Activity Transcript

Segment 1

Steven Treon, MD, PhD: Hi, my name is Steve Treon. In this chapter, I'm going to talk about "The How, Why, and When of Molecular Testing in Waldenström Macroglobulinemia." I think it's important to say that this disease has benefited by whole-genome sequencing. In fact, the key mutation in Waldenström macroglobulinemia is MYD88. This is a mutation that actually affects the Toll receptor pathway, which is critical to downstream prosurvival signaling that involves nuclear factor kappa B (NF-kB). About 95 to 97% of all Waldenström's patients actually carry this mutation in MYD88, which typically involves the change of leucine to proline at position 265. So, you'll be hearing me talk about the L265P mutation. Now, essential to the downstream signaling pathway for MYD88 mutations is actually the activation of Bruton's tyrosine kinase, which is why there's been a lot of interest in the development of BTK inhibitors.

Now, there's also another mutation which is important to keep in mind, and that involves CXCR4. This is a very important receptor that mediates downstream trafficking and prosurvival signaling, and about 40% of all Waldenström patients actually carry mutations in the C-terminal domain. Now, when patients carry these mutations, they can have what's called nonsense mutations, where you introduce a stop codon and you lose part of that C-terminal domain, or you can have frameshift mutations introduced. Now, it's important to know about these 2 different types because both the clinical presentation, as well as the outcome with BTK inhibitors, can be impacted by which one of these variants you have, whether you have nonsense or a frameshift mutation in CXCR4. Now, those patients that carry nonsense mutations in CXCR4 tend to be the individuals that present with very high immunoglobulin M (IgM) levels, they have a lot of infiltration in their bone marrow, they're not as sensitive to BTK inhibitors, and their time to initiation of treatment is much shorter than individuals that don't carry CXCR4 mutations.

Now, prognostically, both MYD88 and CXCR4 mutations are important. One does see inferior survival associated with not carrying a MYD88 mutation, being so called MYD88 wild type, and also you see an increased risk of transformation among those individuals that have the MYD88 wild-type genotype. Now, in a study by the MD Anderson, it was also noted that those individuals that carried nonsense mutations required therapy earlier, but also their posttreatment overall survival was also less than individuals who were wild type for CXCR4 or carried a frameshift mutation.

Now, one of the big challenges in our field is actually being able to detect these mutations. If you use next-generation sequencing, there's a chance you might miss this mutation in MYD88 among individuals that have low bone marrow involvement. This is also true for CXCR4. So, for this reason, new techniques for being able to pick up these mutations are being developed. For MYD88 L265P mutations, the standard should be polymerase chain reaction (PCR), whereas for CXCR4, unfortunately, there's over 40 different types of mutations, it remains next-generation sequencing (NGS). Bidirectional sequencing, as well as molecular barcoding, are helping enhance NGS detection of these mutations.

Now, another reason to get excited for knowing more about these mutations is because they're druggable. Of course, CXCR4, we've known for quite a while can be druggable because of plerixafor, which blocks CXCR12-CXCR4 interactions, and there is interest in developing CXCR4 antagonists for the treatment of Waldenström macroglobulinemia.

Now, clinically, what do these mutations mean? Well, now there've been a number of BTK inhibitor trials, including those with ibrutinib, as well as zanubrutinib, that have actually looked at various outcomes based on CXCR4 mutation status. What we know so far is that the time to major response can be delayed in individuals who carry CXCR4 mutations. The depth of response, including very good partial response (VGPR) attainment, is much less in those individuals that carry CXCR4 mutations. Also, we're seeing differences in progression-free survival, where patients who have these CXCR4 mutations have shorter progression-free survival. Now, some of the updated trials are also telling us that the impact of CXCR4 should be taken into account for treatment decision-making. This has now been shown in trials with ibrutinib monotherapy, but also we're now seeing this with zanubrutinib.

With that, I'm going to stop at this point, and thank you so much for paying attention to this chapter on the why, when, and how of molecular testing in Waldenström macroglobulinemia.

