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.

1st Department of Medicine Faculty of Medicine 1 Charles University General Hospital Prague Czech Republic

AO Spedali Civili di Brescia Lombardia Italy

ASST Grande Ospedale Metropolitano Niguarda Milan Italy

Azienda Ospedaliero Universitaria di Bologna Bologna Italy

BeiGene Co Ltd Beijing China

BeiGene Switzerland GmbH Basel Switzerland

BeiGene USA Inc San Mateo CA

Bing Center for Waldenström Macroglobulinemia Dana Farber Cancer Institute Boston MA

City of Hope National Medical Center Duarte CA

Clinical Hematology Department Sorbonne University Pitié Salpêtrière Hospital Paris France

Comprehensive Cancer Center Ulm Universitätsklinikum Ulm Baden Württemberg Germany

Concord Repatriation General Hospital Department of Haematology University of Sydney Concord NSW Australia

Concord Repatriation General Hospital Sydney Concord NSW Australia

Department of Clinical Therapeutics National and Kapodistrian University of Athens Athens Greece

Department of Haematology Flinders Medical Centre Adelaide SA Australia

Department of Hematology and Cancer Prevention Health Sciences Faculty Medical University of Silesia Katowice Poland

Department of Hematology Collegium Medicum in Bydgoszcz Nicolaus Copernicus University in Toruń Bydgoszcz Poland

Department of Hematology School of Clinical Sciences Monash University Clayton VIC Australia

Faculty of Medicine Dentistry and Health Sciences University of Melbourne Parkville VIC Australia; and

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia Italy

Hospital de La Santa Creu i Sant Pau Barcelona Spain

Hospital Universitario de Salamanca Salamanca Spain

Hospital Universitario Fundación Jiménez Díaz Madrid Spain

Hospital Universitario Vall d'Hebrón Barcelona Spain

Institut Català d'Oncologia Hospital Universitari Germans Trias i Pujol Barcelona Spain

Istituto di Ematologia Seràgnoli Dipartimento di Medicina Specialistica Diagnostica e Sperimentale Università degli Studi Bologna Italy

Medical Oncology Harvard Medical School Boston MA

Monash Health and

Pathology and Laboratory Medicine University of Western Australia Perth WA Australia

Peter MacCallum Cancer Centre Melbourne VIC Australia

Plymouth Hospitals National Health Service Trust Derriford Hospital Devon United Kingdom

Royal Melbourne Hospital Parkville VIC Australia

Royal North Shore Hospital Sydney NSW Australia

Sir Charles Gairdner Hospital Perth WA Australia

St James University Hospital Leeds United Kingdom

St Vincent's Hospital Fitzroy VIC Australia

Szpital Uniwersytecki nr 2 Dr Jana Biziela Kujawsko pomorskie Bydgoszcz Poland

The John Curtin School of Medical Research Australian National University Canberra ACT Australia

University College London Hospital Foundation Trust London United Kingdom

Uniwersytecki Szpital Kliniczny w Bialymstoku Podlaskie Poland

Zobrazit více v PubMed

Gertz MA. Waldenström macroglobulinemia: 2019 update on diagnosis, risk stratification, and management. Am J Hematol. 2019;94(2):266-276. PubMed

Pal Singh S, Dammeijer F, Hendriks RW. Role of Bruton’s tyrosine kinase in B cells and malignancies [published correction appears in Mol Cancer. 2019;18(1):79]. Mol Cancer. 2018;17(1):57. PubMed PMC

Argyropoulos KV, Vogel R, Ziegler C, et al. . Clonal B cells in Waldenström’s macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling. Leukemia. 2016;30(5):1116-1125. PubMed PMC

Treon SP, Xu L, Guerrera ML, et al. . Genomic landscape of Waldenström macroglobulinemia and its impact on treatment strategies. J Clin Oncol. 2020;38(11):1198-1208. PubMed PMC

Treon SP, Meid K, Gustine J, et al. Long-term follow-up of previously treated patients who received ibrutinib for symptomatic Waldenstrom’s macroglobulinemia: update of pivotal clinical trial [abstract]. Blood. 2017;130(suppl 1). Abstract 2766.

