Dr. Andrew Kuykendall:
Welcome to The ASCO Post Roundtable Series on Personalizing Therapy for Myelofibrosis. I'm Dr. Kuykendall from Moffitt Cancer Center in Tampa, Florida, and joining me today are two of my colleagues, and I'll allow them to introduce themselves. Steve, go ahead.
Dr. Stephen Oh:
Hello everyone, my name is Stephen Oh. I'm from Washington University School of Medicine in St. Louis, Missouri.
Dr. Kuykendall:
And Tony.
Dr. Anthony Hunter:
Hey there everybody. Tony Hunter. I'm one of the faculty at Winship Cancer Institute of Emory University in Atlanta, Georgia.
Dr. Kuykendall:
Thank you guys for being here. Today we'll be discussing the treatment and management of myelofibrosis with three patient case studies. Our final installment will focus on a transfusion-dependent patient with myelofibrosis, and severe thrombocytopenia. So, this is an 82-year-old man who presents with progressive decline. He's found to be anemic, with a hemoglobin of 6.8. Platelet count is 48,000, white blood cell count is 4, and he has 2% circulating blast. His MFSAF total symptom score is 35. His spleen is mildly increased in size on ultrasound, at a maximum dimension of 12.5 cm, and he really denies any abdominal pain associated with this finding. A bone marrow biopsy is performed and is consistent with primary myelofibrosis, and an NGS panel shows the presence of a JAK2, SRSF2, ASXL1, TET2, and RUNX1 mutations. Cytogenetics show the presence of a deletion of 7q. All right, so Tony, coming to you first, what signs or symptoms in this case would drive your decision making, as far as kind what jumps off the page as what you need to factor in, in terms of treating this patient?
Dr. Hunter:
Yeah. So I think this is that presentation of a little bit different phenotype of myelofibrosis than we talked about some other cases, as sort of more cytopenic or myelodepleted phenotype, right? We have a patient thrombocytopenic, platelets are less than 50, they're anemic, really to the level of probably becoming transfusion-dependent, and not quite as much splenomegaly here, although pretty symptomatic still, it looks like, based on their TSS score. And certainly this is, as you're seeing from especially the marrow and the molecular data, along with that clinical data, and cytopenia, this is a very, very high-risk patient, multiple high-risk mutations. You've got chromosome changes in addition to cytopenia.
So, you're dealing with someone who I think you know upfront is going to be a challenging case to deal with, with cytopenias, high-risk features, this is an 82-year-old, they're probably not someone that's going to be transplantable. And so, I think those are all sort of factors in the decision-making. Important to know about how this patient is sort of functionally, how are they doing? We seem to see that sounds like they're declining some, what are their comorbidities that we're going to kind of factor in here? All I think things that are going to be important here. I think certainly, again, this is someone not maybe that degree of splenomegaly that we're seeing in some of these other newly diagnosed cases, where that's not necessarily driving things, or maybe the kind of key factor in treatment decision-making, and really cytopenias are going to be a key part of the decision-making here, and sort of determining treatment and how you're going to go about this patient.
Dr. Kuykendall:
Yeah. So I'll come to you Steve. So, with a patient like this, what's your goal? What's your goal of therapy? What are you trying to accomplish? What are you talking with the patient about, hoping to achieve?
Dr. Oh:
Yeah, sure. So, I think considering that this patient is 82 years old, and for sure we're not talking about intensive treatment options, transplant's off the table, our goal here ideally is to help this patient as much as possible, in terms of addressing whatever symptoms they have, not worsening cytopenias any more than we need to, or have to, to achieve that. And it's a bit tricky, right? Because we're starting out with particularly low hemoglobin and platelets, and we want to choose amongst available options, a treatment that is going to find that, as ideal as possible, balance in terms of providing symptom and spleen benefit in this patient, without really being an issue in terms of safety, or essentially making things worse in terms of cytopenias.
