 Waldenström macroglobulinemia is an indolent non-Hodgkin lymphoma. It’s an interesting disease that shares many features of mature lymphomas as well as plasma cell dyscrasias.

Waldenström Macroglobulinemia falls under the umbrella of non-Hodgkin lymphoma because it’s a disease that’s made up of B cells much like many lymphomas that we see. And morphologically, when we look in the bone marrow of patients who have this disease, there are mature B cells, much like the cells we see in lymphoma patients, but also plasma cells. These are cells that we would normally see in patients with multiple myeloma. And there are also cells called lymphoplasmacytic cells that fall in between the two. And so they have features of both.

The way the cells in a patient with Waldenström macroglobulinemia differ is that typically in a lymphoma, you’ll see one type of B cell, that being a mature B cell; but in Waldenström patients you actually have a smorgasbord of B cells. You’re going to have those mature B cells that you see in lymphoma patients, but you’re also going to see these lymphoplasmacytic cells as well as plasma cells. And plasma cells are the cells that we normally see in multiple myeloma patients. So the difference is that you’re going to see the spectrum of cells. In deference to lymphoma patients, most of the disease in patients with Waldenström macroglobulinemia tends to be found in the bone marrow, much as we would see in somebody with multiple myeloma.

It’s very important for one to remember that although this was a lymphoma, it differs because it also makes the IgM protein. This protein can cause many of the disease manifestations. In fact, maybe up to half the disease manifestations that we see in patients with Waldenström Macroglobulinemia are the result of the IgM protein that’s produced. The IgM protein, if it’s in great excess, can make the blood very thick. This can lead to what we call hyperviscosity syndrome, in which you can see blood vessels begin to crack and you can see bleeding. This can lead to loss of vision. It could lead to headaches. It could lead to nosebleeds.

But also in deference to what we see with the other types of immunoglobulins—the IgGs and IgAs, for instance&mdash;IgM can also attack various structures of the body. And so it could attack red blood cells and cause hemolysis. This is a bursting of the red blood cells. They can attack the nerves and cause neuropathy. So there’s really a lot of mechanisms by which the IgM can inflict pain and suffering on patients. And that’s why it’s important to keep IgM in mind when one is looking at the patient trying to determine symptoms. But also keep it in mind as you’re trying to see if a drug is particularly effective. You really want to see the IgM going down because it can cause a lot of manifestations of disease.

The Nature of Waldenstrom Macroglobulinemia

 One of the most interesting questions we’re often asked is, What are the risk factors that can cause Waldenström macroglobulinemia? And I think it’s really important to know that this is a disease that has a high hereditary basis. In fact, up to 25 percent of all patients may have either a first- or second-degree relative with either Waldenström macroglobulinemia, because we do see in families just Waldenström macroglobulinemia running through multiple generations, or other types of B-cell malignancies, including CLL [chronic lymphocytic leukemia].

We see other types of lymphomas as well as multiple myeloma. For this reason, we believe that in many patients there is really a hereditary or genetic basis. But in the other 75 percent of patients who don’t have this kind of hereditary background, there’s been a lot of speculation about rheumatoid diseases possibly predisposing. We know, for instance, people that have Sjögren syndrome, which is an autoimmune disease, have a very high likelihood or predisposition to Waldenström macroglobulinemia. So, this has also been discussed. And chronic infections potentially might also be at the heart of some of these cases. But in reality, the genetic basis for those patients remains to be discovered.

So monoclonal gammopathy of undetermined significance or unknown significance, or MGUS, is a precursor state to Waldenström macroglobulinemia. We believe now that almost all patients go through this phase. This is where the IgM monoclonal protein can be detected in the blood, but if you go searching for the disease in the bone marrow, for instance, you’re not going to find it. If you use cleverer molecular technologies like looking for the MYD88 mutation or use flow cytometric analysis, you might start seeing that those cells are there. But at least under the microscope, because a pathologist would be working to look at for evidence of disease, one wouldn’t find it.

And this is what is considered MGUS: to have the IgM protein without really pathological evidence of the disease. These are usually patients whose course is not well known. If it’s a patient that has MGUS, the probability that they will revert to some type of malignant condition is somewhere around 2 percent per year. And so, if the patient lives with this long enough, they may end up developing a malignant entity. But since this is also a manifestation of older people, most patients with MGUS will never really see that happen in their lifetime.

