A short-term follow up on a phase 2 study found orelabrutinib, a novel small molecule BTK inhibitor, has substantial efficacy in treating patients with relapsed or refractory (R/R) Waldenstrom’s macroglobulinemia (WM); these data were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with immunoglobulin M (IgM) monoclonal gammopathy. Bruton's tyrosine kinase (BTK) plays a key role in signaling pathways for the survival of WM clone, particular in patients harboring MYD88L265P mutations. However, due to target selectivity issue, clinical uses of early BTK inhibitors are still compromised with off-target activities to many other kinases besides BTK,” explained Daobin Zhou, MD, Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, and co-investigators

Thus, Dr Zhou et al presented preliminary efficacy and safety data of orelabrutinib in patients with R/R WM.

The single-arm, multicenter, open label phase 2 study enrolled 47 patients (median age 63) with R/R WM requiring treatment per the IWWM-7. Patients were administered orelabrutinib orally at 150mg daily until disease progression or unacceptable toxicity.

Mutations (MYD88 and CXCR4) were assessed in bone marrow samples at baseline. Blood samples for IgM were assessed at baseline and every cycle for 6 cycles and every 3 cycles thereafter by central lab. Responses were assessed in accordance with IWWM-6 and NCCN guidelines. The primary end point was major response rate (MRR) as assessed by IRC. Key secondary endpoints include MRR as assessed by investigator, overall response rate (ORR), duration of major response (DOMR), progression-free survival (PFS), overall survival (OS), changes in IgM levels from baseline, improvements on hemoglobin levels, and safety.

As of June 1, 2021, the median follow-up was 10.5 months for all patients. The proportion of patients with MYD88^L265PCXCR4^wildtype was 83 percent. The median duration of treatment was 9.2 months, and the MRR was 74.3 percent. The ORR was 87.2 percent with 97.9 percent of patients achieving disease control. The estimated 12-month DOMR was 89.5 percent. The estimated 12-month PFS and OS were 88 percent and 92.3 percent, respectively. The median PFS and median OS were not met. The MRR was higher in patients with MYD88^L265PCXCR4^wildtype (79.5%). The median IgM level was 30.3g/L. The decline in the serum IgM levels from baseline were observed with a median reduction of 79 percent. The median hemoglobin level was 102g/L. Durable improvements in hemoglobin levels were seen in 83 percent of patients with a median maximal improvement of 40g/L.

The most common reported adverse events (AEs) included thrombocytopenia (27.7%), neutropenia (14.9%), leukopenia (10.6%), upper respiratory infection (14.9%), weight increase (14.9%), influenza-like disease (12.8%), and rash (10.6%). The most reported AEs in 89.5 percent of patients were grade 1 and 2. A total of 16 patients reported grade ≥3 treatment-emergent AEs while 9 patients reported grade ≥3 treatment-related AEs. There was no reported grade ≥3 atrial fibrillation and/or atrial flutter, or diarrhea. There was just 1 treatment-related AE (2.1%), which resulted in drug discontinuation.

“Orelabrutinib has demonstrated substantial efficacy in treating R/R WM patients under short-term follow-up. It has shown favorable safety and tolerability profile with limited off-target adverse effects. It has the potential to be a promising treatment option for R/R WM patients,” concluded Dr Zhou et al.—Emily Bader

Zhou D, Jin J, Fu Z, et al. Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Waldenstrom’s Macroglobulinemia Patients. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 46.