Segment 2

Constantine Tam, MBBS (Hons), MD, FRACP, FRCPA: Hi, my name is Con Tam. I'm from the Alfred Health and Monash University in Melbourne, Australia. And my talk today is on applying the molecular testing in Waldenström macroglobulinemia to clinical trial results. I want to start by touching base on a very important study. And this is the phase 2 pivotal study of ibrutinib monotherapy in Waldenström macroglobulinemia. You can see that the 5-year progression-free survival is highly favorable in this study, at 54%. However, you can see that there are major differences in progression-free survival when considering the different molecular subclasses of Waldenström macroglobulinemia. There are 3 major subclasses. Firstly, there is a minority of patients who have MYD88-wild-type disease in the green, and these patients do not do well with ibrutinib. Next, we have patients who have mutated MYD88 that have a wild-type configuration for CXCR4, in the blue curve. And this is approximately 60% of patients with Waldenström, and they do well, with 5-year progression-free survival of 70%. Lastly, we have patients who have MYD88-mutant disease who also carry a CXCR4 mutation. And this is approximately 30 to 40% of patients [with] Waldenström’s, and they do have a relatively reduced progression-free survival of 38% at 5 years.

Indeed, if one looks at the response rate amongst all these 3 different genotypes, you see that patients who have MYD88-wild-type disease, in general, do not achieve a major response to ibrutinib. Those who have MYD88-mutated disease, but without a CXCR4 mutation, have a very good major response rate of 97% and a very good partial remission rate of 47%. But those who additionally carry a CXCR4 mutation have a reduced major response rate, a reduced very good partial remission rate, and a longer time to major response.

The major message here is that patients who carry the CXCR4 mutation have relative resistance to ibrutinib monotherapy. What happens when you add other drugs to ibrutinib? And we now refer to the iNNOVATE study, which studied ibrutinib plus rituximab vs placebo. And in this study, as the audience may well know that the ibrutinib arm is substantially better than placebo, but if you look at the genotype, this group and the response rates by genotype, you see that out of those patients who have MYD88 mutation but who have a wild-type CXCR4 genotype, a larger proportion of patients achieve very good partial remission. That's in the orange, as well as patients achieving complete remission in the green. And those patients in the middle column, who are the ones with the CXCR4 mutation, although they still have a high major response rate to ibrutinib-rituximab, they have a reduced very good partial remission rates compared to those who have CXCR4 wild type in terms of progression-free survival. What this means is that those patients who carry the CXCR4 mutation in the solid blue curve do have an inferior progression-free survival compared to those who have a wild-type CXCR4.

Now, look at these curves, they do appear to be superior to those of the ibrutinib monotherapies, especially, in a CXCR4 mutant arm. And this is hypothesized that perhaps the addition of rituximab to ibrutinib may have neutralized some of the risk of CXCR4 mutations. And further evidence of this observation is noted from what's called arm C of the iNNOVATE study. And these are patients who have a rituximab-resistant disease, where they are assigned to ibrutinib monotherapy. And you can see that within this subgroup of patients, those who carry a CXCR4 mutation, in the red curve, did quite poorly compared to those who have wild-type CXCR4. And once again, this curve reflects the results of ibrutinib monotherapy.

What happens when one goes to a second-generation BTK inhibitor? And for this, I would show you data from the ASPEN study, which compared zanubrutinib vs ibrutinib, and patients who have MYD88-mutant status. And for those patients who have MYD88-wild-type status, they were assigned zanubrutinib monotherapy, as we already know that they do not respond well to ibrutinib. If you look at the patients with CXCR4 mutations in this study and look at their outcomes by the drug use, you see that there is a trend to improved outcomes on zanubrutinib. And indeed, if you look at the very good partial remission rates for the CXCR4-mutant population, the very good partial remission rates are higher with zanubrutinib, at 21% compared to 10% for ibrutinib, but across the individual drugs, if you have a CXCR4-mutation status, you still have an inferior response rate compared to those counterparts of a CXCR4-wild-type status.