When one discusses Waldenström Macroglobulinemia, one has to keep in mind that there can be an ethnicity impact. We tend to see an increased number of cases among individuals of Ashkenazi Jewish descent. We also very, very, very rarely see it in African-Americans, for instance, and this is interesting because when you look at multiple myeloma, it’s exactly the opposite. And there have been some very elaborate studies that have looked at people whose descendancy comes from West Africa compared with Caucasians. And in fact, igM MGUS, the precursor state of Waldenström macroglobulinemia, is very, very rare among people of West African descent, and this might be one of the reasons why we see ethnic and racial differences.

Risk Factors in Developing Waldenstrom Macroglobulinemia

 The diagnosis of Waldenström macroglobulinemia requires a couple of things. First, it requires detection of the IgM monoclonal protein. So that’s a blood test. One would also want to get a bone marrow biopsy, because one wants to see that there’s evidence of an infiltrate in the bone marrow. These are really the essential components of being able to establish a diagnosis. We often also get molecular diagnostic testing for the MYD88 mutation. This is a mutation that’s found in about 95%, maybe even up to 97%, of patients with Waldenström macroglobulinemia. Having this aids us greatly in being able to make the diagnosis of Waldenström macroglobulinemia and differentiate it from other IgM-producing diseases.

The symptoms that can drive individuals to seek medical attention for Waldenström macroglobulinemia can vary quite a bit because there are multiple manifestations of the disease. Anemia tends to be a central feature for many patients. And so you’ll hear patients complaining of fatigue and anemia who can be at the root of their fatigue, but the anemia can be caused by multiple reasons. You can have a lot of Waldenström macroglobulinemia cells in the bone marrow crowding out all the normal red blood cell-producing cells.

You can get this phenomenal hemolysis, where the IgM protein binds to the red blood cells and causes them to burst. But you also see iron deficiency in patients with Waldenström macroglobulinemia, and this is because of a protein called hepcidin that’s overproduced either by the Waldenström macroglobulinemia cells or in reaction to the Waldenström macroglobulinemia cells because of the cytokines they make. And when this happens, what you see is hepcidin blocks the ability of a body to absorb iron from the gut, but it also makes macrophages and monocytes that sit in the bone marrow gobble up all the iron. And it’s like squirrels hoarding nuts. They hold on to that iron, and they deprive the red blood cells from getting it. As a result, these patients have a functional iron loss. And it’s really important to get iron studies when one is working up a patient with Waldenström macroglobulinemia, because many times giving intravenous iron can help remedy that particular reason for having the anemia in Waldenström macroglobulinemia.

It’s important to know that diagnostic challenges can exist in making the diagnosis of Waldenström macroglobulinemia. Being able to have the MYD88 mutation results is very helpful, because about 95% to 97% of all patients have this. And then you can start discriminating this particular diagnosis from others. For instance, IgM myeloma, you never see the MYD88 mutation, but you see cytogenetic findings that are very myeloma-like, like the translocation in the two chromosomes, 11 and 14, which is very typical in that.

Marginal zone lymphomas, which can also make IgM, look a lot like Waldenström macroglobulinemia, but the percentage of cases that actually have the MYD88 mutation are much less common, somewhere around 6% to 10% as an estimation. Sometimes, rarely, CLL [chronic lymphocytic leukemia] can also look like Waldenström macroglobulinemia. It can make IgM, but again, the percentage of cases that actually have the MYD88 mutation are very low.

The real pickle, if you will, is in those patients who don’t have the MYD88 mutation but can look very much like Waldenström macroglobulinemia. And we have to acknowledge that maybe about 5% of all cases of Waldenström macroglobulinemia are like this. Very excitingly this past year we finally sequenced the genomic sequencing of those patients who don’t have an MYD88 mutation but have Waldenström macroglobulinemia, and we’ve discovered several recurring mutations. And I think this is going to help in the long run, being able to sort that patient population as well who don’t have MYD88 mutation but really otherwise look morphologically and pathologically and clinically like Waldenström macroglobulinemia patients.

