BTK Inhibitors for the Treatment of Waldenström Macroglobulinemia

In this video, an international panel of experts sat down with Oncology Learning Network to discuss the 3 Bruton’s tyrosine kinase (BTK) inhibitors active in the treatment of Waldenström macroglobulinemia (WM): ibrutinib, acalabrutinib, and zanubrutinib.

This discussion is moderated by Steven Treon, MD, PhD, Director of the Bing Center for Waldenström’s macroglobulinemia at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, Massachusetts.

Dr Treon is joined by 3 international experts, Christian Buske, MD, Medical Director at the Comprehensive Cancer Center and the Institute of Experimental Cancer Research at the University Ulm, Germany; Marie Jose Kersten, MD, PhD, Professor of Medicine, Amsterdam University Medical Centers, Netherlands; and Prof Judith Trotman, MBChB, FRACP, FRCPA, Concord Cancer Center, Concord Repatriation General Hospital and the University of Sydney, Australia.

Watch Dr Treon, Dr Buske, Dr Kersten, and Prof Trotman explain the data behind each of these drugs, as well as factors a clinician may consider when choosing a BTK inhibitor for a patient, including availability, compliance, need for deeper IgM responses, efficacy, and toxicity.

Transcript

Dr Steven Treon:  This is Steven Treon. I'm a professor of medicine at Harvard Medical School, and Director of the Bing Center for Waldenström's macroglobulinemia at the Dana‑Farber Cancer Institute in Boston, Massachusetts.

I'd like to welcome you to this edition of the Oncology Learning Network, which will be focusing on an overview of BTK, Bruton's tyrosine kinase inhibitors, and Waldenström’s Macroglobulinemia. We have a distinguished international faculty that is joining me for this broadcast. We will be discussing the updates from trials of the 3 major BTK inhibitors that are being investigated in Waldenström’s macroglobulinemia.

This time, I just want to introduce our faculty. We have Dr Christian Buske. Christian, do you want to introduce yourself?

Dr Christian Buske:  Yeah, my name is Christian Buske. I'm coming from Germany Comprehensive Center in Ulm, and I'm involved in European trials for Waldenström’s.

Dr Treon:  Great. We also have from Europe, Dr Marie Jose Kersten. MJ, do you want to introduce yourself?

Dr Marie Jose Kersten:  Thank you, Steve. My name is MJ Kersten. I'm a professor of medicine in Amsterdam, at the Amsterdam University Medical Centers, and also involved in Waldenström’s studies and care for Waldenström’s patients.

Dr Treon:  All the way from Australia, we have Dr Judith Trotman, and Judy, do you want to introduce yourself?

Dr Judith Trotman:  Hello, all. I'm Professor Judith Trotman, and I'm a hematologist at the Concord Cancer Center, at Concord Repatriation General Hospital, and the University of Sydney here in Australia.

Dr Treon:  It's a real pleasure. This is really a multi‑continent presentation for Waldenström’s macroglobulinemia, and we have truly an outstanding faculty joining us.

I thought we would probably start off with Dr. Buske, who will present us a brief overview of studies involving ibrutinib, the first Bruton's tyrosine kinase to be investigated in Waldenström’s macroglobulinemia. Christian?

Dr Buske:  Thanks, Steve. It's really a pleasure, and I think we have first to say that actually ibrutinib was the first BTK inhibitor which really changed the treatment landscape in Waldenström’s, which was more or less based before on rituximab plus or minus chemotherapy proteasome inhibitors, so it's really a new era with ibrutinib.

Thanks to you, Steve, we had this pivotal phase 2 trial in relapsed Waldenström patients, 63 patients. It was a US study, which actually demonstrated that ibrutinib as a single agent is the most, let's say, powerful drug as a monotherapy in Waldenström we have.

What we saw in this trial was that it's actually possible to achieve an overall response rate in around 90 % of patients in this relapsed setting. When we look at the major response rate, it's between 70 and 80%, so it's very encouraging data.

The progression‑free survival was above 50%, 5‑year progression‑free survival in this trial, and the 5‑year overall survival was nearly 90%. Very high single‑agent activity for ibrutinib.