So, even when you use zanubrutinib, the CXCR4 status continues to be a disadvantage. But what about MYD88-wild-type patients? So, these are the ones where we saw from the pivotal study did not do well on ibrutinib, with a larger number of patients here with zanubrutinib, you can see that there is a respectable progression-free survival and overall survival curve. And indeed, there's an overall response rate of 81% in this population.

So, to finish, I wanted to tell you that there are 3 major genotypes in Waldenström macroglobulinemia, which influence the response to targeted therapies. There are firstly that those patients who have MYD88-mutant disease and CXCR4-wild-type status. And for these patients, they both respond well to ibrutinib or zanubrutinib. Then there are those patients who have MYD88-mutant, CXCR4-mutant status. And for these patients, there is relative resistance to ibrutinib. There is also relative resistance to ibrutinib plus rituximab or zanubrutinib, but with the second ibrutinib-rituximab or zanubrutinib, the results do appear to be better than ibrutinib, and maybe are a preferred choice for this patient group. Lastly, we've got patients who have MYD88-wild-type status, where once again, we know that the results of single-agent ibrutinib is inadequate. And for this group, either combination of ibrutinib plus rituximab or zanubrutinib will appear to be more efficacious. Thank you for listening to my talk.

Segment 3

Shirley D'Sa, MD, FRCP, FRCPath: Hello, and welcome to "Answers From the WM Clinic: Managing My Patient With MYD88-Mutated and CXCR4-Wild-Type Disease." I'm here today with 2 other panelists, Professor Constantine Tam, head of the lymphoma service at Alfred Health and Monash University in Melbourne, Australia, and Professor Steven Treon at the Harvard Medical School and Bing Center for Waldenström's Macroglobulinemia at the Dana-Farber in Boston, United States. I am Shirley D'Sa at the UCLH Center for Waldenström's based in London, UK.

So, we will briefly discuss a case of a 67-year-old male who has tested positive for Waldenström's, which is MYD88-mutated but CXCR4 wild type. As we know, there are a variety of chemotherapy approaches, including combinations with rituximab, which can be effective and produce good remissions. But we would like to focus on the role of BTK inhibitors in this setting. And, to that end, I'd like to ask Steve, what you think would be the most suitable treatment option for such a patient.

Steven Treon, MD, PhD​: Thank you, Shirley. Now, I think this is the type of case that we see quite often, and the genomics are very important. In our center, we tend to prioritize BTK inhibitors as monotherapy in such a patient because they represent less risk, both short term and long term, to the patient. I think that's really important to keep in mind. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), even in a small fraction of patients, if you can avoid that by using a BTK inhibitor, I think you're doing the patient a service, especially if they're a younger patient. And these days, everyone is younger as the oncologist get older.

But I think it's also important to keep in mind there are other mitigants to how we would decide on treatment. Somebody coming in, for instance, with bulky disease, you would prioritize bendamustine. Somebody coming in with amyloidosis that needs to be treated, you would prioritize a proteasome inhibitor since these patients don't do as well with a BTK inhibitor. And somebody coming in with neuropathy, IgM demyelinating neuropathy, which we commonly see with this disease, then we would start with rituximab alone, but for more moderate to severe cases, we would either add in a BTK inhibitor or bendamustine.

Dr D'Sa: Thank you, Steve. And what are your views, Con?

Constantine Tam, MBBS (Hons), MD, FRACP, FRCPA: I agree fully with Steve. I think that the BTK inhibitors are an important option in these patients. In my country, chemotherapy is funded for younger patients. But for older patients, we now have BTK inhibitors funded as first-line therapy, where comorbidities made chemotherapy more difficult.

Dr D'Sa: Turning to adverse events, they do raise concern in physicians and patients alike. Steve, how would you regard the adverse event profile of the different BTK inhibitors that you've used?

