Pathophysiology, symptoms and common genetic mutations associated with Waldenström macroglobulinemia (WM)

DR LOVE: Welcome to Oncology Today: Waldenström Macroglobulinemia Edition, a special audio program focused on recently approved and emerging strategies. This is medical oncologist Dr Neil Love.

I met jointly with Professor Meletios Dimopoulos and Dr Steven Treon, and to begin, Dr Treon talked about the pathophysiology and symptoms associated with Waldenström.

DR TREON: When we talk to patients, first off we like to make them aware that patients with Waldenström’s can present with various symptoms. They can range, most commonly, with cytopenias, anemia being the most common. We also see various problems associated with IgM. Peripheral neuropathy is a good example related to IgM. We also see that when the IgM levels are high, patients can present with hyperviscosity crisis. There are many different facets of how the disease can present, and that’s really important to know, because sometimes we have to tailor our therapy around those particular needs.

DR LOVE: Thanos, can you talk a little bit about what’s been learned in terms of genomics in Waldenström’s?

PROF DIMOPOULOS: I think the main advancement in the understanding of the disease has been the discovery by Steve Treon and his group of MYD88 mutation, which occurs in more than 90% of the patients with Waldenström macroglobulinemia and is not only helpful in defining the disease in many cases but also maybe as a prognostic factor. And also, it may explain the action of a class of agents named BTK inhibitors. I think this knowledge, along with mutations of another gene, the CXCR4 gene, have been instrumental in the understanding of the disease and in the development of therapies.

Somatic mutations in MYD88 (L265P) and CXCR4 and implications for prognosis and therapy

DR LOVE: Steve, can you talk a little bit more about what’s known in terms of the genomics of Waldenström’s and in your mind how that ties into the efficacy of various biologic agents, including BTK inhibitors?

DR TREON: I think, Neil, if there’s one thing to say, it’s wonderful to see that whole genome sequencing and genomics really have played out very nicely in Waldenström’s. In fact, it’s a poster child, I think, for how we can leverage the genome to make advances in therapy.

And whole genome sequencing allowed us to understand that there was this highly recurring mutation in the MYD88 gene. This is normally a component of the innate immune system, so when cells are triggered by viruses or bacteria through receptors called the Toll receptors. They activate MYD88. You have the mutation, and when you have this mutation in MYD88, this protein self assembles. It doesn’t need any more any external stimulus, and it continues to fire on. And those signaling cascades depend on Bruton’s tyrosine kinase in large part. This is why our ability to advance BTK inhibitors became realistic.

And the other important gene, as Thanos was also alluding to, is a gene mutation in CXCR4. This is a receptor that normally responds to stromal derived factor 1, made by the bone marrow stroma. And the interesting role about this mutation is that it can explain hyperviscosity, high IgM levels if you have it, particularly if you have the nonsense variant where a stop codon is introduced and part of the molecule is lobbed off. These are the patients, because of regulatory problems that occur with this loss, are the ones coming in with the high IgM levels and symptomatic hyperviscosity. And the other part to this is that CXCR4 mutations also, in various modeling that’s been done, appear to be associated with drug resistance against various therapeutics, including the BTK inhibitors.

DR LOVE: Excuse my naïveté, Steve, but would these be considered driver mutations?

DR TREON: These are somatic activating mutations. So you won’t find them in the germline. They will be in the tumor. The MYD88 mutation can be found in several other B-cell malignancies, but the highest prevalence is in Waldenström’s. Somewhere between 95% and 97% of the patients have it.

And the CXCR4 mutations are actually relatively confined to Waldenström’s. You do see it in a couple of other diseases rarely, but it’s really a hallmark also of Waldenström’s. We see it between 30% and 40% of all patients have these mutations.

DR LOVE: Thanos, how does this vision, in terms of the biology of Waldenström’s, compare to our understanding of myeloma in general? Do you, for example, do you see these mutations in myeloma?

PROF DIMOPOULOS: No. I mean, essentially not. And actually, it is whenever you have this rare entity of IgM monoclonal protein associated with, let’s say, lytic bone lesions or with a pure plasmacytic infiltration, I think MYD88 may be helpful to differentiate the 2 entities: Waldenström’s macroglobulinemia versus IgM myeloma. Multiple myeloma is a much more complex disease, and so far there has not been a mutation or an abnormality that it’s very prevalent or so prevalent in myeloma as is MYD88 Waldenström’s.

DR LOVE: Steve, any comments about the biology of myeloma compared to Waldenström’s?

DR TREON: Yes. I mean, they’re very different entities. You’ve got the relative indolency associated with Waldenström’s versus the more aggressive presentation with multiple myeloma. But that being said, Waldenström’s also has subsets — patients who don’t have the MYD88 mutation. These are individuals that are at higher risk of death. Their disease tends to transform. And when you look at the underlying mutations that define those patients that don’t have the MYD88 mutation with Waldenström’s, they tend to have genomics that look a lot like diffuse large B-cell lymphoma.

DR LOVE: Wow.

DR TREON: This is one of the reasons why we think that this group in particular is at higher risk of transformation and early death. And when you also model out their mutations, they all tend to be under BTK, and they are NFKappa B activating. And this is one of the reasons why we see the relative paucity of activity in the MYD88 wild-type folks for BTK inhibitors.

Diagnostic criteria for WM

DR LOVE: Before we get into a couple of cases, Thanos, can you talk a little bit about the diagnostic criteria to make the diagnosis of Waldenström’s?

PROF DIMOPOULOS: Yes. The diagnosis is pretty straightforward. It starts by the identification of monoclonal protein in the serum, that by the use of immunofixation shows that it is IgM kappa more often — less often IgM lambda. And, of course, in order to diagnose the disease you need a bone marrow infiltration by a variety of cell serrating — ranging from lymphocytes to lymphoplasmacytic cells to plasma cells. And these days the detection of MYD88 mutation is very supportive of the diagnosis of Waldenström’s, but as we mentioned, there are unusual cases that we may have MYD88 wild type.

On top of this, there is extranodal involvement by means of splenomegaly in about 20% of patients. And the more frequent lymphadenopathy, usually small-size enlargement of lymph nodes in the abdomen or the chest. And as Steve mentioned before, there are a variety of symptoms and signs that are indicators that the patient may need or may not need treatment.