Treon SP, Gustine J, Meid K, et al. . Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol. 2018;36(27):2755-2761. PubMed

Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenström’s macroglobulinemia. N Engl J Med. 2015;373(6):584-586. PubMed

Dimopoulos MA, Trotman J, Tedeschi A, et al. ; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia . Ibrutinib for patients with rituximab-refractory Waldenström’s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18(2):241-250. PubMed

Owen RG, McCarthy H, Rule S, et al. . Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study. Lancet Haematol. 2020;7(2):e112-e121. PubMed

Hunter ZR, Xu L, Tsakmaklis N, et al. . Insights into the genomic landscape of MYD88 wild-type Waldenström macroglobulinemia. Blood Adv. 2018;2(21):2937-2946. PubMed PMC

Dimopoulos MA, Tedeschi A, Trotman J, et al. ; iNNOVATE Study Group and the European Consortium for Waldenström’s Macroglobulinemia . Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. 2018;378(25):2399-2410. PubMed

Paludo J, Abeykoon JP, Shreders A, et al. . Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia. Ann Hematol. 2018;97(8):1417-1425. PubMed

Laribi K, Poulain S, Willems L, et al. . Bendamustine plus rituximab in newly-diagnosed Waldenström macroglobulinaemia patients. A study on behalf of the French Innovative Leukaemia Organization (FILO). Br J Haematol. 2019;186(1):146-149. PubMed

Guo Y, Liu Y, Hu N, et al. . Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton’s tyrosine kinase. J Med Chem. 2019;62(17):7923-7940. PubMed

Tam CSL, Trotman J, Opat S, et al. . Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851-859. PubMed PMC

Brukinsa: package insert. Beijing, China: BeiGene Co. Ltd; 2019.

Trotman J, Opat S, Gottlieb D, et al. . Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up. Blood. 2020;136(18):2027-2037. PubMed PMC

Tam CS, Opat S, D’Sa S, et al. . A randomized phase 3 trial of zanubrutinib versus ibrutinib in symptomatic Waldenstrom macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. PubMed PMC

Dimopoulos MA, Kastritis E, Owen RG, et al. . Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus. Blood. 2014;124(9):1404-1411. PubMed PMC

MYD88 Mutation Analysis Fort Myers, FL: NeoGenomics; 2020. Available at: https://neogenomics.com/test-menu/myd88-mutation-analysis. Accessed 24 August 2020.

CXCR4 Mutation Analysis Fort Myers, FL: NeoGenomics; 2020. Available at: https://neogenomics.com/test-menu/cxcr4-mutation-analysis. Accessed 24 August 2020.

Albitar A, Ma W, DeDios I, Estella J, Agersborg S, Albitar M. Positive selection and high sensitivity test for MYD88 mutations using locked nucleic acid. Int J Lab Hematol. 2016;38(2):133-140. PubMed

Poulain S, Roumier C, Venet-Caillault A, et al. . Genomic landscape of CXCR4 mutations in Waldenström macroglobulinemia. Clin Cancer Res. 2016;22(6):1480-1488. PubMed

Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014;123(18):2791-2796. PubMed

Owen RG, Kyle RA, Stone MJ, et al. ; VIth International Workshop on Waldenström macroglobulinaemia . Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013;160(2):171-176. PubMed

Brookmeyer RCJ. A confidence interval for the median survival time. Biometrics. 1982;38(1):29-41.

Greenwood M. A report on the natural duration of cancer. In: Reports on Public Health and Medical Subjects. London, England: His Majesty’s Stationery Service; 1926:26.

Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019-5032. PubMed PMC

Owen RG, Treon SP, Al-Katib A, et al. . Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia. Semin Oncol. 2003;30(2):110-115. PubMed

Morel P, Duhamel A, Gobbi P, et al. . International prognostic scoring system for Waldenstrom macroglobulinemia. Blood. 2009;113(18):4163-4170. PubMed

Abeykoon JP, Paludo J, King RL, et al. . MYD88 mutation status does not impact overall survival in Waldenström macroglobulinemia. Am J Hematol. 2018;93(2):187-194. PubMed

Treon SP, Gustine J, Xu L, et al. . MYD88 wild-type Waldenstrom Macroglobulinaemia: differential diagnosis, risk of histological transformation, and overall survival. Br J Haematol. 2018;180(3):374-380. PubMed

Treon SP, Yang G, Hanzis C, et al. . Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenstrom macroglobulinaemia. Br J Haematol. 2011;154(2):223-228. PubMed

Treon SP, Xu L, Yang G, et al. . MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367(9):826-833. PubMed

Yang G, Zhou Y, Liu X, et al. . A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122(7):1222-1232. PubMed

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia

Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study