Dr Treon: Well, I think what we learned from the ASPEN trial that Con led is that there are differences. We see much less atrial fibrillation, which is a very important concern, than we see with ibrutinib. We see much less of it with zanubrutinib. We also see less hypertension, less diarrhea. But conversely, the yin and yang, we see more neutropenia associated with zanubrutinib and more granulocyte colony-stimulating factor (G-CSF) usage with that, but surprisingly, not more infections. I think this was also a very nice update that we saw at this last European Hematology Association (EHA) [conference].

There is also acalabrutinib. Roger Owens' study, your study, showed us that this is also equally active. But what I saw at EHA, which surprised me a bit, was that the atrial fibrillation rate did climb up, and it was about 12% in those patients with previously treated disease with longer follow up. So, I think the discriminant here is going to be around atrial fibrillation risk as well as neutropenia risk and trying to prioritize based on the patient's presentation, which of the two to use.

Dr D'Sa: Indeed. Con, you led on the ASPEN study, and although neutropenia came out in as a little bit higher in the zanubrutinib arm, my own experience was that it wasn't a clinical problem for patients. What do you think?

Dr Tam: I think as hematologists and oncologists, we're all used to managing neutropenia, and obviously these patients are under observations. So, my own personal experience is that neutropenias occur, but usually are easily treatable. Response was to G-CSF and tends to often resolve once you stop the G-CSF. I would say that I'll agree with Steve. I think that the most important discriminating factor would be the cardiovascular toxicities.

In addition to the ASPEN study, there has now been 2 other head-to-head studies in chronic lymphocytic leukemia (CLL), different disease, of zanubrutinib vs ibrutinib or acalabrutinib vs ibrutinib. And the aggregate of those randomized studies suggest that the atrial fibrillation rate and hypertension rates are lower for the second-generation inhibitors. Of course, there are unique problems. The second-generation drugs are twice a day, and acalabrutinib has problems with proton pump inhibitors. So, for the patients, it could be harder to take for the average patient. But I would say that we are lucky you have 3 very good options here, and really, all we’re choosing by these very slight differences in toxicity.

Dr D'Sa: Thank you very much. Go on.

Dr Treon: I was going to say, I think Con's point about the schedule's really important, because when you dig into the data that Judy Trotman published on once-daily vs twice-daily zanubrutinib, in fact, you see a much more favorable side effect profile with once daily zanubrutinib and similar levels of efficacy. This may also be a very important consideration. And in the US, giving it once a day or twice a day are both approved for the indication of Waldenström's.

Dr D'Sa: Thank you very much. So, in summary, there is efficacy, there are adverse events (AEs), but by and large, they are manageable. Thank you for participating in this activity.

Segment 4

Shirley D'Sa, MD, FRCP, FRCPath: Welcome to this session, "Answers From the WM Clinic: Managing My Patient With MYD88-Mutated and CXCR4-Wild-Type Disease." My name is Shirley D'Sa. I am a clinician at the University College London Hospital, WM service, in London, UK, and I'm joined by 2 colleagues, Professor Constantine Tam from the Alfred Health and Monash University in Melbourne and Professor Steven Treon from the Harvard Medical School and Bing Center for Waldenström's in Austin, [TX], USA.

So, we're going discuss a case study of a woman of relatively young age for this disease, 52 years, who has a diagnosis of Waldenström's, MYD88-mutated and CXCR4-mutated disease. We know from previous studies that the differences in mutation status do [have an] impact on outcome, and so I'd like to ask my colleagues, starting with Steve, how would you manage this patient in the clinic in terms of the most suitable treatment options?

Steven Treon, MD, PhD: I think important to consider in such a patient is the urgency for response. Many of these patients that come in with CXCR4 mutations, particularly the nonsense variants, will come in with hyperviscosity crisis. So, if you have such a patient, obviously plasmapheresis is the first thing you do, but then you can consider appropriate therapy, and we tend to prioritize proteasome inhibitors or bendamustine in these sort of patients because you do want a rapid response. And I think those sort of modalities offer a quicker response, but we also know now that zanubrutinib is active in this patient population and can also be considered. If, on the other hand, a rapid response is not necessary and the patient is MYD88 and CXCR4 mutated, then I think one can consider either ibrutinib with rituximab or one can consider zanubrutinib as monotherapy, and both offer, I think, a very active approach to being able to treat such a patient.