Case (Dr Treon): A man in his late 60s with WM experiences an IgM flare and worsening peripheral neuropathy during first-line treatment with rituximab

DR LOVE: Maybe we can kind of get into that by — in terms of actual management of patients — some of the cases that you brought in here today. Steve, maybe we can start out with your 68-year-old man, if you could just briefly talk a little bit about how he presented.

DR TREON: This was a 68-year-old individual. He was diagnosed with Waldenström’s after he came in with a hive-like rash. And he had blood testing that showed that he had an elevated total protein, and he had an IgM monoclonal protein. He was determined to have a total serum IgM level of about 1,250 with a normal hematocrit.

His physician locally elected to do a bone marrow biopsy that showed 20% involvement with lymphoplasmacytic cells. And at that time, the MYD88 status was not determined. His exam and CT scans were otherwise unremarkable. And so, appropriately, he went on watch and wait.

Now, over the next 6 months things began to change for him. He started having numbness and tingling in his feet first and then his hands. And his serum IgM level had risen to about 1,900 mg per deciliter during that time. His hematocrit still remained pretty good. And this time the repeat bone marrow biopsy showed that he had about 30% involvement. And given his progressing neuropathic symptoms, he had a neuropathy workup that was composed of an EMG study that showed that he had demyelinating peripheral neuropathy, and he also had a very positive anti-MAG antibody. That’s the myelin-associated glycoprotein antibody.

He did have Congo red staining to exclude amyloid, and that was negative. And so given the rapidity, which is kind of unusual to see peripheral neuropathy progressing that fast, you only see that really in a handful of cases. He went on and got plasmapheresis that improved his symptoms, and then he got rituximab. And during the course of the rituximab he actually had a flare, and his IgM went up to about 4,300, and his neuropathy also got worse during that period of time.

And the question that we often ask ourselves as oncologists is how we should manage somebody like this, whether we should just go ahead and give more rituximab, as would be the case. We sometimes do the extended rituximab platform, where we give 4 weekly infusions and repeat it at week 12. Whether we should add another agent to the rituximab. Whether we should just abandon rituximab and start new. Whether we should do pheresis immediately, and then consider one of the other options. Or to actually do a further diagnostic workup to see if the patient is progressing and that this doesn’t represent a flare.

Indications for the initiation of therapy for patients with WM

DR LOVE: In a second I want to ask Thanos maybe what your thoughts are of this type of clinical scenario. But before you comment, Steve, can you talk a little bit about risk stratification of patients with Waldenström’s and indications for treatment? This patient was initially observed. What are the factors you look at to make those decisions?

DR TREON: Yes. This is a great question, Neil, because this divide line between when to treat or when to observe can sometimes be very difficult. Typically, we want to see the patients symptomatic, warranting therapy. We look for evidence of cytopenias, if the hemoglobin is less than 10 or platelet count less than 100,000. Those would be indications to treat. Although again, it’s a fuzzy line, because some people can be very fatigued even at higher hemoglobin levels, and you can also have people at lower hemoglobin levels that feel good. But those are our criteria.

If the patient has significant peripheral neuropathy, as appears to the be the case in this individual, then that’s actually an indication to treat, because if you don’t treat, things will only get worse. There’ll be more demyelination and nerve destruction. And so for this reason, this particular patient met our existing criteria. But we also include moderate to severe cryoglobulinemia, cold agglutinin anemia and those criteria that we use. We look at other evidence of disease — like CNS involvement — that also can prompt us to treat the patient.

Management approach for patients with WM experiencing IgM flare after treatment with rituximab

DR LOVE: Thanos, any reactions to this case? How do you think you might have managed this situation?

PROF DIMOPOULOS: Yes. I think this is an interesting case, primarily because we have an unusually rapid evolution of the peripheral neuropathy. And we know that single-agent rituximab can be associated with a flare. And in this particular case, the IgM flare resulted in a worsening of the peripheral neuropathy.

In this particular patient, I would tend to add another agent to rituximab. This could be either oral cyclophosphamide with low-dose steroids in the context of the DRC regimen or bendamustine to rituximab. I would not add bortezomib in view of the peripheral neuropathy. And one may also consider the addition of other agents or even the use of ibrutinib, which we know that it is a very active BTK inhibitor in the context of Waldenström’s.

An agent added to rituximab may be a way to go in order to decrease rapidly the levels of IgM and to see an improvement of the peripheral neuropathy. Since this patient improved with plasmic change, it is very likely that by reducing the IgM level we’ll have a symptomatic improvement of the peripheral neuropathy as well.

Activity of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib alone or in combination with rituximab in patients with WM

DR LOVE: Steve, what actually happened with this patient, and what’s the current situation?

DR TREON: Yes. This is, again, a very remarkable case, and it teaches us about the potential for this IgM flare with rituximab. This is actually a fairly common problem. We see it in about 50% of all Waldenström’s patients — can actually flare in response to rituximab as a monotherapy. And there are drugs that can actually make that worse or make that better. The IMiDs are particular offenders, because they tend to actually stimulate the immune system, and you can get even worsening of this flare.

The proteasome inhibitors have traditionally been better. They’ve improved it. But I think the best data that we’ve seen so far is from the study that Thanos and our colleagues had in The New England Journal of Medicine, and that’s with ibrutinib. I mean, we see almost a nil flare rate. And it speaks to the fact that when we do see this flare, it’s often driven by an inflammatory response generated by the rituximab. And so using a drug like ibrutinib can certainly bring that flare down.

In this particular case, plasmapheresis would have been very appropriate, as Thanos mentioned, just because we already had a track record. We already knew that the patient responded to pheresis. And given that his neuropathy worsened so acutely, he was plasmapheresed. It did improve his symptoms. And he went on and received combination therapy. In his case, he had bendamustine added to the rituximab.

And this was a case that was just before we had the ibrutinib monotherapy data, which I think is very important to consider in this case, because patients who progress with their neuropathy on rituximab actually have had very nice benefit with ibrutinib. And that was in our New England Journal monotherapy paper back in 2015. I like the idea of combining the rituximab therapy in this particular patient’s case. I think that if ibrutinib were available at that time and we had the knowledge that we now have, it would have been also a very good combination to consider in treating this patient.

