topic) muscle spasm / side effect neutropenia / side effect opportunistic infection / side effect overall survival peripheral edema / side effect phase 3 clinical trial (topic) pneumonia / side effect priority journal progression free survival anemia / side effect randomized controlled trial (topic) rash / side effect respiratory tract infection / side effect second cancer / side effect skin cancer / side effect splenomegaly subdural hematoma / side effect thrombocytopenia / side effect upper respiratory tract infection / side effect urinary tract infection / side effect very elderly *Waldenstroem macroglobulinemia / *drug therapy aged adult pruritus / side effect arthralgia / side effect Article atrial fibrillation / side effect backache / side effect basal cell carcinoma / side effect bleeding / side effect cellulitis / side effect clinical article |
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