Is zanubrutinib the choice of BTK inhibitor for Waldenström macroglobulinaemia?

Zanubrutinib is now registered in Australia for the treatment of adult patients with Waldenström macroglobulinaemia (WM) who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemoimmunotherapy.1 Speaking to the limbic, Melbourne haematologist Professor Stephen Opat described the place in therapy of this second-generation Bruton tyrosine kinase (BTK) inhibitor, drawing on his insights as an investigator for the ASPEN study comparing zanubrutinib and ibrutinib in WM.

Waldenström Macroglobulinaemia is a rare disease with only about 100 new patients in Australia each year,” explained Prof Opat. “In rare diseases, it’s very hard to get good trial data, so we’re really fortunate that there have been a number of international studies in this area, and Australians have had a major input into these studies,” he said.

When considering treatment approaches, Prof Opat noted the importance of seeking out clinical trials for his patients. “We try and put all of our patients on a trial if we can, including clinical trials investigating combination therapies,” he said.

Waldenström macroglobulinemia is a rare B-cell lymphoma

Waldenström macroglobulinemia is a mature B-cell lymphoma. Although clinically indolent it is incurable, and the disease course involves episodes of symptomatic recurrence requiring treatment.2 Patients experience weakness and fatigue from anaemia. High IgM protein levels can result in hyperviscosity syndrome, peripheral neuropathy, cryoglobulinemia, and immune complex vasculitis.2

It’s a disease of older people, so the average age is 70 and a lot of the treatments that younger patients may tolerate are not as well tolerated in older people. Since it’s often an indolent disease, there are many people who never need treatment. You don’t treat until symptoms occur,” explained Prof Opat.

Prof Opat described the options for patients requiring treatment: “There are two strategies in the front line treatment: chemotherapy with an alkylating agent plus rituximab or bendamustine plus rituximab-based therapy.”  The combination of bendamustine plus rituximab is approved on the PBS for first-line therapy in WM.3

While there is no standard treatment in relapsed WM, BTK inhibitors are among a range of agents recommended in this setting.3 The BTK inhibitor ibrutinib is also indicated for relapsed or refractory WM, but is not reimbursed for this indication.3

Zanubrutinib availability in Australia

Zanubrutinib is a novel selective BTK inhibitor exhibiting less off-target inhibition than ibrutinib.2 In addition to its indication as second-line treatment of WM (or first-line treatment in patients unsuitable for chemotherapy), it’s also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

While zanubrutinib received a positive PBAC recommendation in July 2021 for the MCL indication, there is no such recommendation in place to date for WM. There is a pre-reimbursement access program in place for both indications.

Comparing ibrutinib and zanubrutinib in WM: the ASPEN study

The ASPEN study4 compared the efficacy and safety of ibrutinib and zanubrutinib in patients with WM (n=201). “In Australia, we recruited a relatively large proportion of patients for this international study,” explained Prof Opat.

Eligible patients included those with relapsed or refractory WM after one or more prior lines of therapy or treatment-naïve WM unsuitable for standard immunochemotherapy. The primary end point was the proportion of patients achieving a complete response (CR) or very good partial response (VGPR).4

No patient achieved CR, and VGPR was achieved in 29 (28%) patients receiving zanubrutinib versus 19 (19%) patients receiving ibrutinib (not statistically different; P=0.09. Primary endpoint not met). Key secondary end points included major response rate (MRR) (77% for zanubrutinib; 78% for ibrutinib), median duration of response, and progression free survival (endpoints not reached). At 18 months, 85% of zanubrutinib patients and 84% ibrutinib patients were progression free. “Longer follow-up will allow an assessment of whether deeper responses correlate with more durable disease control, as has been observed with conventional therapies,”4 say the authors.

Comparative safety insights from ASPEN

The ASPEN study also aimed to directly compare the safety of ibrutinib and zanubrutinib in an effort to determine whether there was a difference in off-target toxicities between the two agents.4

Zanubrutinib resulted in less atrial fibrillation, contusion, diarrhoea, peripheral oedema, haemorrhage, muscle spasms, and pneumonia, compared to ibrutinib. Zanubrutinib also resulted in fewer adverse events leading to treatment discontinuation. 3 The incidence of neutropenia was higher with zanubrutinib, but grade 3 or higher infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months).4

Commenting on the atrial fibrillation and hypertension data, the authors note, “We observed several clinically significant differences in the safety and tolerability profiles of the 2 BTK inhibitors, likely consistent with the higher degree of selectivity of zanubrutinib for BTK vs off-target kinases. Atrial fibrillation and hypertension were reported at greater frequencies with ibrutinib compared with zanubrutinib. Atrial fibrillation is a well-recognized complication of ibrutinib therapy, and relative to an age-matched controlled population, patients appear to be at continuously increased risk for development of atrial fibrillation over the course of therapy.”4

The authors discussed other aspects of the safety profile that can be troublesome for patients:“…zanubrutinib treatment was associated with less minor bleeding or bruising, as well as fewer major hemorrhages, than ibrutinib treatment….consistent with prior experience, the frequency of diarrhoea among zanubrutinib patients in our study was half that reported among ibrutinib patients, on an exposure-adjusted basis (1.3 and 2.6 events per 100 person-months, respectively), likely due to less potent inhibition of epidermal growth factor receptor by zanubrutinib.”4

The authors suggested the higher rates of severe neutropenia among zanubrutinib patients may be a function of its greater bioavailability: “Importantly, the higher incidence of severe neutropenia did not result in a higher infection incidence compared with that for ibrutinib,”4 the authors note.

The authors conclude, “These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.”4

Considering toxicities in management decisions

Discussing the place of ibrutinib and zanubrutinib in WM therapy, Prof Opat notes, “Most patients will tolerate ibrutinib reasonably well. If zanubrutinib wasn’t available, then clearly ibrutinib would be the BTK inhibitor we’d use second-line.”

However, it’s the toxicity profile that differentiates these agents, explained Prof Opat: “We choose the drug with the most favourable side effect profile, particularly for older patients, or those with cardiac disease or who need anticoagulants…If you have a choice between a drug that doesn’t cause atrial fibrillation and one that does, it’s quite an easy choice,” he said.

The higher rate of neutropenia with zanubrutinib has largely been straightforward to manage, explained Prof Opat. “As a haematologist we’re used to treating (and causing) neutropenia. We don’t often need to use growth factors [for zanubrutinib-associated neutropenia] and the rates of severe neutropenia were low,” he said.

Some patients experience bruising, and we stop zanubrutinib therapy prior to elective surgical procedures,” said Prof Opat. “While less common than with ibrutinib, around 10% of patients in the ASPEN study experienced new onset hypertension, so it’s still important to monitor blood pressure,” he explained.


This article was sponsored by Beigene. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Brukinsa product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.


  1. Brukinsa Australian Product Information
  2. Trotman J et al. Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up. Blood 2020; 136 (18):2027 – 2037.
  3. Talaulikar D & Tam C. (2016) MSAG Clinical Practice Guideline Waldenstrom Macroglobulinaemia. Myeloma Australia.
  4. Tam C et al. A randomized phase 3 trial of zanutrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 2020; 136 (18):2038–2050.

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