Perspective on the use of ibrutinib with or without rituximab as front-line therapy for WM

DR LOVE: Just kind of curious, Steve. If ibrutinib had been available earlier on, would you have used it earlier in this case with the rituximab or instead of the rituximab?

DR TREON: Yes, that’s a great question, Neil. And I think our thinking on how we manage these patients is being challenged. I mean, traditionally we’ve opted to do the least amount of harm to them by using rituximab as monotherapy, which is typified in this case, but it actually seldom makes things better. You’ll see a modest reduction in the IgM. Sometimes you’ll see a flare that makes things worse. So this is not the ideal way to treat these patients. And I think when we look at our options, either bendamustine plus rituximab option, where you maybe give a few cycles of bendamustine, makes sense to treat these patients — or use ibrutinib.

And one of the reasons why the latter may be the better option is, this isn’t just about getting the IgM down now — it’s keeping it down for the longest period of time, because every molecule of IgM in these cases will continue to destroy the myelin sheath. It’s a long-term effort here to get rid of this IgM.

DR LOVE: Thanos, I don’t know whether there are any regulatory constraints on what you do in this regard, but what is your first-line therapy nowadays, and where does BTK inhibition fit in?

PROF DIMOPOULOS: I think it is a great benefit that we have the possibility to use ibrutinib either in the salvage setting or in the front-line setting. And I believe 1 factor that may have a significant influence in the decision to start or not or to give or not ibrutinib is the fact that ibrutinib, as other BTK inhibitors, has to be given continuously, because we know that when you interrupt treatment, within a few days you start seeing an increase of IgM.

It is always a challenge to decide in a disease that has a median survival which exceeds 10 or 15 years after the start of treatment whether you will administer to the patient a treatment for many, many years or you will apply combinations that will allow the patient to have treatment-free intervals. I believe that combination therapy that will involve a BTK inhibitor with another agent — rituximab or even with a proteasome inhibitor or other biological treatment — therapies in the future may give us the opportunity to take advantage of the great potential of BTK inhibitors but also to be able to administer therapy for a fixed period of time.

Symptoms and management of hyperviscosity syndrome associated with WM

DR LOVE: Steve, can you comment a little bit on the issue of hyperviscosity syndrome, which this man had, and the use of plasmapheresis? Any myths or misperceptions out there in the community about that? And what are some of the common issues that come up in this regard?

DR TREON: Yes, it’s a good question, Neil, because 6% to 10% of all patients with Waldenström’s will present with symptomatic hyperviscosity. Typically, this will be the patient who has an IgM level above 6,000 mg per deciliter, and it’s also important for the local practitioners to know that CXCR4 mutations are often at the root of this, particularly those nonsense variants. This is actually the kind of patient that you really need to take the bull by the horns. You need to get control of that IgM level, because it can lead to end-organ damage.

You’ve got to perform a very good retinal eye exam when you see patients with the high IgM level. And that just doesn’t mean do your own exam but also get an ophthalmologist involved, because a dilated exam, particularly looking at the periphery, is very important, because that’s where you’ll see early hemorrhaging taking place.

If the patient presents with symptomatic hyperviscosity symptoms — nosebleeds, headaches, blurry vision — and they have evidence of end-organ damage, you’ve got to plasmapheresis these patients. That’s the most important intervention that you could offer at that point.

DR LOVE: Thanos, again, any myths or misperceptions out there among oncologists in the community about hyperviscosity or about plasmapheresis?

PROF DIMOPOULOS: Yes. I think this is a very good point, because there is no clear correlation between clinical hyperviscosity and the levels of IgM. We can have patients with very high IgM but without any symptoms or signs suggestive of hyperviscosity. And in some patients with moderate elevation of IgM, some symptoms or signs of hyperviscosity may occur.

And I fully agree with Steve that the best way to diagnose this condition is by having a detailed eye exam to make sure that there is no fundoscopic evidence of hyperviscosity. Because otherwise, the symptoms may be subtle — some fatigue, headaches, occasional nosebleed — so it is important to suspect this syndrome and to document it and to treat the patient appropriately.

Role of obinutuzumab in the management of WM

DR LOVE: Steve, any other anti-CD20 strategies that have been looked at in Waldenström’s, specifically obinutuzumab?

DR TREON: Yes. There’s very little that we know about the activity of obinutuzumab in Waldenström’s. We had done extensive preclinical work, working with that molecule, Neil. And one of the reasons why we got excited is because obinutuzumab can overcome the polymorphisms that we see in the receptor that engages rituximab.

And so there is a population of patients that actually have a very favorable polymorphism, and they respond beautifully to rituximab even as monotherapy. But then about half the population actually has an unfavorable polymorphism. It’s called the FF polymorphism for FcGammaR3A.

We had published a very nice paper back in JCO many years ago looking at this in Waldenström’s. And why obinutuzumab to us was exciting is because it could overcome these differences in polymorphisms and could, in essence, even as monotherapy, provide relief across the board. I do think that this is an important molecule, and we’re hoping to actually get a clinical trial looking at this molecule in Waldenström’s.

DR LOVE: Interesting.

Case (Prof Dimopoulos): A man in his early 50s with WM and a MYD88 L265P mutation attains a very good partial response to first-line therapy with bortezomib/dexamethasone/rituximab

DR LOVE: Let’s hear about another case. And Thanos, you had this 51-year-old man. What happened there?

PROF DIMOPOULOS: This is an otherwise healthy gentleman who was found to have an elevated erythrocyte sedimentation rate, and this prompted further evaluation. Serum electrophoresis showed an IgM of 4,000. However, he was completely asymptomatic. His hemoglobin was 14.2. There was no evidence of splenomegaly or lymphadenopathy.

A bone marrow biopsy was performed, which showed a 50% infiltration of the bone marrow by lymphoplasmacytic cells. And the molecular testing revealed a MYD88 mutation. Since the patient was asymptomatic, it was chosen to follow the patient without any therapy at regular 3- to 4-month intervals.

