Exploring Approaches and Strategies for Treating Patients With Relapsed/Refractory Myelofibrosis

Expert Roundtable Part 3

In this expert roundtable series, Firas El Chaer, MD, University of Virginia Comprehensive Cancer Center, Charlottesville, Virginia, leads a roundtable panel discussion on updates in myelofibrosis with Raajit K Rampal, MD, Memorial Sloan Kettering, New York, New York, and Lindsay A M Rein, MD, Duke University Medical Center, Durham, North Carolina.

In part 3 of the roundtable, the experts discuss therapies for patients with relapsed or refractory myelofibrosis. 

Transcript:

Dr El Chaer: Let's switch gears a little bit, unfortunately our patient's disease has relapsed or has progressed on whatever JAK inhibitor you decided to give them in the first line. How do you decide the second-line therapy? Do you take into consideration what you've given in the first line? Are there any other patient factors that you take into consideration? I guess maybe you can start with Dr Rein and then Dr Rumpel, you can give us your approach.

Dr Rein: My approach is really if I've got a patient who's progressed on frontline JAK inhibitor therapy, my go-to tends to be clinical trial enrollment. It's phenomenal to have all these options in different JAK inhibitors, but sometimes we face the law of diminishing returns, so we tend to get maximal benefit from the first JAK inhibitors, and I think sometimes they get [indiscernible]. When I'm looking at patients, what I'll really consider in a second line setting is a trial, so some novel therapeutic with perhaps a different mechanism of action, some alternative strategy for those patients. 

The other big question that we see, and the other question we try to answer was whether or not a patient who has failed ruxolitinib is a transplant candidate because if they've not gone for transplant in the frontline setting or upfront, and they've now failed or are progressing on a JAK inhibitor — is this the right time? For a lot of folks, it is to really consider stem cell transplant as a potential curative option like you mentioned. That tends to be how I approach folks in that scenario.

Dr El Chaer: Dr Rampal, if a clinical trial is not an option for whatever reason, patients does not fit clinical inclusion criteria or just no availability, what is your preferred second line agent in this patient population?

Dr Rampal: I think it depends on what the problem is. We have data, we've got good data from switching from ruxolitinib to fedratinib, ruxolitinib to momelotinib, ruxolitinib, tofacitinib, so we have data to at least give us some sense of what to use and in whom. With pacritinib, I think the bulk of the data has come in patients with under 100,000 platelets, although there is data to use it in higher platelets from the initial studies of the drug. Using that in patients with anemia and or thrombocytopenia makes sense. Sometimes it's useful to also remember comorbidities that occur, right? Somebody, for example, has recurrent squamous cell carcinoma. That might be somebody who would benefit from having just JAK2 and not JAK1 inhibition as a potential mechanism that drives it. We can always think about those issues as well.

With momelotinib, we've clearly seen the data supporting that in the second-line, there can be benefits in terms of symptoms as well as anemia, and that comes from both SIMPLIFY-2 as well as MOMENTUM. Now, there've been a couple of different studies which have shown that really as it pertains to spleen volume responses, you do get a substantial amount of spleen volume response with fedratinib as a second-line agent. It is becoming more complex to know how to order your JAK inhibitors, and one of the things that's going to arise is, well, what do you do with somebody who started with frontline momelotinib? What's the data to switch them to fedratinib? I don't know, but are we going to have to do that in practice? Yes, probably yes. Right? So I think that part of the equation is not yet solved, but we know what at least the drugs can do when being switched from ruxolitinib. 

It's also important not to lose sight of the big picture as Lindsay's talking about. You have to think about when have you gone far enough that you really need to take this patient to transplant because you may have only a limited window of opportunity if somebody is going in the wrong direction to get them to transplant and giving another drug only a short window to work is probably a reasonable thing for some patients who otherwise are going to lose their transplant window.

Dr Rein: The other important aspect of this, kind of thinking back to the patient themselves too. Each of the JAK inhibitors has their own side effect profile in terms of gastrointestinal side effects or other types of things, and so I think that's also an important consideration as we're thinking about different agents for patients. We've seen this in other diseases like the chronic myeloid leukemia (CML), the CML space where a lot of times we choose meds based on side effect profiles and we're getting to a point which is lucky and fortunate that we can tailor therapies to that particular symptom profile for patients as well.

