Waldenström’s macroglobulinemia (WM) is a rare, B-cell malignancy of lymphoplasmacytic cells with production of a monoclonal protein, typically IgM. It causes clinical symptoms due to the involvement of the bone marrow with resultant cytopenias and/or lymphadenopathy as well as organ infiltration. Most importantly, WM is an cancerous disease and thus treatment is focused on controlling tumor, symptom control and durability of therapeutic response with due consideration of potential complications of therapy.
Treatment of relapsed or refractory WM has become a complicated clinical conundrum, especially given the availability of numerous therapeutic options including chemo immunotherapies and most importantly BTK inhibitors. Subsequent therapeutic decisions, in this setting, can depend on several clinical, therapeutic and patient specific variables.
Understanding relapsed or refractory Waldenström macroglobulinemia
Relapsed Waldenström’s is an instance where WM returns following a given period of response to the respective treatment. Refractory disease on the other hand is not responding to a certain treatment or even is getting worse while under said treatment. As noted, the course of the disease can vary for different patients after relapse.
Prior treatment with a BTK inhibitor and disease molecular characteristics such as MYD88 and CXCR4 mutation status can greatly influence the selection of subsequent WM therapy and can dictate treatment in patients with relapsed refractory disease. A good treatment addresses the patient’s current disease and takes into consideration all the patient’s prior WM therapy and associated toxicities.
The role of BTK inhibition
BTK is an important component of B cell receptor signaling pathways. Inhibiting BTK blocks a key signal event used by the malignant B cells of WM to survive and to grow. Thus, BTK is an important target for a therapeutic approach in WM.
Zanubrutinib is an oral BTK inhibitor that is approved by U.S. Food and Drug Administration for the treatment of adults with WM. The approval of Zanubrutinib for WM was based on data from the ASPEN study, a randomized, open-label study comparing Zanubrutinib with ibrutinib in patients with WM. The major response rate (MR) in the MYD88-mutated WM patients in the ASPEN study was 77.5% for Zanubrutinib-treated patients (4). The MR in MYD88-mutated WM patients treated Zanubrutinib and ibrutinib, as reported in the final ASPEN publication, was 78% for both arms of the study. A Novel and Effective Alternative to Ibrutinib. Zanubrutinib Waldenstroms provides a targeted approach for treatment, without needing to utilize traditional cytotoxic chemotherapy.
Addressing disease after previous therapy
Evidence of disease progression after a previous BTK inhibitor is an emerging clinical problem and could be caused by several factors including change of disease biology, suboptimal exposure, adverse effects or acquired resistance to BTK inhibitors.
While there are no defined standards for patients who have received prior therapy for WM, in general, there are several different classes of therapy that can be used, such as other targeted therapy (e.g. idelalisib), chemoimmunotherapy (e.g. bendamustine + rituximab), and the proteasome inhibitor (e.g. bortezomib) therapy. Patients may also be considered for enrollment on a clinical trial.
The choices between possible treatments for WM can be based on several features. The patient’s symptoms, their blood counts, and the IgM-related problems can all play a role in picking the best treatment for a given patient. Other factors, like the degree of response to a prior therapy, a patient’s comorbidities, and the potential toxicity of a given treatment, should also be considered.
Managing IgM-related complications
Waldenström’s macroglobulinemia is characterized by the production of large amounts of monoclonal IgM. Even in the absence of clinical symptoms, high levels of IgM can cause hyperviscosity syndrome leading to symptoms of headaches, blurred vision, transient neurological deficits and more.
The approach to managing WM and IgM-related symptoms is complex and requires consideration of a multitude of factors. That which effects treatment of the malignant lymphoplasmacytic cells and the ramifications of elevated IgM will be critical in managing patients with WM and associated hyperviscosity. Clinicians also need to monitor levels of IgM and consider them in the assessment of disease. Some patients with WM have decreasing levels of IgM during effective therapy, although others do not.
Balancing efficacy and safety
While most serious adverse reactions are reported to occur in less than 10% of patients taking Zanubrutinib, the drug does pose some risk for a variety of adverse reactions including decreased neutrophil count and platelet count, upper respiratory tract infection, rash, hemorrhage, bruising, diarrhea, pneumonia, and cough. In addition to risks of bleeding, effects on the cardiovascular system, infections and drug interactions as well as changes in blood counts must be taken into account when choosing a treatment for patients with WM and must be monitored accordingly.
Treatment sequencing and clinical trials
In WM, as more therapies become available to treat the disease, a strategy of treatment sequencing will become increasingly important. In many cases a patient who has responded well to one treatment may relapse on that same treatment. As a result, it is likely that a different mechanism of action will be required as a second line of treatment rather than administering the same treatment that has already failed the patient.
Access to investigational therapies in clinical trials represents an additional important therapeutic option for relapsed or refractory patients with WM. These trials can provide emerging therapies and establish optimal use of the new agent(s) in patients who have received prior therapy for their WM.
The importance of individualized treatment
Every patient with relapsed or refractory WM is different and therefore needs individualized treatment. There are several factors that need to be taken into account for making treatment decisions such as the type of WM, the prior treatments, the length of time of response to prior treatments, the symptoms, the IgM levels and any comorbid diseases, as well as the patients’ preferences and potential side effects.
Zanubrutinib is a selective BTK inhibitor that has recently been approved for the treatment of Waldenström’s Macroglobulinemia in adult patients with WM. The clinical development of Zanubrutinib Waldenström’s provides increasing evidence that BTK inhibition represents a valuable therapeutic option for WM.
Future directions
Additionally, new treatments targeting the same molecular pathway, different molecular pathways, and combinations of both are being investigated for their ability to improve durability of response, address resistance, and provide effective disease control with minimal toxicity.
As more clinical trials are developed for the treatment of patients with relapsed or refractory WM, the hope is that additional treatment options and sequences will be identified to manage this chronic and often unpredictable disease.
Conclusion
Waldenström’s macroglobulinemia (WM) is a complex and challenging lymphoma to treat in both the relapsed and refractory settings. The disease biology in addition to prior treatment(s) forms the foundation for the approach to management of relapsed or refractory WM and BTK inhibition is a mainstay in WM therapy with Zanubrutinib, an oral BTK inhibitor, approved in adult patients with WM.
Future therapeutic strategies for the management of WM are increasingly based on individual patient parameters such as molecular profile, prior treatment(s), duration of response, acceptable toxicity and the patient’s preference. To address the current unmet needs of relapsed and refractory WM cases, more evidence is required from clinical studies using current as well as novel WM therapeutics in different treatment sequences.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.
Amelia Hart, a psychology graduate from the University of Hertfordshire, has a keen interest in the fields of mental health, wellness, and lifestyle.