After a year and a half of initial diagnosis, the patient complained of fatigue. And at that time, he was found to have a decrease of his hemoglobin at 11.8 grams and despite the fact that serum IgM increased only slightly at 4,400. This indicates what Steve mentioned before, that we should not only look at the absolute value of hemoglobin, but in this particular young patient there was a decrease of the hemoglobin from 14.2 to 11.8, associated with some fatigue.

It was decided that the patient should get treatment at that time, and the patient received a combination of bortezomib with low-dose dexamethasone and rituximab. He responded nicely to this treatment, which was administered for 6 months. And then he was followed without further treatment.

DR LOVE: And so what’s his current situation?

PROF DIMOPOULOS: The patient remained without evidence of active disease in a very good partial response. And so far has been off therapy for more than 2 years.

Selection of therapy for patients with WM in the first-line setting

DR LOVE: Again, Steve, we can maybe talk a little bit about the issue of first-line therapy in a patient who you’ve determined to start first-line therapy on. Can you talk about the various options, the clinical research data behind them, including the Phase III INNOVATE trial?

DR TREON: Yes. This is a very young individual, and I think when you see somebody like this, 51 years old, what you’ve got to do is really plan for the long haul here, and part of that is not only how do you get disease down in the most toxic-free manner, but you also have to make sure that what therapies you’re offering aren’t going to cause other problems, whether it be immunodeficiency, neuropathy or secondary malignancies. And I think with addressing the latter, the fact that Thanos and his colleagues avoided alkylators was right on the money.

We do see with alkylator drugs secondary malignancies. We do see MDS, even though these are relatively uncommon complications. Again, we’re looking at the long haul. And so proteasome inhibitors have offered really a way forward. We are concerned about the consequences of neuropathy, so we’re very careful. We tend to offer weekly as opposed to biweekly therapy with bortezomib. We also have other proteasome inhibitors like carfilzomib and ixazomib that are making their way. I think the use of a proteasome inhibitor would be very appropriate.

But the other way forward in a patient like this is also looking at BTK inhibitors. And we know from both the monotherapy studies with ibrutinib as well as the data generated in the INNOVATE study that ibrutinib, either alone or with rituximab, could be considered for such a patient. And here’s where the art of knowing what the underlying genomics are could help us.

We know from the data that Thanos and our colleagues published in the New England Journal that those individuals that are MYD88 wild type only, not having a CXCR4 mutation, actually do extremely well. They have the good, deep responses, the VGPRs.

When they have the CXCR4 mutation, things get a little bit more complicated. You don’t get those deep responses, and you also see early progression of these individuals. Adding rituximab is good, because you also get over the delay in response that typically occurs with ibrutinib alone in CXCR4-mutated patients. This would be an individual that one could consider either proteasome-based therapy or ibrutinib-based therapy, and around the addition of rituximab, I’d want to know about the MYD88 and CXCR4 mutation status.

DR LOVE: What are the situations, Steve, where you use up-front ibrutinib or ibrutinib/rituximab? And how do you decide whether or not to add rituximab?

DR TREON: In our case, knowing the underlying genomics is fundamental. What helps a lot is the ability to get those genomics done and getting them done correctly.

Across the board I think most institutions can do MYD88 testing. CXCR4 mutations are a little bit trickier to get done, although there are now a number of vendors that offer this type of testing.

I think if you’re armed with that knowledge, you can make a decision in terms of offering therapy to the patient. If they’re MYD88 mutated, I think using ibrutinib makes sense. If they have the add that it’s CXCR4 mutation, then we would consider adding rituximab to that particular patient’s care.

Efficacy and tolerability of proteasome inhibitors for WM

DR LOVE: Thanos, what do you think about that sort of algorithm?

PROF DIMOPOULOS: I fully agree and also believe that there may be a role for adding a proteasome inhibitor to patients with the CXCR4 mutations. And due to the very nice work by Steve and his group, I believe that we should explore more the value of carfilzomib in these particular patients, because bortezomib is associated with peripheral neuropathy, even when given on a weekly basis.

The other very interesting proteasome inhibitor in this disease is ixazomib, and I believe there are data to indicate that the ixazomib with rituximab may be of value, especially in patients with CXCR4 mutation and, of course, with the addition of BTK inhibitor.

DR LOVE: Yes, ixazomib. I’m curious, Steve, what your thoughts are about that. I just was working with your colleague Paul Richardson, and obviously ixazomib is starting to have a bigger and bigger role in myeloma. What about in Waldenström’s?

DR TREON: Yes. All the proteasome inhibitors tested so far, whether they’re bortezomib or carfilzomib or ixazomib, have shown very nice activity in Waldenström’s.

The big differentiating factor is neuropathy. And in Waldenström’s, we tend to see far more neuropathy associated with bortezomib than we do in multiple myeloma. And this likely has to do with the fact that a lot of these patients have an underlying predisposition to neuropathy.

In a study that was done about a decade and a half ago, we actually found those antibodies that target the myelin sheath in Waldenström’s patients in about half of all patients. There is this underlying destruction of nerves. In many patients it’s subclinical, but it does exist based on EMG evidence. And so this is one of the reasons why we think these patients were particularly vulnerable to the effects of bortezomib.

And shifting from twice weekly to once weekly made a big difference. Thanos and his colleagues followed up on our twice-weekly protocol with bortezomib and offered twice weekly for 1 cycle, and then they went to weekly, and that really cut down on the neuropathy rate and maintained the efficacy.

I do think that even for bortezomib there’s a way forward. But we’re very excited about drugs like carfilzomib, where we’ve seen very high activity rates and maintenance of good responses. In our study with ixazomib, dex and rituximab also showed very high levels of activity. This was published recently by Jorge Castillo in our group.

Peripheral neuropathy associated with WM and implications for therapy

DR LOVE: Thanos, any comments about the clinical presentation of neuropathy with Waldenström’s? What are some of the typical things and atypical things that you’ve seen? And how, when you start using a proteasome inhibitor, how does that become modified?

PROF DIMOPOULOS: Yes. This is a very important question, because there are some patients that have very little symptoms from peripheral neuropathy. And these symptoms may go on for several years when the patient is being evaluated.