Waldenstrom Macroglobulinemia: Establishing a Diagnosis

 When one considers a workup for a patient with Waldenström macroglobulinemia, there are a number of blood tests that we will usually get as a standard, if you will. But there are a number of other blood tests that often are taken depending on what we hear in the history of a patient with Waldenström macroglobulinemia. But at the core, what you want to do is get the IgM monoclonal protein. This is done by doing serum protein electrophoresis. You would like to get ideally the total IgM level, the total IgA and IgG. You could ask, Why IgA and IgG? Because these are the good antibodies that normally protect us against infection. And in patients with Waldenström macroglobulinemia, they can be very, very low and sometimes contribute to the recurrent infections that we see.

You’d want to get complete blood counts. You want to know what somebody’s white blood count looks like, you want to know if they’re anemic—so you want to get a hemoglobin or a hematocrit&mdash;and you also want to know what their platelet count is. Platelets actually protect us against bleeding, and so you want to know if those levels are normal or not.

And then we often get the beta-2-microglobulin level. This is an important prognostic marker that we often use to see how a patient is doing. We want to know how their renal function and liver function are. Those tests are usually done as part of our routine. And depending on how the patient presents, there may be other tests that may also be required, those that help us understand the source of neuropathy if a patient comes in, or if they’re having cold intolerance, we would look at cold agglutinins or cryoglobulins. These would be tests that your physician should to be able to react to, based on your history, and obtain.

And then a bone marrow biopsy is very, very essential. We want to know if their lymphoblastic acidic cells that can be detected look like they’re clonal and part of the disease process. And we would use also the bone marrow biopsy to do molecular diagnostics. We would look for the 

And then lastly CT scans. When patients are diagnosed with Waldenström macroglobulinemia, about 20% of them have enlarged lymph nodes or an enlarged spleen, and sometimes we also see other manifestations of disease outside the bone marrow. So for this reason, you’d want to be able to get CT scans in a patient who’s being worked up for Waldenström macroglobulinemia.

There are a number of factors that contribute to the International Prognostic Scoring System. This can include age, being 65 and over. It can include the blood counts, looking at the hemoglobin level itself if it’s 11.5 or under. It can include the serum IgM level, which is based on grams per deciliter, so over 7 grams per deciliter. It can include other factors as well, but those are the essential components of the International Prognostic Scoring System [IPSS].

There’s also a revision now that investigators are working on to revise this prognostic scoring system, keeping in mind that some of these factors need updating. Beta-2-microglobulin is often part of most prognostic scoring systems. That remains. Blood counts are the subject of some prognostic scoring systems but not others. The levels tend to differ. Age is always a factor.

I think what is important for patients to know is that we still don’t know what to do with this information. It becomes one of our debates over and over: how can we use prognostic scoring to make treatment decisions? Well, as of today we can’t. And this is why things just have to get better, and personalized medicine using really genomics is going to help us get at that.

We do know that MYD88 plays a role. Those patients who have the mutation, which is the vast majority of patients, can do better from a survival point of view. And those who don’t have it tend to be at higher risk of disease transformation to a more aggressive lymphoma. And so really getting at the heart of the genomics is very important as far as better understanding the prognosis of the disease. But IPSS, we just don’t know how to use it to make treatment decisions today.

Factors Impacting a Diagnosis and Prognosis of WM

 I think when a patient is diagnosed with Waldenström macroglobulinemia, there are a number of critical questions that emerge. The first really is, do I need treatment at this time? And sometimes both the clinician as well as the patient can be very conflicted on this point. There is a scoring system that we often use that tells us if a patient requires therapy. For instance, if the blood counts are under a certain level, like a hemoglobin less than 10 or a platelet count less than 100,000, we will often treat the patient, but only if those symptoms or those findings are because of the Waldenström macroglobulinemia itself.

We look at peripheral neuropathy for those patients who have it, maybe up to a quarter of all patients who have it. Is it moderate? Is it severe? How fast is it progressing? It would be one of the things that we would actually think about. Does the patient come in with hyperviscosity symptoms? Are they having problems with their vision or nosebleeds? That’s an acute emergency. That patient is going to be requiring therapy. So I think it’s very important once the diagnosis is made is to determine if the patient requires therapy because with a lot of patients, watch and wait is very appropriate: Maybe up to 30 percent of all patients based on the series that we have here at our institute. So I think that becomes the most important question.