What we also saw in this pivotal trial was that it's well‑tolerated, probably we'll come back to this, but the fraction or proportion of patients not tolerating ibrutinib or actually stopping treatment because of serious side effects was very low.

What we also saw was, perhaps what was discussed in the community was, despite this really exciting data, perhaps 2 limitations of ibrutinib. One which probably is still not solved is that we have to give it as a permanent treatment, so after progression, it's not timely fixed‑duration, also in this pivotal trial.

The other issue which is still discussed is that it showed some dependency on the genotype on the mutation status of two genes, which is MYD88 and CXCR4—I'm sure we'll come back to this—with a drop in the major response rate depending on this genotype, from 90, to 60, to 0% when you look at MYD88-mutated, CXCR4 wild‑type, double‑mutated, and double wild‑type patients.

This was also reflected by the observation that the time to response can be substantially delayed when you have these more unfavorable genotypes.

When you have double‑mutated genotypes, the time to response drops or is delayed, prolonged from roughly 2 months to around 7 months, which makes a clinical difference in some of the patients. These were observations from this first pivotal trial.

The efficacy of ibrutinib, done again by you, Steve, could be confirmed also in treatment‑naïve patients. I think that's important. A smaller number of patients, but very clear.

We see also the same as expected efficacy and toxicity profile in treatment‑naive patients, but based on these observations, of course we have in the community the goal to improve on ibrutinib with regards to the efficacy in these different genotypes.

One idea was to combine ibrutinib with rituximab, and this was an international trial, phase 3 trial, with 150 patients, 75 patients were randomized per arm, and they were randomized between ibrutinib‑rituximab, and placebo‑rituximab. This study actually, not surprisingly, showed of course that ibrutinib‑rituximab is much, much better than rituximab‑placebo.

A quite interesting observation was that, in the combination with rituximab, ibrutinib had an efficacy largely independent of genotype when we look at the major response rates, of course with the limitation that the wild‑type patients were smaller in this study.

I have to add, these were including relapsed and treatment‑naïve patients, so it was a mixture. At least for the double‑mutated, where you have more patients in this trial, it looks quite robust that the addition of rituximab to ibrutinib can improve major response rates.

This also seem to be true, again, I think we have still to be cautious, for the time to response for the double‑mutated, which appear to be shorter than in the single‑agent ibrutinib study.

With this, probably I close. It's a short summary of these 2 key trials, which I think set the stage where we want to go with respect to genotype‑independent efficacy, and perhaps the new BTK inhibitors. We will listen now to Marie Jose and Judith make a difference.

Dr Treon:  And with that very nice introduction, we'll segue over to Marie Jose, who will give us an update on acalabrutinib.

Dr Kersten:  Thank you, and thank you Christian for the introduction, also. We have of course less long follow‑up for the patients treated with acalabrutinib, and the results were only just recently published in The Lancet Haematology.

These were the results of a phase 2 study, and 106 patients were treated in this international study which ran in the US and in Europe. There were 14 treatment‑naïve patients, and 96 patients who were relapsed/refractory, with a median of 2 prior lines of treatment.

The first 6 patients on the study were treated with 100 mg, once‑daily, but based on the pharmacodynamics, this was also the results seen in patients with CLL, but the dose was later changed to 100 mg, twice‑daily.

Acalabrutinib is a covalent BTK inhibitor, which is stronger than ibrutinib in vitro, and has a different kinase inhibition profile, which makes it more selective and has less inhibition, for example, of the EGF receptor, and ITK, and the ZAK tyrosine kinase.

This was thought to influence possibly the side effect profile and being a covalence inhibitor might improve also the efficacy.

Also, on the acalabrutinib, trial patients were treated until progression, and the response rate was high. It was 93% in both the treatment naïve and the patients with the relapsed/refractory disease, with a major response rate of 80% in both groups.

A median duration of response with a median follow‑up of 27 months has not been reached. This was at a data cutoff in February 2018. I hope we will have longer follow‑up shortly.

About 90% of the patients were still in remission at the 24‑month mark.

If you look at the side effect profile, it's slightly different from ibrutinib. One thing that struck us already at the beginning is that a lot of patients complained of headache. I don't think that's seen so much with ibrutinib or zanubrutinib. This was usually grade 1 or 2, and present mostly in the first period of treatment.

