Behind the Paper: The Prognostic Impact of CXCR4 and TP53 Alterations on Zanubrutinib in Waldenström Macroglobulinemia

Alberto Guijosa Feb 04, 2026

Over the past two decades, treatment options for Waldenström macroglobulinemia (WM) have changed dramatically. In the past, most patients were treated almost exclusively with chemotherapy-based regimens, which, while highly effective, are associated with important long-term risks, including secondary cancers and treatment-related genetic damage 1,2.


A major turning point came with the discovery that most WM patients carry a mutation in the MYD88 gene. This mutation activates key signaling pathways that drive the survival and growth of WM cells through downstream stimulation of Bruton tyrosine kinase (BTK). Understanding this pathway provided the biological rationale for targeting BTK as a therapeutic strategy, ultimately leading to the development and approval of BTK inhibitors for WM.  The first of these, ibrutinib, demonstrated high efficacy and, for the first time, offered a frontline treatment comparable to chemotherapy, while avoiding its genotoxic effects 3.


More recently, zanubrutinib has become the preferred BTK inhibitor for WM. This is largely based on the ASPEN trial, which directly compared ibrutinib and zanubrutinib. The trial showed similar effectiveness for both drugs, but zanubrutinib had a better safety profile, particularly with fewer cardiac-related toxicities such as atrial fibrillation, which occurs in up to 20% of patients treated with ibrutinib and around 5% of patients treated with zanubrutinib 4.


Currently, the two main frontline treatment options for most patients with WM are zanubrutinib and chemoimmunotherapy. However, much of the existing knowledge about zanubrutinib in WM still comes largely from a single clinical trial. At the same time, WM care is increasingly moving toward personalized medicine, in which genetic features of the tumor influence treatment selection and outcomes. In this context, understanding how specific mutations, such as CXCR4 and TP53, affect response, durability, and resistance to zanubrutinib outside of clinical trials is essential for optimizing treatment strategies and improving patient care.

Our Study

We analyzed 236 consecutive patients with WM treated with zanubrutinib at Dana-Farber Cancer Institute, representing, to the best of our knowledge, the largest cohort reported to date.

We focused on three key genetic alterations that are known to influence WM biology and treatment response:

  • MYD88
  • CXCR4
  • TP53

We evaluated how these mutations affected treatment response, measured by IgM reduction, and progression-free survival, defined as the time to disease progression or death.

CXCR4 Mutations: Delayed Response but Durable Benefit

CXCR4 mutations have long been thought to lead to poorer outcomes with BTK inhibitors, largely due to their significant link with resistance to ibrutinib. However, this view was challenged by the ASPEN trial, which demonstrated the superiority of zanubrutinib over ibrutinib in patients with CXCR4 mutations 5.

In our study, we found that patients with CXCR4 mutations treated with zanubrutinib often experience delayed responses. However, their longer-term outcomes are not compromised, as CXCR4 mutations were not associated with worse 2-year progression-free survival.

These findings, together with the results of the ASPEN trial, have major clinical implications. It suggests that zanubrutinib is largely effective regardless of CXCR4 mutation status and should be considered the preferred BTK inhibitor in this setting. As a result, the presence of a CXCR4 mutation should not be a reason to favor chemoimmunotherapy over BTK inhibitor-based treatment.

Moreover, in routine clinical practice, treatments are sometimes changed if deep responses are not achieved quickly. Our results highlight the importance of continuing zanubrutinib in patients with CXCR4 mutations, even when early responses are delayed, since longer-term disease control is preserved.

TP53 Alterations: An Ongoing Challenge

TP53 is a well-known tumor suppressor gene, and its alterations are associated with poor outcomes in many cancers, including WM. Over the past several years, the negative impact of TP53 across multiple WM therapies has become increasingly clear 6.

At present, no approved WM therapy is fully independent of TP53 status. Chemotherapy-based regimens, in particular, are strongly affected by TP53 alterations.

In our study, TP53 alterations were associated with significantly worse outcomes in patients who had received therapies prior to zanubrutinib. In contrast, among treatment-naïve patients receiving first-line zanubrutinib, no negative effect was observed within the available follow-up period.

TP53 alterations can be present at diagnosis but are more commonly acquired later during disease progression, and these different patterns may have distinct prognostic implications in patients treated with zanubrutinib 2,7. Mutations that emerge over time may reflect more advanced and treatment-resistant disease, whereas baseline TP53 alterations may still respond well to zanubrutinib early in the disease course. Altogether, this supports the use of zanubrutinib as a preferred frontline option for patients with TP53 alterations.

Still, TP53 remains an important unmet need in WM, especially in the relapsed and refractory setting, where these mutations are more common. A recent study suggested that non-chemotherapy approaches, such as BTK inhibitors, may be associated with lower rates of acquired TP53 abnormalities over time compared to chemoimmunotherapy 2, further supporting the broader use of zanubrutinib in the general WM population.

 

MYD88 Status: Technical Challenges and Clinical Implications

The MYD88 mutation is the biological foundation for the use of BTK inhibitors in WM. Ibrutinib, for example, is highly effective in MYD88-mutated disease but performs poorly in true MYD88–wild-type cases 3,8.

The ASPEN trial demonstrated that zanubrutinib is active in MYD88-mutated disease. Although activity was also observed in patients classified as MYD88 wild-type, interpretation of these results is limited 9. One important reason is that MYD88 mutations may be present at low levels and can be missed by standard testing methods. More sensitive approaches, such as CD19-enriched testing, can detect low-level mutations that conventional assays may overlook 10. Because ASPEN did not use CD19 enrichment, some patients classified as MYD88 wild-type may in fact have harbored undetected MYD88 mutations.

In our study, we did not identify any patients with confirmed CD19-enriched MYD88–wild-type disease who received zanubrutinib. We did, however, observe responses in patients classified as MYD88 wild type by conventional testing. These findings further support the use of zanubrutinib when MYD88 testing is performed using standard methods. However, at present, its use in definitively confirmed MYD88–wild-type disease (using enriched techniques) cannot be firmly recommended, as this has not yet been adequately studied.

Conclusions

As zanubrutinib becomes the preferred BTK inhibitor for Waldenström macroglobulinemia and an increasingly common alternative to chemoimmunotherapy, understanding how genetic features influence treatment outcomes is essential. Our study provides large off-trial evidence that zanubrutinib is effective across major molecular subgroups of WM, including patients with CXCR4 and TP53 alterations and independent of MYD88 status for those tested with conventional methods.

These findings support the broad use of zanubrutinib in routine clinical practice and reinforce its role as a cornerstone of modern WM management. By clarifying how key genetic alterations affect response and long-term outcomes, this work helps guide personalized treatment decisions and supports evidence-based use of targeted therapy in WM.

References

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