And then, of course, we decide what to treat with if you require therapy. And make no mistake that even today we don’t have any trials that tell us that one answer is better than the other, and that’s why being able to have the patient come to a center of excellence ideally to make those treatment decisions, perhaps even participate in clinical trials, is very important. And I think it’s important to keep in mind for a patient that once that decision of needing treatment is required, really look and see what clinical trials are available, look and see what the current state of therapy is.

Some of these therapies are leveraged by the underlying genomics. For instance, BTK [Bruton tyrosine kinase] inhibitors are a good idea if you have the MYD88 mutation. If you also have the CXCR4 mutation, they may still be a good idea depending on how fast you need a response. And so these are the things that we talk to patients about once they come here and see us.

I think an important decision point is when to start therapy. Many patients are often not wanting to start therapy, when in fact, it’s appropriate to do so. And other times we find that patients have come with the recommendation to start therapy, when in fact, they didn’t need at that point in time to have therapy started. For this reason, I recommend being able to seek the expertise of somebody who sees Waldenström macroglobulinemia patients. They’re uncommon. To be quite honest, they’re uncommon. But going to a center of excellence is very important because that decision making can be made with the benefit of an expert. And in many cases, not most cases, the patient can then go back to their local oncologist and perhaps be better informed and coguided by a Waldenström macroglobulinemia expert along with their local hematologist-oncologist.

Waldenstrom Macroglobulinemia: When to Initiate Therapy

 Historically we’ve leveraged Rituxan, either by itself or more commonly with other drugs, in the first-line treatment of Waldenström macroglobulinemia. The traditional drugs that we’ve used have included alkylating drugs, either cyclophosphamide or more recently bendamustine. Proteasome inhibitors like bortezomib, which is also known as Velcade, or carfilzomib, also have been used.

We have shied away from using nucleoside analogs like fludarabine or cladribine because of the effects on the bone marrow and the immune system, as well as the potential for increased risk of secondary malignancies that have also been recognized with that class of drugs. That used to be the mainstay of therapy in the past but not so more recently. Those predominantly form the core of drugs that we’ve traditionally used to treat people with Waldenström macroglobulinemia.

Plasmapheresis is a modality that we use particularly for patients who have very high IgM levels and have symptomatic hyperviscosity. That’s an oncological emergency. If a patient is coming in, they have high IgM, they’re having nosebleeds or headaches or blurry vision, and there could be other symptoms as well. The first, second and third right answer is plasmapheresis, plasmapheresis, plasmapheresis. You need to get that out of the way.

In patients who have very high IgM levels but who don’t have symptomatic hyperviscosity, if they’re going to get rituximab, we often recommend that plasmapheresis occur because rituximab can actually make the IgM go up even further and can prompt hyperviscosity. So we either use plasmapheresis or we give the chemotherapy without the rituximab until we can get the IgM down.

But there are also circumstances in which the patient presents with severe cryoglobulin. That’s when the IgM falls out of solution because of cold exposure. We might use plasmapheresis, but then we put warmers on the machine to make sure that we’re not cooling the blood down. Severe cold agglutinins. That’s when the IgM can bind to red blood cells under cold conditions. Same thing. We sometimes might use it. Again, we put warmers on.

For severe peripheral neuropathy, when it’s progressing very, very fast, we will often use plasmapheresis in such cases until we can get the therapy to start working. So those are the examples that we’d use plasmapheresis. One size doesn’t fit all, but I think it’s important to recognize that this could be a very helpful modality to get the IgM down, at least for a couple of weeks’ time while therapy sets in and works. And some patients do require ongoing plasmapheresis, so it’s important to think about who that patient might be and how to integrate definitive therapy.

A Historic Perspective on Frontline WM Management

 We have an evolution right now because of all the new BTK [Bruton tyrosine kinase] inhibitors that either have been approved, like ibrutinib, or are in the pipeline that have shown efficacy in patients with Waldenström macroglobulinemia. And BTK inhibitors represent a very important new mainstay of therapy for this disease. We know that in relapsed and refractory patients, ibrutinib is now approved by the FDA. This is a very, very effective drug in patients with Waldenström macroglobulinemia, producing very high response rates and even durable responses. And we also know that these drugs are effective in patients who are seeing treatment for the first time.