Dr. Kuykendall:
Yeah. So, Tony, I'm going to ask you a bit of a historical question. So, before the approval of momelotinib and pacritinib, which we'll talk about for this case, what would've been the different kind of treatment approaches you could use in this patient, right? Again, we're talking about someone whose platelet count is 48,000, so probably not able to use ruxolitinib and fedratinib in this patient, but what was our historic approach to these folks?
Dr. Hunter:
Yeah, I mean I think that we didn't have a great approach, is the short answer. I think this is someone who, we don't know what exact symptoms they're having, we just know they're relatively symptomatic. You got to imagine probably a lot of that's driven by some of the cytopenias, and anemia fatigue, and things like that. So probably someone you're going to think more about anemia-directed agents for historically. Think about ESAs, things like danazol have been used in the past, IMiDs occasionally, for things like anemia in these sort of patients. But certainly, none of those are the most exciting thing in the world for a patient like this. And so, I think certainly historically, this was a very tough patient population to treat, and certainly still today, although we have a little bit better options, or at least some additional options now, but certainly one where it's a challenge, and I think addressing the cytopenias certainly historically was going to be the primary probably target of some of our treatments.
Dr. Kuykendall:
All right. Now we've moved into the modern world, Steve, we have other options. We still have these older options too. So, what kind of things would you think about when approaching this patient? What different options are on the table? I think there's a few. I think that it's certainly not a clear cut case.
Dr. Oh:
Yeah, absolutely. So, I think the most obvious here with the platelets being 48 or 46 or whatnot would be pacritinib. We know that pacritinib is approved specifically for patients with myelofibrosis with platelet count less than 50,000. So, if you just go from there, that seems like the obvious choice, and that I think is a very reasonable option in this patient, and in general, in patients with this so-called cytopenic MF subtype or phenotype.
But, we do have momelotinib as an option as well, and this can be used in patients with low platelets. We can use the drug down to platelet count of 20, per the package insert. So I think you do have those two options available. And with both of those drugs, not only can they be used with platelets in this territory, there is some prospect of anemia benefit, or at least anemia stabilization, with both of these agents. This has been shown in various ways with both drugs, that there is some capacity to improve anemia, but I think in general we would look at the two drugs as having overlapping profiles, where both can be used with low platelets, momelotinib perhaps a little bit stronger data with regard to anemia benefit overall, and in these cytopenic patients both could be reasonable options.
Dr. Kuykendall:
Yeah. And where would you factor in the idea of clinical trials to this, right? So, obviously, I mean we're limited in clinical trials, as many require a platelet count to be higher as well, but is this something that you would look for for a patient like this? What would you like to see out of a clinical trial to put this type of a patient on?
Dr. Oh:
I think absolutely this is a situation where if there were suitable clinical trial option, it would be a conversation worth having, knowing that although we do have a couple of the options that we just discussed as ones that we could consider, they're not going to solve everything, and there is certainly room for improvement. And so if there were clinical trial options, I would definitely want to bring those up for discussion. And thinking about what types of clinical trials, or what might be the appeal of that. Again, as you mentioned with platelets less than 50,000, there aren't going to be a whole lot of studies that will be for patients in that profile will be eligible, but there certainly are some that could be either for agents that could be used with low platelets, or even with the notion that it can improve the platelet count. And then there are a number of different investigational agents and studies with a focus on anemia. So, that is in particular, I think, where looking at clinical trial options could be relevant.
Dr. Kuykendall:
Yeah. So Tony, we have a lot of agents that are currently in development that are coming down the pipeline, that are targeting anemia in various different fashions. We have certainly luspatercept is approved for myelodysplastic syndrome, not yet approved for myelofibrosis. We have certain agents in development acting on the similar pathways. Let's say those were around, or let's say when you're making the decision in a patient like this who has some symptoms, a symptom score, at least it's listed as being on the higher side, but the spleen's not really bothersome. How do you decide between a JAK inhibitor, that we would say is more likely to, like pacritinib, or momelotinib, more likely to stabilize anemia, may improve it slightly, but also has these ancillary benefits of spleen, and symptoms, though those aren't necessarily present in this case as much, vs an agent that's really going to be targeting more directly anemia, and how do you make that choice?