Dr D'Sa: Indeed, yes. Thank you. And how quickly do patients respond with BTK inhibitors in this situation, do you think?

Dr Treon: Well, it takes time. I think that's 1 thing that our clinician colleagues should be aware of that when you're CXCR4 mutated, it takes time. So, I think this lends itself to anticipation, which is why if the response that's needed is urgent, you may want to prioritize a different approach to treating the patient than a BTK inhibitor, but the fact that you want to consider, these are very active drugs. Slow and steady will get you to the end, but it's all a matter of how urgent you need to get that response. But important for clinicians to know it will take time so don't abandon therapy because you don't see a response in the first few months in somebody who CXCR4 mutated, don't abandon abandoned therapy early, just anticipate it'll take longer.

Dr D'Sa: Yeah. Yeah. That's certainly my approach. As long as there is clinical improvement, don't be worried too much by the numbers. And stick with it. What about you, Con, how would you approach this patient in your practice?

Constantine Tam, MBBS (Hons), MD, FRACP, FRCPA: So, I would agree entirely with Steve. So, the 1 thing we know for this group of patients is that with ibrutinib monotherapy they do not do as well as those who have CXCR4-wild-type status. So, these patients are relatively more resistant to ibrutinib monotherapy with a slower time to response, a less deep response, and a shorter progression-free survival. So, if they need to be urgently treated, you would want to use a chemotherapy-containing regimen. But for those patients where the urgency is less, in our center, we would typically use a second-generation drug like zanubrutinib as a monotherapy, because we have shown that is more effective than ibrutinib monotherapy in this subgroup of patients. Alternatively, you use ibrutinib with the addition of rituximab, which does seem to bring the responses back up to quite good levels. So, this is the one scenario where in the country like the US, where you have got both ibrutinib and ibrutinib-rituximab licensed that you might want to choose to use the rituximab combination.

Dr D'Sa: And regarding side effects or adverse events, Steve, is there anything specific in this particular group of patients to note for BTKIs?

Dr Treon: Yeah, not per se, Shirley, but I think the differences in AEs, between the BTK inhibitors needs to be considered. Patients that are at risk or have a history of atrial fibrillation, you might want to prioritize zanubrutinib and individuals that may have pancytopenia or neutropenia, you might want to prioritize ibrutinib. Acalabrutinib also represents an option for treating these patients, although, as we just saw from EHA, atrial fibrillation rate is very similar to what we observed with ibrutinib alone. So that, per se, isn't a discriminate, but those are the sort of informed approaches to treating a patient based on how they present and what might be some of their risk factors.

Dr D'Sa: Thank you very much for participating in this activity.

Segment 5

Shirley D'Sa, MD, FRCP, FRCPath: Welcome to this session on "Answers From the WM Clinic: Managing My Patient With MYD88-Mutated and CXCR4-Wild-Type Disease." My name is Shirley D'Sa. I'm the clinical lead at the UCLH Center for Waldenström's in London, UK. And I'm joined today by my colleagues, Professor Steven Treon from Harvard and the Bing Center for Waldenström's at the Dana-Farber in Boston, Massachusetts, USA, and with Professor Constantine Tam, Head of Lymphoma at Alfred Health and Monash University of Melbourne, Australia. So, we have a case of a patient who is double wild-type for both MYD88 and CXCR4. I guess Steve, the first question is, is this really wild-type WM?