There’s also a study looking at the combination of ibrutinib plus rituximab alluding to the fact that we can start combining BTK inhibitors with monoclonal antibodies. So we have really a very exciting, new and bright future ahead of us. And what I think is important for patients to know is that this is all homegrown. Unlike in the past, when we borrowed drugs from other diseases and just saw how they worked in Waldenström macroglobulinemia patients, this all came because of genomic discovery and this was centered on MYD88, and knowing that MYD88 activated ibrutinib tyrosine kinase, BTK, allowed us to be able to develop BTK inhibitors for this disease. And so this is completely homegrown, and I think it really represents the future of new treatments for Waldenström macroglobulinemia.

A very good question is, how do we select today in the absence of head-to-head comparisons? And this is where I think having the skill of somebody who works in the field of Waldenström macroglobulinemia is very, very important. We try to personalize therapy around the patient. We try to take into account how fast we need a response. We try to take into account what the risks of therapy are. What are we exposing our patients to? Because some of these drugs can have long-term side effects. And it’s important, especially now that we have new drugs emerging like the BTK inhibitors, to keep some of these risks in mind from prior therapies that we used to use.

We consider both patient factors as well as disease factors. And in fact, for our practice, genomics are very important. We take into account the patient themselves, the age of the patient, and how well their physical status is. But the genomics play a big role. We want to know what their MYD88

mutation status is, because that helps us understand the role of BTK inhibitors compared with other traditional therapeutics. So as part of the workup for our patients, being able to get the genomics is very important.

Waldenstrom Macroglobulinemia: Evolving Frontline Treatment

 Treatment tends to change in the second line for many patients because they’ve been exposed to particular agents in the first line. If they’ve had a long response, we will sometimes go back and reuse that therapy. But otherwise, more and more these days if the patient hasn’t seen a BTK inhibitor, we tend to go to a BTK inhibitor for the treatment of Waldenström macroglobulinemia. And this is really where the field has changed considerably, because in the past we either tried to recycle frontline drugs or use an alternative frontline agent, but now more and more, we’re resorting to the use of BTK inhibitors because the number of prior lines of therapy doesn’t make a difference.

Whether a patient is relapsing after a response or was refractory to that frontline therapy doesn’t appear to make a difference. So for all these reasons we know that BTK inhibitors represent very effective targeted therapy in the treatment of Waldenström macroglobulinemia. And this is really becoming more and more now the mainstay of relapsed — at least first relapsed therapy &mdash; in Waldenström macroglobulinemia.

I think it’s really important when one looks at a patient with Waldenström macroglobulinemia that you keep the sequencing in mind. Some drugs that we use sometimes will affect the stem cells, and so it becomes harder to be able to give a particular therapy. The use of Rituxan is also something that we’re very concerned about because IgA and IgG levels can go down. These are the good antibodies that protect against infection. And so particularly with reusing rituximab, one can see that these levels go down so much so that the patient has recurring infections, and many times we have to give replacement therapy with intravenous immunoglobulin, giving that back because the good cells have gone away and so has the IgA and IgG.

So in many of our patients we tend to spare now the use of ongoing Rituxan or maintenance Rituxan therapy. It’s not to say that we wouldn’t give maintenance Rituxan, but we might be more willing today to cut off that maintenance earlier than we would have in the past knowing what we see with IgA and IgG levels going down.

Quality of life is very important. I think it’s important to keep in mind both the short-term side effects of therapy as well as the long-term ones. When we use proteasome inhibitors, we are very concerned about the neuropathy that we’re seeing, and many times the neuropathy resulted in a side effect that was permanent for some patients. And debilitating in the sense that if you were somebody who relied on your feet or your fingers to be able to do your job, which is most of us, using a proteasome inhibitor, particularly in the past like using bortezomib, was oftentimes problematic.

Looking at the immune system, many of the drugs that we used to use in the past also compromise the immune system, and patients ended up with recurring sinus and bronchial infections. We also are concerned about secondary malignancies. Alkylators that we used a lot in the past could set patients up for either secondary malignancies or myelodysplasia where the bone marrow becomes injured. And this is why quite honestly seeing the evolution today to new drugs, particularly the BTK inhibitors, is very exciting for us because a lot of the problems that we used to see with our therapeutics in the past have been overcome now with these new drugs that represent really targeted therapy for this disease.

