The potential of zanubrutinib in the management of patients with Waldenström macroglobulinemia (WM) has been highlighted in two international studies led by Australians.

Professor Judith Trotman, from Concord Hospital and the University of Sydney, led a 3-year follow-up of the BTK inhibitor in a phase 1/2 study in WM.

The study, published in Blood, comprised 77 patients – almost a third who were treatment naive and the rest relapsed or refractory – from 24 sites across six countries.

All patients who were relapsed or refractory had been previously exposed to chemotherapy and most had received rituximab (94.3%), alkylating agents such as cyclophosphamide or chlorambucil (90.6%), and glucocorticoids (73.6%).

Most (84%) of participants tested had a MYD88^L265P mutation and 19% of those also harboured a CXCR4^WHIM mutation.

The study found long-term treatment with zanubrutinib resulted in an overall response rate of 95.9%.

An overall VGPR/CR rate of 45.2% was higher in the R/R participants than the treatment naive group (51.0% v 33.3%).

When assessed by genotype, the subset of patients who had MYD88^L265P/CXCR4^WT WM had the highest VGPR/CR rate of 59.0%.

The study also found that long-term treatment with zanubrutinib was well tolerated in both treatment-naïve and relapsed/refractory patients.

“In summary, these results showed that long-term treatment with zanubrutinib resulted in deep and durable responses in the majority of patients with WM and was well tolerated. Deep responses were seen in patients with both TN and R/R disease and in all molecular subtypes, including MYD88^WT,” the study said.

Also published in Blood was a randomised, open-label phase 3 study comparing the safety and efficacy of zanubrutinib with ibrutinib in 201 patients with WM.

The international ASPEN study, led by Professor Con Tam from the Peter MacCallum Cancer Centre, found no patients achieved a CR.

While the rate of VGPR was higher among zanubrutinib patients than ibrutinib patients overall (28% v 19%; p=0.09), and in both R/R and treatment naive groups, the differences were not statistically significant.

“The rates of VGPR were mostly comparable between the arms for prognostically important subgroups (eg, intermediate- or high-risk, based on the International Prognostic Scoring System; age >65 years; hemoglobin ≤110 g/L; platelet count ≤100 × 109/L; and β-2 microglobulin >3 mg/dL),” the study said.

“Although the study did not meet its primary end point, there was a trend toward better disease control for zanubrutinib vs ibrutinib, including higher rates of VGPR, greater and more sustained IgM reduction, and greater improvement in most QoL measures.”

A Comment article by Mayo Clinic’s Assistant Professor Prashant Kapoor and Professor Steven Treon, director of the Bing Centre for WM at the Dana-Farber Cancer Institute, said the two studies have “broad implications for WM therapeutics”.

“The two trials showcase how extraordinary international collaborative efforts were instrumental in the development of zanubrutinib at warp speed for treatment of a rare B-cell malignancy,” they said.

And although the ASPEN study did not meet its choice of primary endpoint, they said zanubrutiniib would still likely become an important treatment option for WM.

“In hindsight, should ASPEN triallists have adopted a noninferiority design (with PFS as the primary endpoint), particularly when it is not necessarily the greater degree of BTK inhibition, but the reduced off-target effects (as exemplified by more favuorable toxicity-profile and quality-of-life assessments) that is more likely to strike a chord with patients and practicing hematologists alike?,” they said.

“Or will once-a-day convenience and longer clinical experience with ibrutinib drive clinical decision making?