UPDATED RESULTS OF THE ASPEN TRIAL FROM A COHORT OF PATIENTS WITH MYD88 WILD-TYPE WALDENSTRÖM MACROGLOBULINEMIA
Author(s): ,
Meletios Dimopoulos
Affiliations:
National and Kapodistrian University of Athens,Athens,Greece
,
Ramon Garcia Sanz
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Spain
,
Hui-Peng Lee
Affiliations:
Flinders Medical Centre,Adelaide, South Australia,Australia
,
Marek Trneny
Affiliations:
Vseobecna fakultni nemocnice v Praze,Prague,Czech Republic
,
Marzia Varettoni
Affiliations:
Fondazione IRCCS Policlinico San Matteo,Pavia,Italy
,
Stephen Opat
Affiliations:
Monash Health,Clayton, Victoria,Australia;Monash University,Clayton, Victoria,Australia
,
Shirley D'Sa
Affiliations:
University College London Hospital Foundation Trust,London,United Kingdom
,
Roger G. Owen
Affiliations:
St James University Hospital,Leeds,United Kingdom
,
Gavin Cull
Affiliations:
Sir Charles Gairdner Hospital,Perth, Western Australia,Australia;University of Western Australia,Perth, Western Australia,Australia
,
Stephen Mulligan
Affiliations:
Royal North Shore Hospital,Sydney, New South Wales,Australia
,
Jaroslaw Czyz
Affiliations:
Szpital Uniwersytecki nr 2 im dr. Jana Biziela,Kujawsko-pomorskie, Bydgoszcz,Poland;Department of Hematology,Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń,Bydgoszcz,Poland
,
Jorge Castillo
Affiliations:
Dana-Farber Cancer Institute,Boston, MA,United States;Harvard Medical School,Boston, MA,United States
,
Marina Motta
Affiliations:
AO Spedali Civili di Brescia,Lombardia,Italy
,
Tanya Siddiqi
Affiliations:
City of Hope National Medical Center,Duarte, CA,United States
,
Mercedes Gironella Mesa
Affiliations:
Hospital Universitario Vall d'Hebrón,Barcelona,Spain
,
Miquel Granell Gorrochategui
Affiliations:
Hospital de La Santa Creu i Sant Pau,Barcelona,Spain
,
Dipti Talaulikar
Affiliations:
Australian National University,Canberra, ACT,Australia
,
Pier Luigi Zinzani
Affiliations:
Institute of Hematology 'Seràgnoli' University of Bologna,Bologna,Italy
,
Elham Askari
Affiliations:
Hospital Universitario Fundación Jiménez Díaz,Madrid,Spain
,
Sebastian Grosicki
Affiliations:
Department of Hematology and Cancer Prevention,Health Sciences Faculty, Medical University of Silesia,Katowice,Poland
,
Albert Oriol
Affiliations:
Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol,Barcelona,Spain
,
Simon Rule
Affiliations:
Plymouth Hospitals NHS Trust, Derriford Hospital,Devon,United Kingdom
,
Janusz Kloczko
Affiliations:
Uniwersytecki Szpital Kliniczny w Bialymstoku,Podlaskie,Poland
,
Alessandra Tedeschi
Affiliations:
ASST Grande Ospedale Metropolitano,Milan,Italy
,
Christian Buske
Affiliations:
CCC Ulm - Universitätsklinikum Ulm,Ulm, Baden-Württemberg,Germany
,
Veronique Leblond
Affiliations:
Sorbonne University, Pitié Salpêtrière Hospital,Paris,France
,
Wai Y. Chan
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Jingjing Schneider
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Sunhee Ro
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Aileen Cohen
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
,
Jane Huang
Affiliations:
BeiGene USA, Inc.,San Mateo, CA,United States
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Centre,Melbourne, Victoria,Australia;St Vincent's Hospital,Fitzroy, Victoria,Australia;University of Melbourne,Parkville, Victoria,Australia;Royal Melbourne Hospital,Parkville, Victoria,Australia
(Abstract release date: 05/14/20) EHA Library. Dimopoulos M. 06/12/20; 293669; EP1180
Prof. Dr. Meletios Dimopoulos
Prof. Dr. Meletios Dimopoulos
Contributions
Abstract

Abstract: EP1180

Type: e-Poster

Background
Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with Waldenström macroglobulinemia (WM) harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. The ASPEN trial evaluated ZANU, a potent and selective BTK inhibitor, in patients with WM.