Other side effects are more common, of course, such as diarrhea. We saw very few rashes, but we did see neutropenia, infections, and relatively low grades of atrial fibrillation. There was one patient with grade 3 a-fib.

There was bruising in a lot of patients, mild hematomas, and there was one case of a fatal intracranial hematoma in a patient who was on a DOAC in this trial. There were very few other grade 3 bleeding events.

In the treatment naïve group, it was very small, about half of the patients at some point discontinued treatment. In the relapsed/refractory group it was 25% of the patients. This was in part due to progression and in part due to side effects or a physician's choice.

One downside to the study is that there was no central MYD88 and CXCR4 mutation status performed. The MYD88 data were only available for about half of the patients.

We saw slightly lower overall response rates and major response rates in the patients who were MYD88 wild type, but the data are only available for half of the patients. That's, in hindsight, a missed opportunity.

Dr Treon:  Thank you so much for that wonderful overview. Off to Sydney, Australia, where Judith is going to give us an overview for zanubrutinib. A lot of exciting data breaking at this year's ASCO.

Dr Trotman:  There sure is, Steve. I have to say first up, though, what a privilege it has been to treat patients with these BTK inhibitors, whatever BTK inhibitor they're on. It's really been quite transformational to the lives of patients and their treating doctors.

Having participated in both the INNOVATE study and the studies with zanubrutinib, formerly known as BGB‑3111, I find that the data that's coming out has confirmed my clinical impression about how they're both great drugs, but that the real value is the difference in the side effect profile.

Firstly, our phase 2 study for zanubrutinib enrolled 77 patients, a mix of mostly patients with relapsed/refractory disease, and then about a third of patients who were treatment naïve.

The good thing about the phase 2 study is that we've got 3 years of follow‑up. We've seen, with what would we say in clinical trials, a very long follow‑up, that we're getting virtually everyone. It was something like over 95% of patients responding, with almost half of those patients having at least a very good partial response.

We're definitely seeing that with time the response continues to improve to BTK inhibitors. That's true for all of them.

With this great response, we're seeing 80% of patients who are free of progression at 3 years. I had this clinical impression that the side effect profile with zanubrutinib, because it's a more selective inhibitor of BTK with fewer off‑target effects, I was seeing less bruising, less diarrhea, and less atrial fibrillation.

What was really valuable about the phase 3 data, the head‑to‑head study comparing ibrutinib with zanubrutinib in essentially 100 patients in each arm, that we saw that the difference in response rate was not statistically significant.

What was really important data that came out of the study was the improved tolerability profile, reduced toxicity of the zanubrutinib, with a significant reduction in the bruising and, in particular, the major bleeding, reduction in the atrial fibrillation, and also the hypertension.

The hypertension is particularly relevant. If you've got a grade of hypertension of 17% on ibrutinib and it's only 11% on zanubrutinib, that's important when you've got a switch that is switching off the activity of the disease and is going to do so for many years. You get the competing risks, the cardiac risks that start interfering with patients' longevity, so that reduction in toxicity is certainly important.

However, it wasn't all on the positive ledger for zanubrutinib. There was an increased rate of neutropenia for the patients on zanubrutinib, but pleasingly that was not associated with a high rate of infection.

The other thing that is important to note with all these BTK inhibitors, and in particular I found with zanubrutinib, was the very low rate of grade 3 and above toxicity. One particular one is the issue of the diarrhea. I wouldn't like to have grade 2 diarrhea at all, so having a drug that has very little diarrhea is really clinically important for patients.

The phase 3 data is great data. I'm looking forward to teasing out the details from this randomized trial, which, by the way, was just conducted in patients who are MYD88‑positive, the randomization. Patients who didn't have the MYD88 mutation were assigned a separate individual cohort.

I'll stop there.

Dr Treon:  Great. Judy, thank you so much. That's a wonderful overview of zanubrutinib. Thank you for breaking some of the data that's been presented at ASCO. Very, very helpful.

Now we have 3 very effective BTK inhibitors in Waldenström’s. We're hearing from each of us about the high response rates, just north of 90% across the board. We're hearing of major response rates that are in the high 70s to 80% range. We're also hearing about similar durations of response based on the data that we have. Of course, with ibrutinib, the data are far more mature.