Selecting Therapy Through Multiple Lines in WM

 The rationale behind targeted therapies that you’re really getting at the Achilles’ heel of the tumor itself. You want to be able to rationally shut down the pathway that’s contributing to the growth and survival of Waldenström macroglobulinemia cells. And by doing so you want to also spare all the other good cells, including good B cells, that are out there. And I think this is very important because it alleviates both short-term as well as long-term toxicities for patients due to the drug itself.

So using targeted therapy either alone or in combination has been one of the areas of exploration in Waldenström macroglobulinemia. We and others have looked at use of proteasome inhibitors, mTOR inhibitors, as well as BTK inhibitors in Waldenström macroglobulinemia. Proteasome inhibitors are often used in combination with steroids as well as monoclonal antibodies like rituximab. There, this results in very high overall response rates in patients, even durable ones. In fact, in our study of Velcade, which is also known as bortezomib, dexamethasone and rituximab, we saw in the frontline setting median progression-free survival, that being the average amount of time that a patient remained in a response upward of and over 5 years’ time. So we know that these are very effective drugs. The converse is that you tend to see neuropathy as well as good immune cells being injured and as a result, patients can face increasing risk of infection.

The mTOR inhibitors were a class of drugs that were meant to shut down a very important growth and survival pathway that is mediated by AKT. This is one of those mastered genes that helps control a lot of growth and survival programs. But what we found in our studies was that despite that we were getting good responses and response rates and we had a lot of toxicity. And this is one of the reasons why we tend to use those more in the third- or fourth-line setting of treating patients with Waldenström macroglobulinemia.

BTK inhibitors, Bruton tyrosine kinase inhibitors, are perhaps right now what we’re most excited about. These are inhibitors that actually clobber a very important protein called Bruton tyrosine kinase. This is turned on by the MYD88 mutation, which is found in about 95% to 97% of patients. And so it’s on the pathway that turns on very important growth and survival proteins in the nucleolus that help keep these cells alive and growing.

I think it’s important for patients to know that BTK inhibitors are now a very important mainstay of treating Waldenström macroglobulinemia. And really the art now is trying to optimize their use in Waldenström macroglobulinemia. A lot of this is now based on what we’re learning from the genome. If the patient has an MYD88 mutation, we’re seeing that BTK inhibitors are a great idea. If they also have the CXCR4 mutation, then here’s where the art is really necessary, because those patients that have CXCR4 mutations are likely to have a lower response rate, particularly the deeper responses. They’re likely to have a slower time to get those responses, and they’re also more likely to progress, have their disease progress on a BTK or on ibrutinib, which is the drug that we have the most follow-up for at this point in time. And so, we’re looking now at developing CXCR4 antagonists, drugs that actually suppress CXCR4. Maybe this is one way we can overcome this.

We know from the study that was done just recently combining ibrutinib with rituximab that at least the time to getting into response was improved. But we still saw patients progressing faster who had the CXCR4 mutation. So those are the kind of innovations that we’re now working around, looking at combinations that we can actually put together to treat patients when they have a mutation like CXCR4. And there are a lot of really good ideas out there. There are a number of CXCR4 antagonists that we’re looking at. We’re also looking at the drug venetoclax, which is a BCL2 inhibitor. This has also shown a lot of activity in Waldenström macroglobulinemia patients, and the combination with ibrutinib is one of the combinations that we’re looking at starting this year in a clinical trial.

Targeted Approaches in Waldenstrom Macroglobulinemia

 We will often sit down and tell patients about every drug that may be considered for their treatment. We’ll talk about the efficacy of those drugs. And when we talked about efficacy, we look at the overall response rate as well as what the depth of response is. That’s a very important patient question. Will this get me into a deep response, and how long will that response last for?

It’s also very important to ask about adverse effects, or side effects, to know what those side effects are, both the short term, while you’re on therapy, as well as the long-term ones. Am I going to see something further down the line? And I have to say that many of the studies that we did, it was really the side effects further down the line that we were often surprised by. And so this is really why we need to do clinical studies and maintain vigilance over long periods of time.