Dr El Chaer: Since we're talking about the second line therapy and refractory relapse disease, some of those patients develop accelerated phase myelofibrosis or blast phase myelofibrosis. What has been your approach to that? Do you add an HMA [hypomethylating agent] to the JAK inhibitor? Do you combine it with venetoclax plus a JAK inhibitor in order to buy time or control their disease to get them to stem cell transplant? This is one of the very many unanswered questions and this field, but it's just to see how you approach your patients with accelerated phase or blast phase myelofibrosis. Maybe Raajit, do you want to take that first?

Dr Rampal: To me, the first question is, is this patient a transplant candidate or not, right? Are we going for curative therapy or not? The real reason is if the patient is not going to go to transplant or has no opportunity to go to transplant for whatever reason, there is really no benefit of intensive therapy whatsoever, and this has been shown in prior studies. The patient's outcomes are just as unfortunately, poor as if you use lower intensity therapy. So why subject to a patient to induction chemotherapy in the hospital? But in a patient who were going for curative approach and curative attempt, we have to think about first, does this person have BIC P 53 events? And if they do, it is highly unlikely you're going to get a response with conventional induction chemotherapy. In those patients an HMA plus venetoclax regimen is a very reasonable thing to consider.

There is now data from a number of different papers showing the CR [complete remission] rate, roughly speaking is in the 40% range. Granted, it seems that there is a little bit more toxicity in these types of patients versus de novo AML [acute myeloid leukemia] patients, so that's the caution. Having a singular p53 mutation probably is not something that should bother us too much. It's really having complex karyotype p53 or bioallelic p53 or p53 with a del [deletion] 17. That is a very different group of patients for whom we do not have any good answers at the moment. 

The next thing is does a patient have an IDH2 mutation? These mutations are IDH1 and 2 are much more frequent in post MP [myeloid proliferation] and AML than they are in de novo AML, and they count for about 20% of patients. There's some retrospective data that seems to suggest that patients have a good response, and there is one perspective trial that has been presented at ASH from the MPN Research Consortium showing that you can actually combine ruxolitinib and asciminib to good effect, in terms of getting responses in patients. So that may be a nice quick way without many toxicities to get patients into remission.

Aside from the other combinations that have been used, JAK inhibitor has been combined with HMA. These are studies from the MPN Consortium as well as MD Anderson that have looked at these combinations. It's relatively well tolerated. Remission rates are in the 30 to 40% range. It solves a practical problem, which is that a lot of patients come into transformation events already on a JAK inhibitor, and so sometimes it's hard to know what do you do with it? 

Sometimes people are inclined to say, "I should stop it," but that creates its own problems. You can keep it and you can add HMA, and then there is some data for combining HMA, venetoclax, and ruxolitinib, which may be a little bit aggressive, but at least there's 1 reported study of this. Others are probably forthcoming and there is synergy data about chemically for venetoclax and ruxolitinib, but that's something that needs more data behind it before we make that a suggestion, but either way, you do have HMA combination backbones that you can certainly think of in this space.

Dr El Chaer: I just want to caution as well, when we're starting to combine 2 agents, 3 agents. For example, in AML, venetoclax is used 21 to 28 days in the first cycle or so when you combine a JAK inhibitor on top of that, you might want to shorten the venetoclax dose cycle just to prevent major cytopenias that can lead to infections and stuff like that. For sake of completion, when Lindsay, maybe when do you use splenectomy or spleen radiation in your practice? Where do you think that would still have a role these days?

Dr Rein: There is data to support splenectomy and it's out there. Personally, it's a really challenging procedure for somebody to undergo. The patients who we think about splenectomy and splenic radiation for are folks who have really large spleens and are highly symptomatic. By nature of the fact that you've got these massive spleens and a bone marrow that's not functional, or not functioning well, it makes these procedures particularly high risk and fraught with complications. 