If you look at the point in time where we were at 2 years, one would say that these response rates are comparable. In terms of providing guidance to our fellow clinicians, how is one to make a decision about which BTK inhibitor one ought to be thinking about for a particular patient?

Just wanted to perhaps put out a couple of thoughts for discussion points. Would you be making any decisions around the mutation status of the particular patient, whether they are MDY88 positive or negative, or if they have the CXCR4 mutation? We know the MDY88 mutation can be present in about 90 to 95% of patients, whereas CXCR4 can be present in 30 to 40% of patients.

I'm wondering if you think that mutation status could be a discriminator among these various BTK inhibitors.

Dr Kersten:  As I said, unfortunately, for the acalabrutinib study, we don't have the data. We have MYD88 mutation status only for half of the patients, and no CXCR4 data, because there were too few patients in whom it was determined. I think an effort should be made to do this in a different way maybe at later time points. I can't answer that for acalabrutinib.

Dr Treon:  Christian, from your perspective?

Dr Buske:  Probably, I would put it a little bit different. I would say when you have a patient who is MYD88 mutated and CXCR4 wild type, I think this is a good constellation to use ibrutinib. We have longtime experience with ibrutinib. We know it has excellent efficacy in this kind of mutation constellation.

Also, I think quite importantly, when we talk about today, most of my colleagues and myself, we have most experience with ibrutinib. The other drugs are still new, even when they would be accessible and approved. In this situation, probably I would take ibrutinib single agent. When you now have the double mutated ones, then you start to think a little bit.

These are patients who mostly have more treatment pressure. Then you think about perhaps not to take ibrutinib single agent, but to combine it with rituximab. I think it's still an option, based on this phase 3 trial, or to go to zanubrutinib. I think for me, the acala trial had some limitations. I agree with Marie Jose.

I think the phase 3 trial Judith talked about is a very strong trial. Of course, we still today don't have the data public, but let's say they are as great as Judith says, and I'm sure they are, then probably an option for me would be ibrutinib⁄rituximab or to go to zanubrutinib, to test this and also to collect experience with this new drug, which also to my mind is very well tolerated.

Dr Treon:  Judith, any comment on mutation status?

Dr Trotman:  I think we're all crystal‑ball‑gazing with respect to mutation status, because the subset of patients who have the CXCR4 mutation, that was so small in every trial. We're trying to work out whether the response rates are lower and slower, and what does that mean, because I don't think we've yet answered whether it really matters to have a VGPR or not with the BTK inhibitors.

I think that the duration of response, we're all getting a sense that these are the patients who progressed earlier. There's no doubt we're all getting that sense.

I think Christian's point about the fact that it's still the first thing you would reach for to use, a BTK inhibitor, is a really important and it's something I would love to be able to use it with rituximab as well. I'd like to have been comfortable with the data on zanubrutinib with rituximab in this patient population, which of course, we have nothing.

I hear what Christian is saying about we don't have as much experience. We only have experience of several hundred patients on zanubrutinib and only less than 300 patients with WM, but the personal experience I've had with it makes me feel very comfortable about reaching for it as a first line BTK inhibitor for these patients.

I think we're going to have to come up as a community with some better answers than just a BTK inhibitor for these mutated patients.

Dr Treon:  Some of the questions that have arisen about choosing a BTK inhibitor for a particular patient have included compliance. With acalabrutinib and with zanubrutinib, dosing is twice a day, although there may be an option for zanubrutinib for once a day dosing. With ibrutinib, it's once a day.

I wonder whether or not, from your perspectives, compliance may be an issue or a consideration in choosing a BTK inhibitor for a particular patient. Maybe we can start with MJ.

Dr Kersten:  Yeah, I agree. It's definitely an advantage, of course, if you can dose once daily. In some of the patients on the acalabrutinib study, the dose had to be reduced because of toxicity and it was given once daily. In general, I would say patients are highly motivated to take their medication. Of course, we haven't done monitoring for that, but I think in general, they are so motivated.

