Updated results of the aspen trial from a cohort of patients with MYD88 wild-type waldenstrom macroglobulinemia.

Abstract

Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with Waldenstrom 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. Aim(s): To evaluate the efficacy and safety of ZANU in patients who have WM with MYD88 wild-type (MYD88WT) mutation status. Method(s): 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. Result(s): 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-naive (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. Summary/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.