Aims
To evaluate the efficacy and safety of ZANU in patients who have WM with MYD88 wild-type (MYD88WT) mutation status.

Methods
In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics) using a wild-type–blocking polymerase chain reaction method. This MYD88 mutation assay detects all mutations in the region encompassing amino acid Ala260-Pro278, which includes the predominant mutation in WM (MYD88L265P), with enhanced sensitivity (Int J Lab Hematol. 2016;38:133). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 (MYD88 mutation) or cohort 2 (MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression.

Results
In total, 28 patients (n=26 MYD88WT; n=2 MYD88 mutation status unknown) were enrolled into cohort 2. The median age was 72 years and 42.9% were >75 years old; 5 patients were treatment-naïve (TN), and 23 patients were relapsed/refractory (R/R; ≥1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With a median follow-up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. In 26 confirmed MYD88WT patients, the overall response rate was 80.8%, with a major response rate of 50.0%, including a very good partial response rate of 26.9% (Table). Progression-free survival event-free rate at 12 months was 72.4%. The 2 patients with unknown MYD88 mutation status achieved best overall response of partial response.  In cohort 2 patients (n=28), the most frequently reported adverse events (AEs) were diarrhoea, anaemia, contusion, pyrexia, and upper respiratory tract infection. Major haemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient.

Conclusion
ZANU showed clinically meaningful antitumor activity, including achieving major responses and durability of responses, and was considered well tolerated with a low discontinuation rate due to AEs, in patients with MYD88WT WM. ClinicalTrials.gov: NCT03053440.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): Kinase inhibitor, Waldenstrom's macroglobulinemia

Abstract: EP1180

Type: e-Poster

Background
Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with Waldenström macroglobulinemia (WM) harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. The ASPEN trial evaluated ZANU, a potent and selective BTK inhibitor, in patients with WM.

Aims
To evaluate the efficacy and safety of ZANU in patients who have WM with MYD88 wild-type (MYD88WT) mutation status.

Methods
In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics) using a wild-type–blocking polymerase chain reaction method. This MYD88 mutation assay detects all mutations in the region encompassing amino acid Ala260-Pro278, which includes the predominant mutation in WM (MYD88L265P), with enhanced sensitivity (Int J Lab Hematol. 2016;38:133). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 (MYD88 mutation) or cohort 2 (MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression.

Results
In total, 28 patients (n=26 MYD88WT; n=2 MYD88 mutation status unknown) were enrolled into cohort 2. The median age was 72 years and 42.9% were >75 years old; 5 patients were treatment-naïve (TN), and 23 patients were relapsed/refractory (R/R; ≥1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With a median follow-up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. In 26 confirmed MYD88WT patients, the overall response rate was 80.8%, with a major response rate of 50.0%, including a very good partial response rate of 26.9% (Table). Progression-free survival event-free rate at 12 months was 72.4%. The 2 patients with unknown MYD88 mutation status achieved best overall response of partial response.  In cohort 2 patients (n=28), the most frequently reported adverse events (AEs) were diarrhoea, anaemia, contusion, pyrexia, and upper respiratory tract infection. Major haemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient.

Conclusion
ZANU showed clinically meaningful antitumor activity, including achieving major responses and durability of responses, and was considered well tolerated with a low discontinuation rate due to AEs, in patients with MYD88WT WM. ClinicalTrials.gov: NCT03053440.

Session topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical

Keyword(s): Kinase inhibitor, Waldenstrom's macroglobulinemia

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