Actually, in patients where we were discussing for example, one of our patients who had atrial fibrillation, whether or not we should continue the study medication, the patients were so reluctant to go off treatment there. Very happy with the side effect profile. I haven't had that many complaints about twice daily dosing. In general, of course it's an advantage, absolutely.

Dr Treon:  Those are good points. Christian, what's your take on once a day versus twice a day?

Christian:  As Marie Jose said, I think for sure, it's better to take a pill just once a day, in particular when you have elderly patients. Not everybody is medically fit. Let's say it has a lot of comorbidities. I think even for relatives who monitor or doing the treatment of their husband or whatever, it's easier once a day, for sure.

On the other hand, as Marie said, normally, these patients are very highly motivated and very disciplined. I think for the majority of patients, probably it makes no difference.

What will be much more important is what Judith alluded to, when these drugs are better tolerated, when one BTK inhibitor is better tolerated by an individual patient compared to ibrutinib, I think then the BID doesn't play a major role and is outweighed by, let's say, a better tolerability in this individual patient.

Yeah, for sure, I think once a day is the best way to go. We know ibrutinib is also, we have no different dosing per pill, let's say. The number of pills you have to swallow is also reduced. This is for sure an advantage of the good old, now we say already, the good old ibrutinib.

Dr Treon:  Judy, your thoughts?

Dr Trotman:  This has made me just think about 2 issues with respect to what Marie Jose and Christian have said. The first one is your comment, Marie, about how highly motivated this patient population is. They certainly are, particularly our patients prior to being exposed to a BRK inhibitor. These were the patients who dragged themselves in with a hemoglobin of 60 and the IgM of 50.

We might not see quite the same awareness and motivation in the patients to whom we’re introducing the BTK inhibitor well before they're as desperate as our patients used to be. We might not find quite so dedicated with their compliance. That's just one thought that occurred to me.

This might be heretic. I'm not even sure I should even say this. The saturation, the sustained BTK inhibition and the BTK occupancy with the twice daily dosing was certainly better on zanubrutinib than the once daily.

There were 2 different doses. I have to say, the once daily receptor occupancy reassures me so that we are not actually counseling the patient about taking it twice a day.

I say, "Please take it twice a day, but don't panic if you happen to forget 1 of your doses. If you can remember your twice daily dosing 95% of the time, then you're going to be safe." I don't want these patients having a terrible fear that because they've accidentally gone to their sister's place for dinner and forgot to take their zanubrutinib, that their disease is going to lose control.

I think the twice daily is definitely the best and safest way to go, but I don't think we need to be absolute zealots.

Dr Treon:  Judith, the next point I think you might be...

Dr Kersten:  Can I ask about something, sorry?

Dr Treon:  Of course.

Dr Kersten:  I was wondering, Judith, is it something that comes up on the WhiMSICAL platform, because it's something we would really love to test, what are patient preferences? Of course, if you ask patients, "Do you want a pill once a day or twice a day?" they will probably all say once a day.

Dr Trotman:  It's really the thought. We're really ready now. We've got such a robust platform, 450 patients, that we're really ready to start doing patient preference research and questionnaires. I think that once daily versus twice daily is a good thing.

There are definite advantages to once daily, but there's also that added security potentially of a twice daily.

Dr Treon:  Judy, earlier, you alluded to the fact that in the ASPEN trial, more deeper responses, VGPRs, and some CRs were seen over ibrutinib. Do you think circumstances such as patients who have a need for deeper IgM response, an individual, say, with hyperviscosity, or cold agglutinins or cryoglobulins or IgM neuropathy perhaps, more to the point where you might envision one BTK inhibitor being better than another, because you can get those deeper responses?

Dr Trotman:  Look, Steve, I'm not convinced that that truly deeper response makes such a difference. I see patients feel so much better with a less than partial response. I see the hemoglobins coming screaming up, and they feel fantastic and feel absolutely normal, even though their IgM has gone from 40 to 24 grams per liter.

Some patients really, really, and I as the clinician, want the best response possible. I'm not yet seeing with BTK inhibitors, I'm not yet absolutely convinced that the depth of response improves the symptomatic response. We need to see whether the depth of response on a BTK inhibitor translates to a prolonged duration of response.