Steven Treon, MD, PhD​: Yes, that's a great question, Shirley. And it's important, I think, for our viewers to know that you can miss the MYD88 mutation, especially if you're using next-generation sequencing and the patient has low tumor burden. So ideally, you want to use PCR and you also want to make sure that we're not talking about another IgM-secreting malignancy. An IgM myeloma frequently can smuggle in under this MYD88-wild-type Waldenström's diagnosis. So, be sure to check for translocation (11;14) and Cyclin D1, if your pathology is, of course, concerning and if the patient especially has a high IgM level.

Dr D'Sa: Absolutely. And what would be the most suitable treatment in this situation do you think, Steve?

Dr Treon: Well, this is a good one to also ask because when you look at BTK inhibitors, in aggregate, their response levels vary. With ibrutinib, you see no major responses. With zanubrutinib, you do see major responses. So, one can consider zanubrutinib in this particular setting, but also proteasome inhibitors and bendamustine are also very good options for the patient. And some of the things, of course, that might drive you in 1 direction or the other whether the patient has bulky disease, in which case bendamustine might be appropriate, or if the patient is presenting with amyloidosis, in which case maybe a proteasome inhibitor might be more appropriate.

Dr D'Sa: That's great. Thank you. And Con, as the lead for the ASPEN study, I wonder if you could comment on the wild-type cohort that was focused on this study of zanubrutinib vs ibrutinib?

Constantine Tam, MBBS (Hons), MD, FRACP, FRCPA: Sure. So, the ASPEN study was, of course, a randomized study in Waldenström's, but for those patients who are MYD88-wild type at screening, these patients, we knew were relatively resistant to ibrutinib. So, they were assigned to zanubrutinib monotherapy, and we had 28 patients that were treated. We saw actually quite reasonable major response rates and progression-free survival in these patients suggesting that zanubrutinib is active in this population.

But I'll probably back track to say that, in fact, although ibrutinib monotherapy seems to be less effective in this population. If you look at the iNNOVATE study, there's actually data in there to suggest that patients who took ibrutinib with rituximab for patient with MYD88-wild-type disease actually did quite well. So, if you are going to go down the BTK pathway, I think the important message for the MYD88-wild-type patients are that ibrutinib is probably not going to be a first choice. The first choice is either going to be zanubrutinib or ibrutinib-rituximab.

Dr Treon: Yes. Thanks. Con, just to keep in mind, too, is that these studies also use different ways of assessing MYD88, so in the iNNOVATE trial, next-generation sequencing was used. And I think that sort of does raise a little bit of concern that maybe some of these patients who are on the MYD88-wild-type track actually did have the MYD88 mutation.

Dr Tam: That is a very true concern, indeed, yes.

Dr D'Sa: Yes, so accuracy with testing is very important, of course. And the other aspect is the managing adverse events with these drugs. They can overcome some of these genetic problems, but how do we go about managing adverse events, and how do the various entities perform?

Dr Treon: Well, I think we learned a lot from Con's study, ASPEN. It does show us that they're both great drugs, ibrutinib and zanubrutinib. And of course, we also know from Roger Owen's study that acalabrutinib also very, very active. And I know Shirley, you took part in that study, as well.

So, there's going to be differences in side effect profile, which we need to keep into account when we're thinking about an individual patient. Somebody who's predisposed, for instance, to arrhythmia, or has had a history of arrhythmia, you might want to prioritize zanubrutinib because the data right now shows that's of all the BTK inhibitors at our disposal that are covalent.

This one is the one that has the least amount of atrial fibrillation associated with it, less hypertension, less diarrhea. But if you have somebody presenting with, say, cytopenias or neutropenia, we saw more of that with zanubrutinib than we did with ibrutinib. So, you might want to prioritize in that case ibrutinib. And I think also convenience is so important. When we consider these drugs, in the US, we can give zanubrutinib either once daily or twice daily. And we do see less side effects with once-daily dosing. This is based on Judy Trotman's phase 2 study. So not only do I think BTK inhibitors the choice of play a role in our AE profiling, but also potentially whether we give it once or twice daily.

Dr D'Sa: Thank you very much for participating in this activity.

This is a verbatim transcript and has not been copyedited.