Dr. Hunter:
Yeah, I think it's where it gets back to this is a personalized approach, and that's the tagline for the series here, but I think it's important, and certainly that sort of shared decision-making is really important too. I think if you kind of dig into that MPN SAS score, and really all their symptoms are driven by fatigue, and things that are really related to anemia, then probably you're going to get your most bang for your buck by trying to really target that anemia, and see what you can get for improvement there, knowing that from a platelet standpoint, most of what we have doesn't really help platelets. Some are less negatively impactful than others, but you're not going to probably have a huge impact on that.
And so, I think in a patient, if it's really is sort of cytopenias that are driving a lot of that symptomatology, symptomatic anemia, transfusion dependency, I think targeting that makes a lot of sense. And like you said, someone whose spleen is kind of borderline, on the edge of really enlarged at all, what's really going to be the impact as much of a JAK inhibitor here, I think it's a little bit more questionable. I think it's a little bit different if it's someone who's got anemia, and they've got night sweats, and bone pains, and itching, these sort of things, I think it's an easier answer there to say, "Hey, we're going to do one of these more cytopenia..." Cytopenic-directed JAK inhibitors makes a lot of sense vs someone where really it is more isolated to those cytopenias kind of driving the whole clinical picture.
Dr. Kuykendall:
Yeah, I think you made a good point there, with the platelets. I think oftentimes... I think pacritinib, especially, given its accelerated approval for platelets less than 50,000, there's the expectation that then when you use pacritinib, it's going to make the platelets go up. And that's not really it, right? It's that before this we didn't have any options for patients with platelet counts less than 50,000. And so, it's approved, but still your expectations with pacritinib should be improving quality of life, total symptom score, splenomegaly, and maybe some benefit with anemia that we're starting to realize more recently.
And so, I think that reasonable expect... Sometimes the expectations, given the approval, are a little bit different, but it helps to level set there. And then I mean, the last option, which we haven't mentioned yet, Steven, I don't know where the place could be for this, because when you look at this clinically, this patient's presenting almost with what looks like a myelodysplastic syndrome. And so, when we think about myelodysplastic syndrome, we often think about azacitidine, decitabine, now we have oral decitabine. So, is there a place for those types of agents in myelofibrosis? And if so, where is it?
Dr. Oh:
That's a great question, and I think really, a difficult question. I think, yeah, when you think about these cytopenic MF patients in particular, and it becomes a little bit more reminiscent of MDS, it does more so bring that question into your mind. But I would say overall, in terms of considering hypomethylating agents, generally speaking, I would be thinking of those in particular for patients who are more in the accelerated phase, or moving towards the blast phase. And careful consideration of risk vs benefit ratio in a older patient who may have other comorbidities, and the possibility that that line of treatment may essentially not help with the cytopenias, or make them worse. So, it would be a consideration, but as I mentioned, generally speaking, I would be thinking of those more so in the accelerator blast phase.
Dr. Kuykendall:
Yeah. And to be fair, the MDS world is often looking at the MPN world to try to take agents over, to see if they make sense over there. We're not just drawing on their field, they're drawing from us as well. So, I think this has been a great discussion. I do want to say that we got a few clinical takeaways. So, we know that pacritinib is approved for patients with myelofibrosis, and severe thrombocytopenia, that here defined as the platelet count less than 50,000.
Momelotinib has shown clinical benefit across three phase III clinical trials in patients with myelofibrosis, and thrombocytopenic patients have largely been included on those studies. Cytopenic myelofibrosis often presents with less prominent splenomegaly, more high-risk mutation, and has an overall very poor prognosis. Neither momelotinib nor pacritinib have been shown to reliably increase platelet counts. Rather, they can safely be given at full dose in patients that have preexisting thrombocytopenia, in an effort to achieve these spleen symptoms, quality of life benefits that we're aiming for.
So, with that, this brings us to the end of our case. Please see the other segments for further discussion about the latest research in myelofibrosis, or visit ascopost.com. Thank you guys for having me.