I guess I’ll give that question back to you Steve, given you've got so much more duration of experience with ibrutinib year, after year, after year. Is getting a partial response almost as good as a very good partial response? Is there much difference?

Dr Treon:  Yeah, it's a good point. We haven't seen the data to that effect. There could be circumstances where a deeper IgM response could conceivably motivate an individual clinician. Christian, I wonder if you have any thoughts around this.

Dr Buske:  Yeah. From our perspective, I think I agree with what Judith said. I think the clinical benefit is not correlating very well with the depth of response. This is one issue. Perhaps depth of response is not as important as, let's say, how good one of these BTK inhibitors can control the dynamic of the disease.

When you talk of patients with hyperviscosity, which have a quite aggressive IgM dynamic, then it would be great to have a BTK inhibitor which goes deep, which is, of course, great. Also, for the patient, when there's a certain threshold where they get hyperviscosity, they know this and they are from the values deeper with one BTK inhibitor than the other.

I think it's also psychologically, it might be important for patients. More importantly is how stable this remission then is. We come back to the duration of remission. I don't know whether these data, I think they are not public, I don't know, but really interesting.

We have a head‑to‑head comparison between ibrutinib and zanubrutinib in the ASPEN trial, which we will hear at ASCO. The one uses deeper response, but the question is whether this translates in a different PFS, and whether this translates in a different duration of remission.

When this is not the case, then it's really perhaps more psychological than medical benefit. When it goes deeper but the dynamic is unchanged and the rise in IgM is aggressive as before as with the other BTK inhibitor, then it's tough, I would say.

Dr Treon:  MJ, how...?

Dr Trotman:  Steve. Sorry, if you don't mind me saying. One reason why I wasn't mentioning was I didn’t actually participate in the phase 3 study, although in some ways, I regret I hadn't. This whole concept of VGPR within a year, I saw from iNNOVATE, I saw from my zanubrutinib experience. I have a feeling you get there faster with zanubrutinib, just a little bit faster. But they get there in the end anyway with ibrutinib. I think it's a matter of time.

I actually don't think that the VGPR...Forget about Cialis. It's not relevant. It's the VGPR rate. To me, that's not the be‑all and end‑all. To me, it's how well the drug is tolerated. Maybe in a few years' time, you want to be able to say, "Look, see? VGPR really matters."

The other problem with VGPR is these artificial cutoffs. PR is 50%, VGPR is 90%. They're really clumsy parameters.

Dr Treon:  Thank you. That's a great perspective. Marie Jose, we'll give you the last word on this one.

Dr Kersten:  Thank you. I think if we want to really make progress, probably in this respect, we will have to go to combination therapy. There's obviously different candidates like venetoclax, which could be combined with a BTK inhibitor, which can lead to deeper responses, and hopefully in the future also, fixed duration treatments like we're seeing now also for CLL.

I think that would be, for me if I have to guess, the way to go forward. We need, of course, clinical trials to prove it. We did participate in the ASPEN trial, but we didn't have very many patients on that trial.

Dr Treon:  Are there any specific morbidities? I'm thinking about Bing Neel Syndrome as an example, where you have CNS involvement by Waldenström. Are there any specific morbidities like BNS that you might choose one BTK inhibitor over another?

Dr Kersten:  I think outside the BTK, the ibrutinib data does not match data in Bing Neel for other BTK inhibitors as I'm aware of. I don't know if you have other information.

Dr Buske:  I think what I mentioned before, I think in the real world, the experience a colleague has with a certain BTK inhibitor will play a major role in Bing Neel. I think it's ibrutinib. The people will be very reluctant at the moment to take acala or zanubrutinib, because the data are very scarce or not existing, Steve. I don't know.

Dr Treon:  Right. Judy, is there any data on the use of zanubrutinib in Bing Neel, for instance?

Dr Trotman:  I've certainly used it in patients who had Bing Neel and they have persisting fatigue and have been very impressed that their Bing Neel hasn't come back 4 years down the track. I'm not aware, and I might be wrong, of what the data is about the CNS penetration of zanubrutinib, but I'm not aware that it would not penetrate the CNS.