Bruton tyrosine kinase [BTK] inhibitors also have side effects, and it’s very important that the physician discuss those potential side effects with the patients. Typically, this would include a decrease in blood counts. This tends to be more of a manifestation of people who have seen a lot of prior therapy. We’ve seen very little decrease in blood counts when the patients get treated as their first treatment with ibrutinib as an example in the study that we ended up doing.

There’s always a risk of atrial fibrillation. This is an arrhythmia of the heart. We see this now in somewhere between 10% and 15% of all patients. It’s important to keep in mind that there could be other reasons for atrial fibrillation, so one wants to explore for that as part of somebody’s workup. An amyloid of the heart is one of those etiologies.

Now, getting atrial fibrillation on a BTK inhibitor doesn’t mean you have to stop that therapy. In fact, with very few of our patients treated with ibrutinib did we actually have to stop the drug. We’re often able to manage around the atrial fibrillation. We do this by first making sure that it is probable that it’s the drug that’s causing this. And so in many of our patients, we’ll then, working with a cardiologist, start an antiarrhythmic drug. If that doesn’t work, we will consider cardiac ablation if it’s appropriate for the patient. It’s one of the techniques that’s used to help cauterize the tracks that may contribute to the atrial arrhythmia. And then in some cases we’ll just put the patient on an anticoagulant, a blood thinner, in order to make the atrial fibrillation safer. Those were all things that should be taken in the context of a cardiologist, but it’s important for the patient to know that even in the setting of atrial fibrillation, in the vast majority of cases, we can continue therapy.

Bleeding is also another risk that we see with BTK inhibitors. Usually these are minor in nature, such as bruising. But if you’re going to have a procedure, it’s very important for the patient to know that they need to stop the drug before and after the procedure. The length of time should be determined with your doctor because not every procedure is created equally, and so it’s very important. And also think about whether or not the procedure can be varied. We sometimes have talked to the surgeon only to realize that we didn’t need the big operation, that perhaps an alternative procedure could be done. So those are all the discussions that you would have.

There are also other side effects with BTK inhibitors that your doctor would know more about that could tell you a little bit about those. There are foods and supplements that one may need to also avoid during the time you’re on a BTK inhibitor. I remember when we had patients coming in on fish oils. They were taking marine oils. They were seeing a lot of bleeding from their nose while they’re on a BTK inhibitor. And we recognized that it was really the fish oil thinning out the blood. We stopped those, and the bleeding went away. So keep in mind that there could be things that could also provoke bleeding that are not good ideas to have it together with a BTK inhibitor.

BTK Inhibitors in WM: Understanding Safety/Efficacy

 One of the important aspects of treating a patient with Waldenström macroglobulinemia is involving other individual physicians who may bring additional expertise to the treatment of a Waldenström macroglobulinemia. We know that peripheral neuropathy can occur in about 25% of all Waldenström macroglobulinemia patients. We also know that sometimes the Waldenström macroglobulinemia cells can get into the brain and spinal cord and cause a syndrome called the Bing Neel syndrome. And this is the type of patient who one would want to have a neurologist onboard to be able to do all the important testing that’s required.

I think it’s important for patients with Waldenström macroglobulinemia to note two very important things. One, survival is changing, all for the better. When I first got involved in macroglobulinemia many, many years ago, people used to talk about overall survival of about 3 to 5 years. That’s out the window now. Our most recent survival curves now show that survival may be as high as 18 to 20 years plus. And I want to emphasize the word plus, because that’s how much things are changing. We have new drugs — you know now many new drugs available to us that I think are going to change the future even further. So it’s important for patients to keep that in mind.

Now, that’s not to say that every patient is benefiting the same, which is why we still have a very important mission ahead of us. I think it’s also important for the newly diagnosed patient to understand that we also have one other advantage, and that is that we actually understand the genomics of this disease better than they do for many other diseases that patients have with hematological cancers. We know what the key mutation drivers are, and this is really enabling us now to innovate new drugs at a pace that was never seen before. So the future is really bright. We’re seeing only the beginning of new drugs that actually are emerging that are truly targeted in nature for this disease. And for me really it couldn’t be a more exciting time to be involved in Waldenström macroglobulinemia.

BTK Inhibition for Waldenstrom Macroglobulinemia

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