I have in recent years not turned to splenectomy for a lot of folks, I do utilize splenic irradiation. That's something that I use more as a palliative approach for patients. If I've got, for example, an older patient who's already on a JAK inhibitor and whose spleen is growing or somebody that we've tried a couple of JAK inhibitors and they're really not getting that response with ongoing symptoms, those are folks that I'll send for consideration of radiation to the spleen.

We've got a phenomenal group here. We will give low dose radiation. I find it does a really good job of alleviating symptoms and some of those constitutional associated symptoms that patients have with the big caution that it can lead to pretty significant and persistent and prolonged cytopenias, which again is the challenge. In somebody who may not have had low platelets or low hemoglobin, we can create that in the process of doing a radiation. Personally, I tend to use it more as a palliative modality for folks. Also, we have used it in patients who are going to transplant if we really do need to gain spleen control more rapidly.

Dr El Chaer: Raajit, is there still a role for hydrea [hydroxyurea] or pegylated interferon in this patient population?

Dr Rampal: Early on? Yes, right. Interferon can be used in patients with prefibrotic MF or maybe early myelofibrosis. Now again, it's uncontrolled data. It's data for a single agent and there are reports, published reports where it has been able to improve anemia, reduce the amount of marrow fibrosis. For somebody who's for a patient who's really motivated to be aggressive, it's a reasonable thing.

Hydrea can be useful still, but not as a single agent. It's really for patients who have really proliferative disease, sometimes even you put them on a JAK inhibitor and the white count keeps going up. Or these are for example, post PV or post ET patients where the platelets are, they come in with high platelets and they don't always get good reduction with just the JAK inhibitor alone and so sometimes sprinkling on some hydrea can be helpful, but I think to me that's the major utility of hydrea.

Dr El Chaer: Awesome. Just to conclude with the FDA-approved drugs, some problems about each drug, I guess ruxolitinib mainly is anemia. That can happen the first 8 to 12 weeks for which you can use a different dosing mechanism or scenario by the REALISE study that was published in Leukemia a few years ago, where you start low doses and then you increase every 12 weeks or so depending on response and shrinking. The platelet count and withdrawal syndrome from ruxolitinib is something that we should definitely be aware of and very cautious when we stop the drug and we switch to a different JAK inhibitor or if you're stopping it before stem cell transplantation. For fedratinib, I think Wernicke encephalopathy and vitamin B1 deficiency is extremely important. 

I know the FDA package insert states "test vitamin B1 before you start the medication. If it's slow replete, then make sure it's normal and then start fedratinib and keep checking levels thereafter". In my practice, I put everyone on vitamin B1 supplementation, and I still check for vitamin B1 level, but I feel like this is much easier than having to worry about Wernicke encephalopathy in that patient population. 

Momelotinib is the neuropathy, although in MOMENTUM it was not reported significantly, but to SIMPLIFY I and II, there's definitely more neuropathy that was reported and honestly, I still struggle a lot. I've been using it now momelotinib more often, some of my patients have developed neuropathy and besides dose reduction and potentially dose interruption, I'm not aware of anything else that can help that patient population. Pacritinib and fedratinib have the diarrhea, common side effects that they get Imodium. Did I miss anything that our audience needs to be aware of? Anything to add?

Dr Rein: The side effects of the secondary malignancy, well the skin cancers that we typically see with JAK inhibitors, I think that's really important just from that perspective. Then the reactivation of atypical infections and most common being shingles just as other cautionary measures there.

Dr Rampal: And tuberculosis, I think we've seen that happen more than once. Right? So usually before we start somebody for example in ruxolitinib we'll get a QuantiFERON test just to make sure they don't have latent TB.

Dr Rein: I was going to point out, I loved your comment about the interferon utilization and where that plays a role. I really do think that this is something that we're going to see, we're starting to see more data and we're going to see more data coming out. Especially because now that there's data to show that MPNs really exist on a spectrum and perhaps JAK mutations exist long before people develop the phenotype of disease, whether it be ETPV or ultimately MF. 

That poses a really great question, is there a role for even earlier intervention than what we already think of as early intervention and is something like interferon which potentially has disease-modifying properties a reasonable consideration, especially in that early disease or profibrotic patient population?