For low-level symptoms and chronic symptoms, oftentimes it is appropriate just to follow the patient without specific intervention, especially if you have a chronic condition and the EMG shows that you have more exonal deterioration. Then it is very unlikely that these patients will have symptomatic improvement, whereas the patients that will improve are those that you can identify a period of deterioration of the disease.

On the other hand, I believe that with the new therapies that we have, we can induce a symptomatic improvement. And what we do oftentimes to patients having peripheral neuropathy as the primary symptom of their disease, we administer therapy for a certain period of time, and if we see that there is no symptomatic improvement whatsoever, then we kind of scale down therapy, because we feel that this patient may have a relatively chronic condition that will not improve in the long run.

DR LOVE: A lot of times you see younger patients in referral centers, but what is the typical age distribution of Waldenström’s, Steve?

DR TREON: Yes. So in the United States, it’s about 62. And, of course, patients can present at different ages. In fact, the youngest one I think we’ve had is 24 years old. And the oldest that we have currently that we’re caring for is 101. You have quite a dimension of age. And, of course, the way you go about treating patients will depend a lot on the age. As the oncologists get older, everybody is younger, so I think we’re paying more and more attention to long-term side effects.

Duration of ibrutinib therapy for WM and impact of treatment holidays

DR LOVE: Yes. No, I was thinking also about the issue — I guess, Thanos, the ibrutinib is given indefinitely, correct?

PROF DIMOPOULOS: Yes. Of course, we need to have trials to investigate ibrutinib and the other BTK inhibitors in combination with other agents, where we could evaluate a fixed duration of treatment. And I believe, for example, a combination of a BTK inhibitor with an anti-CD20 monoclonal antibody may provide such an opportunity, especially a 3-drug combination, for example, with a proteasome inhibitor.

DR LOVE: Yes, I was going to ask about that in terms of duration, Steve. Obviously CLL it’s an issue, the fact that patients have to take the therapy indefinitely, although now you’re seeing short-term treatment like with venetoclax and ibrutinib, for example. Do you keep these patients on ibrutinib indefinitely, or do you give them holidays?

DR TREON: No, we keep them on indefinitely. And that’s really important for our community oncologists and colleagues to know, because when you stop the drug, the disease does progress. You see the IgM go up. You see the hemoglobin go down. And, in fact, it’s hard to get the horse back into the barn if you stop the therapy. Sometimes it can take many, many months before you can that IgM back down to its nadir.

We’re very, very conscious these days about the hold periods. We used to hold ourselves to 7-day before procedure and 7-day after procedure hold periods, but we realized we were doing a disservice to patients.

It’s important to talk to the surgeon or whoever is going to be doing the procedure. Figure out how morbid it’s going to be, how much blood loss is anticipated. And if it’s a minimal procedure, try to tailor your hold periods around that. And in some cases we’ve even been able to use an alternative to a surgical procedure to get at the problem. And I think that may be even more desirable. Hold periods around ibrutinib can be problematic.

DR LOVE: That is really amazing that a week hold actually could be a problem.

Side effects associated with ibrutinib; monitoring and management of atrial fibrillation

DR LOVE: Thanos, what have you seen? There has been a tremendous amount of discussion again in CLL about the problems that patients run into with tolerability issues on long-term ibrutinib. What about in Waldenström’s, what kind of issues come there?

PROF DIMOPOULOS: In Waldenström’s usually the ibrutinib treatment is well tolerated. The cases of atrial fibrillation are there, but they are not so common. Some patients may have some fatigue, some headaches, but overall we have had patients who have been on ibrutinib for many years without any negative affect on the quality of life.

And I believe with other BTK inhibitors that are being evaluated — and as you know, there are comparative studies that will be reported in the next few months — we will see if there is further improvement in the safety profile of ibrutinib, which is a, overall, very safe drug.

DR LOVE: Steve, one way to get a good conversation going in a meeting is to say, what do you do if the patient who has CLL where you want to give the patient ibrutinib, but they have a history of atrial fibrillation and on anticoagulation? I don’t know if you ever run into this situation with Waldenström’s, a much less common disease. But if you did, what are the options? Would you ever consider, for example, acalabrutinib? And what do we know about acalabrutinib?

DR TREON: Across the board I don’t think so far the evidence that’s been provided shows really any difference in atrial fibrillation risk based on the different BTK inhibitors. I think it’s important for all of us to keep in mind that this is a continuum, that the longer a patient is on ibrutinib, you’re going to see an increase in atrial fibrillation. We went, actually, from 5% with a median follow-up of 19 months on our ibrutinib monotherapy study, and we were at 11% when we were looking at a median follow-up of 48 months. And, in fact, that’s about the rate that we see in CLL, so it’s about comparable.

Now, what is important in Waldenström’s that’s different in CLL is, when you see atrial fibrillation, don’t necessarily assume it’s ibrutinib. Do an echocardiogram or even get a cardiac MRI if the suspicion level is high, because we’ve seen a lot of cardiac amyloidosis accounting for that atrial fibrillation. And so it should be an alert if you see it to do at least the basic workup and make sure that the patient doesn’t have another cause.

Now, the other thing to keep in mind is that just because the patient does get atrial fibrillation, it’s not a cause for abandonment of therapy. In fact, even in the pivotal monotherapy study, almost all the patients who had atrial fibrillation we were able to continue on with medical management, and that can include using an antiarrhythmic, referring the patient for cardiac ablation or just adding on an anticoagulant and monitoring the patient. In the vast majority of cases we can continue ibrutinib therapy, much like the experience that’s emerged out of the CLL world.

DR LOVE: I just want to clarify, though. You said you didn’t think there was any difference in potential for atrial fibrillation on the BTK inhibitors. Were you referring to the data in Waldenström’s or just in general, everything?

DR TREON: No, I’m referring to the data we’ve seen so far in Waldenström’s. With the follow-up periods that have been reported on the Phase II data that have been reported so far, they reflect basically the same level of atrial fibrillation at that moment in time that’s been reported. If you wind back the clock and look at what ibrutinib A-fib rates look like at the same time as those other BTK inhibitors, they’re no different. Ibrutinib just has a longer track record, a longer history. And so I think that for us to really know if there’s going to be differences, we’re going to really need to look at this in Phase III data context and look at the same time periods.

