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Tam C, et al. "ASPEN". Blood. 2020. 136(18):2038-2050.

Clinical Question

Among patients with WM, how do the BTK inhibitors zanubrutinib and ibrutinib compare in terms of efficacy and safety?

Bottom Line

Among patients with previously treated WM or those who are treatment naive and ineligible for chemoimmunotherapy, zanubrutinib and ibrutinib yielded similar efficacy results but safety seemed to favor zanubrutinib.

Major Points

The MYD88L265P mutation is present in >90% of patients with Waldenström macroglobulinemia (WM) and leads to enhanced B-cell receptor pathway signaling and cell survival. BTK inhibitors including ibrutinib block B-cell pathway signaling and are very effective in WM, as demonstrated in the 12-015 trial. Several studies have explored whether the toxicities of ibrutinib, chiefly arrhythmias, bleeding/bruising, rash, and GI toxicities, can be improved upon with more selective BTK inhibitors such acalabrutinib and zanubrutinib.

The ASPEN study evaluated patients with WM who were previously treated or who were previously untreated but ineligible for conventional chemoimmunotherapy. Approximately 200 patients were randomized to either zanubrutinib (160 mg twice daily) or to ibrutinib (420 mg/d), with continuous therapy until disease progression or undue toxicity occurred. The reasons for initiation of therapy included fatigue (57%), anemia (44%), B symptoms (30%), hyperviscosity (27%), peripheral neuropathy (22%), thrombocytopenia (12%), amyloidosis (10%), and symptomatic or bulky adenopathy (9%). The primary endpoint was the proportion of patients achieving very good partial response (VGPR) or complete response (CR). A complex hierarchical statistical analysis plan was employed to adjust for multiplicity, and involved first testing for VGPR/CR superiority of zanabrutinib. At a median follow-up of 19.4 months, no patients achieved CR in either group, VGPR rates favored zanubrutinib over ibrutinib (28% vs. 19%; P=0.09), and major response rates were similar (77% vs. 78%). Median progression-free survival (PFS) was not reached for either group at a median follow-up of about 18 months. Estimated overall survival (OS) rate at 18 months was 97% with zanubrutinib and 93% with ibrutinib. Rates of adverse events were similar between treatment arms, although there were notable differences: zanubrutinib was associated with more neutropenia (hazard ratio [HR] 2.18), but less atrial fibrillation (HR 0.14) and hemorrhage (0.65).

The ASPEN study suggests that zanubrutinib and ibrutinib have similar efficacy in patients with treatment-naive and relapsed/refractory WM, and provides some evidence that zanubrutinib may be better tolerated than ibrutinib. With costs similar between the two agents, zanubrutinib may be the preferred BTK inhibitor in this disease.


NCCN Waldenstrom Macroglobulinemia / Lymphoplasmacytic Lymphoma (1.2022, adapted):[1]

  • Zanubrutinib is a preferred regimen for primary therapy for WM/LPL (category 1)
  • Zanubrutinib is a preferred regimen for previously treated WM/LPL (category 1)


  • Randomized controlled trial
  • N=201 patients with MYD88L265P WM
    • Zanubrutinib (n=99)
    • Ibrutinib (n=102)
  • Setting: 58 international sites
  • Enrollment: 2017-2018
  • Mean follow-up: ~18 months
  • Analysis: Hierarchical fixed-sequence procedure
  • Primary outcome: VGPR/CR rate


Inclusion Criteria

  • Patients with Waldenström macroglobulinemia
    • Relapsed/refractory with ≥1 prior line of therapy, or
    • Treatment-naive and ineligible for chemoimmunotherapy on the basis of age/comorbidities
  • Measurable disease
  • Adequate end-organ function
  • Adequate blood counts (ANC ≥0.75K, PLT ≥50K)

Exclusion Criteria

  • Prior BTK inhibitor exposure
  • Disease transformation
  • Active CNS lymphoma
  • Clinically significant cardiovascular disease
  • Requirement for warfarin or other vitamin K antagonist

Baseline Characteristics

From patients assigned to zanubrutinib.

  • Age: 70 years (33% >75 years)
  • Female: 32%
  • ECOG PS: 0-1 (94%), 2 (6%)
  • WM IPSS prognostic group: Low (17%), Intermediate (37%), High (46%)
  • Time from initial diagnosis: 4.4 years median
  • Prior lines of therapy: 0 (19%), 1-3 (75%), >3 (7%)
  • Prior stem-cell transplant: 2.9%
  • Serum IgM: ≥4,000 mg/dL (35%), <4,000 mg/dL (65%)
  • B2M: >3 g/dL (74%)
  • CXCR4 genotype: WT (89%), WHIM (11%), Unknown (0%)
  • Bone marrow involvement: 60% median
  • Extramedullary disease: 79%
  • Hemoglobin ≤11 g/dL (66%), Platelets ≤100K (12%), ANC ≤1.5K (11%)


  • Cohort 1 (which is the subject of this analysis) randomized patients with MYD88L265R WM in a 1:1 fashion to:
    • Ibrutinib 420 mg PO daily
    • Zanubrutinib 160 mg PO twice daily
    • Randomization was stratified by CXCR4WHIM mutation status.
  • Cohort 2 was a nonrandomized arm which assigned patients with MYD88WT or MYD88 unknown status to zanubrutinib.
  • Crossover due to progression or intolerance was not allowed.


Outcomes are zanubrutinib vs. ibrutinib.

Primary Outcome

28% vs. 19% (P=0.09)
No patient achieved CR in any group.

Secondary Outcomes

Overall response rate (ORR)
94% vs. 93%
Major response rate (MRR)
77% vs. 78%
Duration of VGPR/CR
Median not reached in either group.
: 18-month event-free rate: 93% vs. 64%
Duration of major response
Median not reached in either group.
18-month event-free rate: 85% vs. 88%
Progression-free survival (PFS)
Median not reached in either group.
18-month event-free rate: 85% vs. 84%

Subgroup Analysis

There were no significant differences in responses across subgroups defined by age, sex, geographic region, treatment phase, prior lines of therapy, performance status, CXCR4 mutation status, IgM, B2M, hemoglobin, platelets, extramedullary disease status, or prognostic group.

Adverse Events

29% vs. 13%
Atrial fibrillation/flutter
2% vs. 15%
Any bleeding
4.4 vs. 7.0 per 100 person-months
Major hemorrhage
0.3 vs. 0.6 per 100 person-months
Dose reductions
14% vs. 23%
Discontinuation of therapy due to AE
4% vs. 9%


Funding and medical writing support came from BeiGene Inc., the makers of zanubrutinib.

Further Reading

  1. NCCN Guidelines 1.2022