Switching to Zanubrutinib Maintains Outcomes in Waldenström Macroglobulinemia

For patients with Waldenström macroglobulinemia (WM), transitioning from ibrutinib (Imbruvica) to zanubrutinib (Brukinsa) may offer comparable clinical outcomes, as suggested by interim data from a long-term extension study (BGB-3111-LTE1; NCT04170283) of the phase 3 ASPEN trial (BGB-3111-302; NCT03053440).¹

The study published in Blood Advances reports data of 47 patients who switched from ibrutinib treatment in ASPEN to zanubrutinib. At a median follow-up of 15.3 months, a majority (85%) of patients remained on zanubrutinib treatment. The 46 efficacy-evaluable patients saw a high rate of best overall response (96%), with responses either maintained (63%) or improved (33%) from the last response in the ASPEN study.

In addition to favorable efficacy, the transition was found to be safe, even with increasing age. Treatment-emergent adverse events (TEAEs) occurred in 80.9% of patients, with 36.2% deemed to be related to treatment. Notably, most ibrutinib TEAEs of interest associated with Bruton tyrosine kinase (BTK) inhibitors did not recur or worsen on zanubrutinib treatment.

The extension study, which includes patients from 15 parent studies of zanubrutinib, was initiated to facilitate long-term access to zanubrutinib for patients with B-cell malignancies while collecting long-term data on the agent. Here, patients are receiving zanubrutinib at a dose of 160 mg twice daily or the last dose level received in the parent study.²

“Although limited by sample size and nonrandomized/ad hoc analyses, data suggest that patients who tolerate ibrutinib may switch to zanubrutinib without compromising safety or efficacy,” study authors García-Sanz et al wrote.¹

Follow-up for the study remains ongoing.

ASPEN Trial: Zanubrutinib in WM

The ASPEN trial was a global, randomized, open-label phase 3 trial evaluating the comparative efficacy and safety of the BTK inhibitors zanubrutinib vs ibrutinib in 201 patients with MYD88-mutated WM.³ The study population included 164 patients with relapsed or refractory disease and 37 with treatment-naive disease. Patients were randomized 1:1 to receive either 160 mg of zanubrutinib twice daily or 420 mg of ibrutinib once daily in 28-day cycles until disease progression or intolerance.

Results from this study showed high rates of very good partial response (VGPR) with zanubrutinib compared with ibrutinib as assessed by an independent review committee (28.4% vs 19.2%).⁴ Although these figures did not reach statistical significance, these data, along with safety data trending favorably over ibrutinib, supported the FDA approval of zanubrutinib’s supplemental new drug application for adult patients with WM in August 2021.

Additional 2-year follow-up data published in 2023 confirmed the durability of this trend, with continued higher VGPR rates of 36.3% (95% CI, 27.0%–46.4%) with zanubrutinib vs 25.3% (95% CI, 17.1%–35.0%) with ibrutinib after a total of 60 months of treatment.⁵

Regarding safety, the most common AEs observed with zanubrutinib included neutropenia, upper respiratory infection, and diarrhea; with ibrutinib, diarrhea, upper respiratory infection, contusion, and muscle spasms were frequent.⁴ Zanubrutinib’s safety profile was favored over ibrutinib’s primarily due to less cardiovascular toxicities such as atrial fibrillation and hypertension.

REFERENCES

1. García-Sanz R, Owen RG, Jurczak W, et al. Outcomes after transition from ibrutinib to zanubrutinib in patients with Waldenström macroglobulinemia from the ASPEN study. Blood Advances. 2025;9(24):6538-6546. doi:10.1182/bloodadvances.2024015596

2. Long-term extension study of zanubrutinib (BGB-3111) regimens in participants with B-cell malignancies. ClinicalTrials.gov. Updated October 21, 2025. Accessed January 5, 2026. https://clinicaltrials.gov/study/NCT04170283

3. A study comparing BGB-3111 and ibrutinib in participants with Waldenström's macroglobulinemia (WM) (ASPEN). ClinicalTrials.gov. Updated October 26, 2024. Accessed January 2, 2026. https://www.clinicaltrials.gov/study/NCT03053440

4. 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

5. Dimopoulos MA, Opat S, D'Sa S, et al. Zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: Final analysis from the randomized phase III ASPEN study. J Clin Oncol. Published July 21, 2023. doi:10.1200/JCO.22.02830