DR LOVE: That’s really interesting. Thanos, what do you do if a patient’s already on anticoagulation and you want to use ibrutinib?

PROF DIMOPOULOS: This is a good question. If the patient needs to be on anticoagulation, I would like to see whether there is an alternative option. If indeed ibrutinib is the single option for this particular patient, I think we would take the chance and follow the patient closely. We usually want to start at a low dose and then try to increase it.

Case (Dr Treon): A woman in her mid-60s diagnosed with WM and a MYD88 L265P mutation experiences a dramatic response after receiving ibrutinib as first-line therapy

DR LOVE: Again, let’s get into another case here. And we were talking about ibrutinib, and Steve, you have a 66-year-old woman, a swimmer. Can you talk a little bit about her?

DR TREON: This was a 66-year-old female swimmer. So she was having progressive fatigue, and she also had shortness of breath while she was swimming her normal laps. And then she went to urgent care clinic when her breathing problems became more profound, and she was noted to have a hemoglobin level of 5 grams per deciliter. The rest of her counts were good.

Her reticular site count was very, very elevated at 10.45, and her haptoglobin was very low, consistent with an autoimmune hemolysis. Her cold agglutinins, interesting, were negative, so this appeared to be on the basis of a warm antibody. She got steroids. She had modest improvement. And no further response with intravenous immunoglobulin.

When she was being worked up, it was noted that her total protein was elevated, and she had a further workup that showed she had an IgM kappa monoclonal protein. And her IgM level was about 2,500. Bone marrow biopsy confirmed the Waldenström’s diagnosis, with 25% involvement. She did have the MYD88 mutation, but no CXCR4 mutation. And the rest of her workup was unremarkable — CT scans did show some prominent mesenteric retroperitoneal and inguinal adenopathy, and viral studies that she had in order to elucidate a causation of her autoimmune hemolysis was unremarkable.

At that point she did get some red blood cells. And then the time was to try to make a decision around her treatment. We had a number of different options, including using rituximab alone or in combination using ibrutinib. Those would have been the thoughts that were going through our team’s mind when we saw her.

Response and tolerability with ibrutinib in the front-line setting

DR LOVE: Thanos, how would you be thinking through a case like this?

PROF DIMOPOULOS: Depending on the availability of treatment, I think ibrutinib may be a good option, because we know that it can induce a rapid response, either alone or in combination with rituximab. I think if these drugs are readily available, this would be a reasonable treatment approach.

DR LOVE: Just out of curiosity, do you think it’s likely if you had access you would use rituximab as well in combination?

PROF DIMOPOULOS: I think yes. Whenever I have this option, I prefer to use the combination based on the results of the iNNOVATE trial.

DR LOVE: Yes, I want to hear a little bit more about the details of the iNNOVATE trial, Steve. But first, can you talk about what happened with the patient?

DR TREON: Yes. This is actually a very, very gratifying case. She was started on ibrutinib as monotherapy at 420 mg a day. And over the course of a year, her IgM went from 2,500 down to 60. Her adenopathy also resolved. Her bone marrow biopsy repeat showed only 5% disease involvement. But the highlight of this case was, she went from a hemoglobin of 5 to 15, 14.9, and this actually happened very quickly, within a few weeks’ time. I mean, she was already showing a profound increase in her hemoglobin that steadily rose over the next years’ time. This is a good case to be able to illustrate how BTK inhibitors can really change the course of someone’s life.

DR LOVE: Any tolerability issues with the ibrutinib?

DR TREON: This patient tolerated her ibrutinib with minimal issues.

DR LOVE: One of the things that I hear people talking about with ibrutinib is arthralgias. Have you seen that, Steve?

DR TREON: We do. With prolonged periods of time, patients can present with arthralgias. Sometimes they can present also with rash. Almost always a reduction in dose will make things better, but there are really those occasional patients who, even with dose reduction, you have only a mild impact on their arthralgias.

I have to say, that’s uncommon. We see it from time to time. But for most patients, when they do develop these Grade 1 or 2 arthralgias or rashes, you’re able to ameliorate it with a modest dose reduction in ibrutinib.

Case (Prof Dimopoulos): A woman in her early 80s with a history of hypertension and atrial fibrillation is diagnosed with WM with a MYD88 L265P mutation and receives ibrutinib and anticoagulation therapy

DR LOVE: Thanos, let’s hear about another patient who got ibrutinib. This is an 80-year-old woman. What happened there?

PROF DIMOPOULOS: Yes. This is an 80-year-old woman with a past medical history of hypertension, paroxysmal atrial fibrillation and depression.

She was evaluated for normocytic anemia of hemoglobin of 7.5 and weight loss. The serum protein electrophoresis revealed a very high level of IgM at 6,200. And the bone marrow biopsy showed extensive infiltration by monoclonal lymphoplasmacytoid cells and a MYD88 mutation.

The patient was very reluctant to receive any kind of chemotherapy or immunotherapy. And she was treated with ibrutinib as a front-line treatment.

The patient had a very prompt decrease of monoclonal IgM protein. But also, she developed atrial fibrillation, and also, a pacemaker was placed. And this resulted in some infectious problems that led to a temporary discontinuation of ibrutinib.

And then as Steve mentioned, what happened is, we saw an increase of IgM, which actually doubled from the nadir within a month. And the patient was rechallenged with ibrutinib. She responded again, and she’s now on ibrutinib with anticoagulation.

Perspective on the use of ibrutinib for elderly patients and those with a history of atrial fibrillation

PROF DIMOPOULOS: I believe that this shows that for very old patients who chemoimmunotherapy may be problematic, ibrutinib may be a treatment that can induce responses, and also, it shows that even when we have atrial fibrillation, we can either continue or start a treatment with ibrutinib, and we can even use anticoagulation. In this particular case, apixaban was used for anticoagulation.

DR LOVE: Wow, really fascinating case. Steve, any thoughts about this case? If you could, would you try acalabrutinib in a patient like this?