Dr Treon:  The last point which I think you're going to, perhaps each one of you will have something to say, is about toxicity profile. Would the toxicity profile that you've heard, we've discussed it today, for a particular BTK inhibitor influence you as to which one you would choose? If so, is there a particular patient population that you might choose one BTK inhibitor over the other?

Judith, you want to take that one first since you just reported the ASPEN trial and the toxicity profile for zanubrutinib and for ibrutinib?

Dr Trotman:  I would use zanubrutinib for everyone except for the neutropenic patient.

Dr Treon:  Christian?

Dr Buske:  A certain patient population. Again, we in Europe, we don't have so far a lot of experience with acala and zanubrutinib in Waldenström patients. This I have to state as a limitation. It might change. At the moment, I don't know.

I think in total, the side effect profile is not hugely dramatically different. Of course, to have diarrhea, as Judith says, it's not nice. To have headaches is perhaps worse. Probably, what we would do is we would take the BTK inhibitor we have a lot of experience with and start an individual patient. If this patient is tolerating the BTK inhibitor well, we stay on this.

When this patient has difficulties, you have perhaps more tendency to bruise or whatever, then we might shift to one of the other approved BTK inhibitors, anticipating that they are approved.

This would be probably more an intra‑individual approach where we would not say...or let's say where I would have difficulty to really state with this patient, I would take this one, and this one, and this one. I would probably go intra‑individually.

Of course, when you have a patient with…let’s say with this neutropenia issue, who has a low bone marrow reserve, for instance, and you know that with zanubrutinib, if more neutropenia, you might argue than against ibrutinib, and so on.

You can shift a little bit between the 3, but probably in real life, you would take the one which we know, which is accessible, then only intra‑individually move to another one when it's not well tolerated.

Dr Treon:  Marie Jose, how about you? When you think about the toxicity profile of these three different BTK inhibitors, are you motivated to choose one over the other based on toxicity?

Dr Kersten:  Yeah. To be fair, it's a numbers game, right? We have much more and much longer experience in many more patients with ibrutinib. We have only relatively small phase 2 studies for the other 2. I think at the moment, it's quite hard to really base your treatment decisions on that.

I think the headaches, to be fair, were mild and reversible. I wouldn't take that as a decision rule not to give it as a drug, because otherwise, as I said, it was very well tolerated by most patients.

I would like to argue that we need more real-world data, and that it would be really good if we would record also the real-world data for the patients treated outside clinical trials. If you look at the exclusion criteria of the different trials, they also differ, right?

We don't have exactly the same patient population, so we cannot make any cross-trial comparison. Of course, we have one randomized trial, but that's based on relatively few cases.

Dr Treon:  Judy has a comment.

Dr Trotman:  Steve, I think for me, just as I was hearing more or less, the cincher is going to be the quality‑of‑life data in the ASPEN study when we're comparing 100 compared with another 100 patients. I think the quality‑of‑life data is going to hopefully help answer it. I have no idea that qual data was.

I was begging Beijing to add quality‑of‑life even late to the phase 2 study, and we had nothing from the phase 2 study. We only have numbers rather than patient testimonies about these drugs.

Dr Kersten:  I do think, though, that probably, this is based on ERC quality‑of‑life scores. I'm not sure they are sensitive enough to capture this. I'm pitching actually for WhiMSICAL.

Dr Trotman:  Oh, thank you!

Dr Kersten:  I think they should report it. The outcomes are really important but should be captured more in better ways than just a number.

Dr Buske:  I think the quality of life in Waldenström’s really depends on how quickly the hemoglobin goes up in these patients. This you have seen in other trials. When both drugs are very good in, let's say, improving the hemoglobin level, I think it's going to be very tough to see a difference, and must be a major difference in the increase in hemoglobin over time between the 2 drugs. If this is not the case, then probably it's difficult.

Dr Treon:  I'd like to take this opportunity to thank our distinguished faculty, Professor Kersten from University of Amsterdam, Professor Buske from the University of Ulm, and our wonderful colleague in Sydney, Australia, Professor Trotman.

Also, I'd like to take the opportunity to thank the Oncology Learning Network for covering this very important and timely topic for Waldenström’s macroglobulinemia. Wish you all the best and look forward to seeing you again on a future edition of the Oncology Learning Network.