Understanding the Evolving Strategies in WM Care and Management

The management of Waldenström macroglobulinemia (WM), a rare form of blood cancer, requires a nuanced approach with up-to-date treatments and the collaborative treatment of caregivers, according to Dr. Shirley D’Sa.

Utilizing these up-to-date approaches remain vital, as previous therapeutics in this treatment landscape relied heavily on toxic chemotherapies; however, these newer approaches, including BTK inhibitors, have greatly improved outcomes and reduced complications.

D'Sa, a consultant hematologist and clinical lead for the University College London (UCL) Hospital Centre for Waldenström’s Macroglobulinemia and Associated Disorders, sat down for an interview with CURE to delve into the nuances of treating WM.

She also serves as well as an honorary associate professor at the UCL Cancer Institute. She also serves as the hematological lead in the joint neurohematology service at the National Hospital for Neurology, Queen Square, London.

CURE: How has your approach to managing WM, a rare disease, evolved over time?

D’Sa: I've been involved in the world of WM for about 20 years. I trained and specialized in a hospital in London where I actually started off as a myeloma doctor, and there are many connections between WM and myeloma. The cell types share some characteristics, and in particular, there's the production of proteins which are so key to most people with WM in some form.

So, I began in the myeloma setting, and then I realized that there were a number of WM patients who would be in our clinic, separate from the lymphoma team's clinic. I gradually started putting them to one side and focusing a little bit on them. From a once-every-two-month clinic, it became once a month, then every other week, and now we're seeing 40 patients a week in our WM clinic at our center.

I have to say, during that time, there's been a steady array of advancements in the area and field, which are extremely positive in terms of unified criteria for diagnosis, for response to treatment, and then a range of genetic discoveries that have been made. These discoveries tell us much more about the biology of the disease and how it behaves, how to confirm or refute the diagnosis, and how to differentiate it from other quite similar conditions when you look under the microscope and overall.

How have treatment strategies for WM evolved over the course of your career

Over the years, it's been great; it's been great to witness the developments because, in the beginning, there was just a handful of chemotherapy treatments which, while quite effective in themselves, were also very toxic. The addition of Rituxan (rituximab), an antibody against CD20 found on B cells, which form part of WM, was a help and contributed to the improvement in outcomes. As time went on, in my own practice, we moved a little bit away from medicines like fludarabine. We actually did a number of high-dose chemotherapy treatments in some younger patients, like autologous stem cell transplants, and we tried to focus that treatment on those who were younger and had high-risk WM based on its biological behavior.

One has to bear in mind that back then, there were no targeted therapies for WM, so we had to make the most of chemoimmunotherapy. Regarding immunotherapy or Rituxan, that brings its own challenges, and over the years, we learned through investigators across the globe, notably the Boston group under Stephen Treon, about phenomena such as the Rituxan flare that occurs if IgM is raised and you give Rituxan, potentially causing a quite acute flare, which can lead to hyperviscosity.

So, over the years, we've nuanced the approach to managing WM by using different treatments in a more targeted and careful way, trying to circumvent potential complications. And of course, recently, I would say in the last 10 years, there's been the introduction and advent of targeted therapies, including BTK inhibitors.

At our center, we were involved from the early stages in trials of Imbruvica (ibrutinib) and also Brukinsa (zanubrutinib), both of which have proven to be extremely effective treatments. So yeah, it's been an interesting evolution throughout my career as a specialist because the disease area took off. There was also the gathering of an amazing community of physicians and researchers that continues to this day. And it's such a pleasure to be involved in that group because we work well together, and because WM is a rare disease, it's super important for that to happen. In fact,

Even with all these amazing advancements that have been seen within the world of this disease, peripheral neuropathy is a common and debilitating symptom of the disease. How do you approach balancing effective treatment with quality-of-life considerations within your practice?

Peripheral neuropathy is common in people with WM, but one has to remember that peripheral neuropathy is also prevalent in the general population. There are hundreds of causes of neuropathy. Some are more common than others, such as diabetes, and frankly, things like excessive alcohol consumption can damage nerves. Anything toxic to nerves over a long period can cause problems. So, we always consider this background when we assess a patient. We don't want to instantly attribute it to WM, because often, it's not the WM causing the problem.

Our approach involves a joint clinic where we see patients together. We bring our respective viewpoints from neurology and hematology. The patient's history is paramount — taking a detailed account of their neuropathy experience. How quickly did it develop? What makes it worse? What makes it better? What is the distribution? Is it mainly in the hands or feet? Do they have other symptoms? Do they have balance problems? Do they have autonomic symptoms, which relate to the autonomic nervous system that regulates blood pressure and appetite? A detailed history is crucial, followed by a clinical examination, particularly of the nervous system.

My colleague conducts this in a very systematic and recorded manner. We then follow up with additional tests, such as imaging scans like MRI and inflammatory nerve antibody testing. The most common antibody is against myelin-associated glycoprotein. Sometimes IgM [immunoglobulin M] antibodies have this property. We sequentially consider the possible causes, and occasionally, we biopsy a nerve if necessary. There's quite a range of possibilities, and only if we feel there is as firm a connection to WM as we can prove — and the patient has progressive symptoms — do we consider offering or recommending treatment.

How do you approach the treatment of this often debilitating side effect?

Ultimately, the treatment involves addressing the underlying WM, because the WM cells are responsible, indirectly via mechanisms like antibody production or occasionally by directly invading nervous tissue. So, it's really about very clear diagnostics, consistent testing, a careful analysis of causality and establishing very good, clear guidelines for each patient.

What are we trying to achieve in that patient? If they have progressive disability, for example, then it's almost an emergency to get them treated. If it's mainly sensory symptoms like pain and loss of temperature, they are less likely to respond well to treatment, and we will then address that with symptomatic measures such as special pain-relieving medication, given in a supervised manner.

People do worry if pain medication might mask anything, but the answer is no. It is important to monitor the rate of change, so we do keep people under follow-up. If people have what we believe is a WM or IgM-related neuropathy, then we will consider treatment with Rituxan, chemotherapy plus Rituxan or BTK [Bruton tyrosine kinase] inhibitors, for example. This is not done sequentially but based as far as we can on guidance.

There are some pretty up-to-date guidance documents coming out from the recent international workshop, and one will be on peripheral neuropathy. So, I hope this is helpful for a professional audience, but it's worth pointing that out to your caregiver or doctor if you encounter this, because it's something that many doctors find quite challenging to manage — neuropathy — as it's a tricky subject, and hematologists are not neurologists. Close collaboration is essential.

The other thing to remember is that if people are facing problems with their functionality, there are many ways to adapt. There are aids to help you handle things, pick things up, prevent foot drop, etc. So ideally, there should be a comprehensive strategy to treat these patients.

Transcript has been edited for clarity and conciseness.

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