DR TREON: I think it’s a remarkable case. It shows that we can give BTK inhibitors to older patients. In fact, our oldest is over 100 years old receiving ibrutinib. The potential to be able to give this therapy and manage it, even through complications of atrial fibrillation, should be recognized.

I probably just would want to know if the patient had any cardiac amyloid. I would have looked at her echo very carefully. And if there was any evidence for infiltrative disease, then we might have resolved that further.

But she’s also in the age bracket where atrial fibrillation is quite common. We see it in about 5% of all individuals above the age of 75. It’s a quite common predisposition that exists.

I don’t know, Neil, if using a different BTK inhibitor would have made any difference here. Again, as we talked about earlier, when we look at the relative A-fib rates that have been reported at different points in time, we tend to see a similar level of atrial fibrillation — it can be cumulative over time. And usually the folks that get it early are people that have had paroxysmal atrial fibrillation or some arrhythmia event even earlier in their lives, sometimes prompted by cold medications. But you always hear something in that history for those individuals that get the early atrial fibrillation. The late one seems to be a different entity, with really no background history. And that’s why in those particular patients we’d want to make sure that we weren’t dealing with cardiac amyloid.

DR LOVE: Yes, it’s really interesting to hear your perspective on atrial fibrillation. Because, like, I think maybe I hear a little bit different thoughts coming from the lymphoma people, but not so much based on data. It’s just like, for example, you present an older patient with mantle cell, and a lot of investigators will just start with acala because they think maybe it’s safer. But I don’t know that there isn’t any data right now, as you’re pointing out.

Activity of the BTK inhibitor zanubrutinib in patients with WM

DR LOVE: Thanos, what about other BTK inhibitors? I saw one — I kind of like this name — zanubrutinib. I don’t know if it’s very effective, but any of the other BTK inhibitors that look promising in Waldenström’s, Thanos?

PROF DIMOPOULOS: Yes, that’s a very good point. There has been a single-agent study with zanubrutinib, which indicates a high response rate. And, actually, we had a poster recently at EHA, which showed that zanubrutinib was associated with gratifying responses in patients with MYD88 patients with germline MYD88 and the CXCR4 mutations.

And as you know, Neil, there is a prospective, randomized trial comparing head-to-head ibrutinib to zanubrutinib primarily in previously treated patients, but there are also some newly diagnosed symptomatic patients. And we hope to have a readout of this trial in 2020.

This trial will also provide not only a comparison regarding the efficacy of these 2 BTK inhibitors but also, as Steve mentioned, to see whether there’s any difference in the safety and toxicity profile of these drugs. So far, I believe this is the first study that will compare 2 BTK inhibitors. And it is an important trial that will give us significant information.

Results of the Phase III iNNOVATE trial evaluating ibrutinib with rituximab versus rituximab alone for patients with previously untreated or relapsed/refractory WM

DR LOVE: Steve, can you talk a little bit about specifically the iNNOVATE trial, what the design was and the primary findings?

DR TREON: Yes, so the key message out of that study was that if you add ibrutinib to
rituximab, it’s better than rituximab. And one may ask, why rituximab as a control arm. Because that’s really the community standard, whether you look at our SEER data here in the United States or you look at the wonderful data generated by Christian Buske and Thanos in Europe looking at practice patterns. What you’ll see is, in the real world, in the community, patients get as their first line single-agent rituximab. I think that was a fair comparator. And if we were to move the field ahead in any way, we had to look in a randomized way as to what was better than rituximab alone.

That’s why the trial was designed where patients got ibrutinib along with rituximab, and they were followed. And I think also, the importance of that trial is it also looked at the underlying genomics. It looked at how patients fared based on their MYD88 and CXCR4 mutation status.

We did see superiority in terms of overall response, major response and even progression-free survival when ibrutinib and rituximab were compared to rituximab alone, but we also saw differences based on the genomic subtypes. And I think the key takeaway message there was that the CXCR4 mutations did, in fact, impact response in the MYD88-mutated individuals and that we did also see early progression.

Ongoing investigation of CXCR4 inhibitors and the Bcl-2 inhibitor venetoclax for WM

DR TREON: Now, I think for everybody out there, it’s important to know that maybe there is a way forward, because you keep hearing about CXCR4’s impact on BTK inhibitors. And there are actually CXCR4 inhibitors. We have a trial right now with the drug ulocuplomab — that actually is very exciting. We are seeing — even in the early data that we presented at our Waldenström’s workshop last year — we are seeing that the depth of response and getting earlier responses can be impacted by targeting CXCR4.

And there’s actually another very large trial that’s about to begin looking at an oral CXCR4 antagonist. And, of course, people know plerixafor has been used in studies even in CXCR4 WHIM patients that shows that they can tolerate CXCR4 antagonism over long periods of time. I think there is a way forward here, even with the CXCR4-mutated patients.

DR LOVE: Thanos, I’m curious, as you look forward in terms of new agents and new strategies in Waldenström’s, what are some of the areas that have you most excited?

PROF DIMOPOULOS: I believe that venetoclax is an agent that should be studied further in patients with Waldenström’s. There are already single-agent data by Steve Treon, and I believe that a combination of venetoclax with ibrutinib is worthy of further evaluation in an attempt, also, to see whether we can use a treatment of fixed duration.

Furthermore, we, within the European Waldenström’s Consortium, would like to initiate a trial that will investigate a combination of ibrutinib with carfilzomib, again in an attempt to administer the treatment for fixed duration. We believe that with the potency of both agents, we may be able to discontinue ibrutinib after a certain period of time and follow the patient to see whether we have long-lasting remissions.

Biologic rationale and role for venetoclax in WM

DR LOVE: Steve, maybe you can comment a little bit — you presented the Phase II study of venetoclax last year. I don’t know if you’ve presented anything more recently.

DR TREON: The venetoclax single-agent study was presented actually at EHA last year, and we did show very high levels of response. What was exciting about that trial was the ability to actually clear the marrow. Venetoclax is a drug that I think distinguishes itself from ibrutinib in the sense that you get this very nice cleaning out of the marrow. There is a study going forward here combining ibrutinib with venetoclax. It’s supported by preclinical data that we and others have generated showing that you can overcome this antagonism by BCL2 that’s imposed on BTK inhibitors. And I think this is going to be a very exciting trial going forward.

