FDA Approves Zanubrutinib in Adults With Waldenström Macroglobulinemia


The approval of zanubrutinib makes it just the second therapy indicated for this rare type of lymphoma.

The FDA has approved zanubrutinib (Brukinsa) for the treatment of adults with Waldenström macroglobulinemia (WM), a rare type of lymphoma.

The approval was based on results from the phase 3 ASPEN trial, which compared zanubrutinib against ibrutinib in patients with WM. Results were published in Blood in October 2020.1

Both agents are Bruton tyrosine kinase (BTK) inhibitors. However, as a next-generation BTK inhibitor, zanubrutinib is more targeted, which reduces toxicity while improving outcomes, explained Peter Hillmen, PhD, MB ChB, professor at the University of Leeds and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust, when he presented results of zanubrutinib at the European Hematology Association 2021 Virtual Congress (EHA2021) in June.

“The ASPEN trial provided compelling evidence that Brukinsa is a highly active BTK inhibitor in Waldenström’s macroglobulinemia, and compared to the first-generation BTK inhibitor, showed improved tolerability across a number of clinically important side effects,” Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, said in a statement. “The approval of Brukinsa provides an important new option for targeted therapy in Waldenström’s macroglobulinemia.”

The primary end point of ASPEN was very good partial response (VGPR) in the intention-to-treat population. For zanubrutinib, the VGPR rate was 28% compared with 19% for ibrutinib, based on the modified Sixth International Workshop on Waldenström’s Macroglobulinemia (IWWM-6).

Using IWWM-6 criteria, the response rate of partial response or better was 78% for zanubrutinib vs 78% for ibrutinib (95% CI, 68%-85% vs 95% CI, 68%-86%). At 12 months, the event-free duration of response was 94% for zanubrutinib compared with 88% for ibrutinib (95% CI, 86%-98% vs 95% CI, 77%-94%).

The most common adverse events (AEs) occurring in at least 20% of the safety population of 779 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.

In the study results published in Blood, the authors noted that 23% of patients on ibrutinib required dose reductions for AEs vs 14% of patients on zanubrutinib. In addition, the zanubrutinib group had lower incidence and severity of most toxicities associated with BTK inhibitors compared with ibrutinib.

“The approval of Brukinsa in Waldenström’s macroglobulinemia, which is the second therapy approved specifically for the treatment of this rare type of lymphoma, is positive news for patients,” said Pete DeNardis, chair of the board at the International Waldenström’s Macroglobulinemia Foundation. “Expanded treatment options offer new hope for those living with this disease and can potentially improve patient experience, especially oral therapies that can be given as a single agent.”

At EHA2021, additional research on zanubrutinib in WM found:

  • Compared with dexamethasone-rituximab-cyclophosphamide (DRC) and bendamustine-rituximab (BR), zanubrutinib had significantly longer 12- and 24-month progression-free survival and overall survival.
  • Zanubrutinib had a higher incidence of neutropenia vs DRC but a lower incidence vs BR.
  • Zanubrutinib is cost-effective vs ibrutinib based on life-years, quality-adjusted life-years, and treatment costs. Zanubrutinib reduced the cost of disease management by $2935 and other direct costs by $2964 vs ibrutinib.

Zanubrutinib is already approved in the United States for adults with mantle cell lymphoma. It is under investigation in the MAGNOLA trial for marginal zone lymphoma and the ALPINE study for relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia.


1. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038-2050. doi:10.1182/blood.2020006844

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