DR LOVE: And of course that strategy, as we talked about before, there’s a lot of excitement about that in CLL.

What about the biology, Steve, of Waldenström’s as it relates to venetoclax? I don’t know exactly how you would assess BCL2 and how it compares with different cancers. But biologically, is Waldenström’s BCL2 overexpressed?

DR TREON: It is indeed. We did a transcriptome study, and others before us did gene expression profiling, and it appears to be very indicative of the MYD88 status. In those MYD88-mutated patients, you do see BCL2 overexpression. It has nothing to do with underlying CXCR4, because they all express the same levels of BCL2. But the BCL2 dependence is what’s really critical to note, because when you use venetoclax in primary cells, as well as Waldenström’s cell lines, you can induce them to apoptose.

Now you add ibrutinib to the venetoclax, and you get even a bigger bang. These cells will show a very nice apoptotic activity. And for this reason, I think much like what the folks in the CLL world and MCL world have observed, using the 2 drugs together is a very exciting opportunity for us to advance the field.

DR LOVE: Just kind of curious, Thanos. What is the usual cause of death in patients with Waldenström’s?

PROF DIMOPOULOS: Yes. This is a very interesting question, because this is an indolent disease and there are many patients who die from unrelated causes. This is something that we have to keep in mind, especially when we evaluate the trials. It is important to be able to define whether death was related to the disease or unrelated.

We had several patients that died of comorbid conditions. Also, there are several patients who develop secondary neoplasms. And it is not clear whether this is the natural evolution of the disease or due to therapies. Of course we have MDS, which used to be much more frequent in older days when chlorambucil was extensively used or when we had the use of nucleoside analogs. And, of course, the profound immunosuppression, which was induced when fludarabine or cladribine were used extensively was associated with opportunistic infections as well.

Tumor lysis syndrome associated with venetoclax

DR LOVE: Steve, what about TLS with venetoclax in Waldenström’s? Do you see it? Do you use the same preemptive strategy as with CLL, for example?

DR TREON: Yes. In the single-agent study, we saw no clinical TLS. And as a result of that observation, we actually start patients on 400 mg of venetoclax, unlike in CLL, where they have to start at much lower doses. Even though there’s BCL2 overexpression, that dependence on BCL2 for apoptotic activity isn’t as great as it appears to be in CLL.

DR LOVE: Again, all outpatient, or do you ever hospitalize people for TLS prevention?

DR TREON: We don’t hospitalize. We start patients on venetoclax, and then we increase their dose on a weekly basis. They start with 400. We go to 600. And then we go up to 800. But we do check TLS labs. We like checking those just after the drug is administered, and then we have the patient come back 24 hours later for another TLS lab check. And we do this during every dose escalation. And then from that point on, we’ll just follow the patient on their therapy.

Novel agents and approaches under investigation for WM

DR LOVE: Again, in terms of future directions, Thanos, we live in an immunotherapy world. Anything with checkpoint inhibitors or CAR-T therapy in Waldenström’s?

PROF DIMOPOULOS: I believe that these are treatments that may not be indicated due to their toxicities and potential toxic side effects in an indolent disease such as Waldenström’s, where, due primarily to the pioneering work of Steve Treon and his colleagues, we know today that BTK inhibitor-based therapy is a very rational and a very effective treatment.

I think the future is more towards CXCR4 inhibitors or antagonists combined with BTK inhibitors, and with a key role of venetoclax in this disease. I believe that anti-CD20 inhibition is of importance, especially when we want to develop therapies of fixed duration. And also, I see a role for proteasome inhibitors, especially in patients with CXCR4 mutations. I believe that overall, we have an abundance of therapies.

Therapeutic options for patients with WM after disease progression on ibrutinib

PROF DIMOPOULOS: We are in the phase now to investigate therapies in patients who develop resistance to ibrutinib. So this is a field that it is of significant interest as well. And I believe that there may be even a role in some patients for plain old chemotherapy-based treatments. We have to keep in mind the significant activity of bendamustine and rituximab. And even in some patients with refractory disease and failures after BTK inhibitors, we are investigating or we are using off-protocol treatments like fludarabine/cyclophosphamide and rituximab.

DR LOVE: Steve, I’m not sure how easy or difficult it might be to access venetoclax in the United States for Waldenström’s. Are there situations where you think it makes sense to use it outside a trial setting?

DR TREON: I do, actually. I think it does represent a way forward. The activity of venetoclax was shown in both patients that had no prior ibrutinib exposure and in patients that had seen a BTK inhibitor previously.

The depth of response is impacted by whether you saw BTK inhibitor earlier and also by CXCR4 mutation status. I think that’s something, as we go forward, to keep in mind, because here too, maybe using a CXCR4 antagonist may actually also be important for other drugs than BTK inhibitors.

I do think it’s a very exciting agent looking at it also in combination with ibrutinib and the other BTK inhibitors. And I’m sure we’re going to be seeing a lot of trials very, very shortly. But in the US, of course, if we have a drug that’s approved and you have compendium listing, one can use that to help support your choice of venetoclax to treat a patient.

DR LOVE: Keeping that in mind, Steve, and every patient is different, of course, but what agents or sequence of agents are you thinking about once a patient gets past ibrutinib?

DR TREON: I think what Thanos mentions is very important — we can’t forget that we do have also non-BTK inhibitors that are effective. We tend to use alkylators, and in particular, bendamustine is our choice in terms of alkylators — we do tend to use those after a patient has seen ibrutinib if they have not been previously exposed to bendamustine.

We do have the ability to leverage proteasome inhibitors. Most typically we use bortezomib, but carfilzomib and ixazomib also remain at our disposal. And there are also other effective drugs as well that one could consider — everolimus did show activity in this disease. We tend to use it in our third or fourth line to treat patients. I do think there is a continuum of drugs that we can use, but more is needed. And here I think venetoclax will certainly add to our armamentarium, so we’re very excited to see its development, both as a single agent as well as in combination.

DR LOVE: This concludes our program. Special thanks to our faculty, and thank you for listening. This is Dr Neil Love for Oncology Today: Waldenström Macroglobulinemia Edition.