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 now. Steve, can you go ahead?
Dr. Stephen Oh:
Yeah, thanks, Andrew. My name is Stephen Oh. I'm an Associate Professor of Medicine at Washington University School of Medicine in St. Louis, Missouri. Thanks for having me.
Dr. Kuykendall:
And Tony?
Dr. Anthony Hunter:
Yeah, thanks for having me. Tony Hunter. I'm one of the faculty members here at the Winship Cancer Institute of Emory University in Atlanta, Georgia.
Dr. Kuykendall:
Awesome. So, today we'll be discussing the treatment and management of myelofibrosis, utilizing three patient case studies. So, our first installment will focus on the management of a newly diagnosed patient with myelofibrosis, and moderate anemia.
So, here we have a 62-year-old male, presents to his primary care doctor with progressive abdominal pain, fatigue, and night sweats. He's found to have anemia, hemoglobin of 8.5, leukocytosis of 12, mild thrombocytopenia, with platelet count of 115. His abdominal ultrasound shows that he has some splenomegaly, with a maximum spleen length of 19 cm.
A myelofibrosis symptom assessment form, total symptom score is performed, and shown to be 28. A bone marrow biopsy is then done, which confirms primary myelofibrosis, and molecular testing reveals the presence of a JAK2 mutation as well as a U2AF1 mutation. Normal cytogenetics are found and the EPO level is 42. So, patient initially is referred for a transplant, but expresses at least at this point in time, unwillingness to proceed down that road. And so, now we kind of turn our attention to how to approach this patient in general. And so, Tony, I'm going to draw you in first. So, in evaluating this case, what factors did you see from this presentation that would drive this patient's prognosis the most?
Dr. Hunter:
Yeah, so I think a couple of things in this case that lend itself to our risk stratification methods. And I think certainly there's several of these out there that we use, more clinical models like the DIPSS and the DIPSS Plus model. Obviously some of our more molecular models that we use now, the MIPSS70 model. So, a couple of things that would sort of upstage him or upstratify him in this case. I think certainly one is the degree of anemia, so hemoglobin was 8.5 in this patient. So, certainly this is something that's going to be present in really all of our risk stratification models, certainly in a number of studies, has been shown that anemia is really impactful in prognosis in myelofibrosis patients, and certainly a fair degree of anemia here for this patient. Certainly that's one factor for here.
Another one would be the mutations. So, this patient does have the U2AF1 Q157 mutation, so that's going to be another one that is now classified as one of our high molecular risk mutations. Certainly one that's going to show up in our more molecularly based models, like the MIPSS model, that's going to upstage them a little bit too in that risk stratification. So, those are probably the two of the biggest things. Certainly has some symptomatology here. Not entirely sure what all those symptoms are, if they would sort of classify as our constitutional symptoms or not. That would also sort of give them a point in some of these models as well. But number of these factors that would play into some of our risk stratification, and sort of assigning prognosis for this particular patient.
Dr. Kuykendall:
So in your practice, what are you using the most? Do you have a specific model you use? Or is it kind of a mashup of a few different models?
Dr. Hunter:
Yeah, honestly, I do usually punch it into a few models, just to give us the best answer. I do think obviously there's added value by incorporating these molecular features in this day and age, and certainly we have next generation sequencing done on certainly all of our patients at our cancer center. But really in the community too, most centers are getting this done. So, we have that data for most patients. I think it does add certainly the presence of these higher risk mutations, especially when thinking about things like transplant, and sort of selecting the right patient for that. So, certainly using multiple models, but certainly favor the more molecularly based models at this point in time.
Dr. Kuykendall:
Yeah, I think I find using these different models, or at least thinking about prognosis to be something that we certainly do, especially on initial visits with patients, but I think it is a challenging aspect of things. So, Steve, I'd kind of... From your perspective, how much time are you spending discussing prognosis with patients on their initial visit to see you? Or is there a timeframe, or approach that you have?
Dr. Oh:
Yeah, I try to individualize that discussion with each particular patient, especially on that first visit, because when we have at our disposal, as was mentioned, a variety of different prognostic scoring systems that we can look at to get an understanding of overall survival, risk of transformation to acute leukemia, and that is very helpful to understand the overall severity of the disease, and the longer term outlook. But I think on the first visit, it's important to consider, what is the utility of that information from the patient's perspective? And understanding as well that in many cases on the first visit, the patient may be feeling quite overwhelmed, and their most practical focus will be on what are the treatment recommendations.
So, when we take that into account, and understanding that for the most part, these prognostic scoring schemes in terms of the treatment decision making, largely ties initially to the question of transplant or not, if that is addressed already, or is off the table for a variety of reasons, then that part is not necessarily as relevant to that treatment decision making. I do ask every patient when I first see them, "How much information do you want me to cover about prognosis? Are you wanting those kind of hard numbers? Would you prefer to focus on treatment recommendations?" So, it depends. Some patients want every single piece of information you can give them, with the most granularity. And others, again, would prefer to say, "Let's just talk about what you recommend for treatment."
Dr. Kuykendall:
Yeah, I think that's actually a good point, because our prognostic scoring systems rarely impact the therapies that we offer. Really, they should almost be very separate. Aside from transplant, they're not asking the same questions. And I think one of the things that I try to mention with patients is that these prognostic scoring systems are made up of historical patients, and ideally we are moving the needle to some degree in this disease, at least the different options we have, and maybe a better understanding of the disease. We'd like to move the needle more, for sure, but we should be outperforming some of our prognostic models in many cases, because we're drawing from databases that go back decades.
So, kind of turning our attention back to this patient. So, as a reminder, this 62-year-old, not wanting to go to transplant right now, coming in with some kind of constitutional-ish symptoms, splenomegaly, mild, kind of moderate anemia, leukocytosis, mild thrombocytopenia. So, Tony, what variables are you looking at right now, beyond prognosis, and talking about just approach to treatment? What are you looking at when trying to formulate a treatment plan?
Dr. Hunter:
Yeah, I think Steve's comments about the risk stratification, and how it impacts treatment, it is a good one. I think it's an important initial fork in the road for transplant, but it really doesn't impact beyond that a whole lot necessarily how I'm starting treatment in these patients. And so, I think certainly when we're thinking about things like JAK inhibitors, obviously the presence of splenomegaly, and symptoms related to that are key. Obviously symptomatology. Some of these constitutional symptoms, sort of this patient in the case was fairly symptomatic by the MPN SAF score and total symptom score. So, those are I think, key factors about determining, for example, who needs a JAK inhibitor right now, and as far as part of their treatment regimen, because although we have them available, not necessarily every patient needs one, at least not right away.
I think beyond that, certainly other factors that come into play. Obviously, cytopenias are a big one, especially this day and age. We finally have a few treatment options available, instead of just sort of one to fall back on. And so, we are able to tailor therapy at least a little bit more. And certainly cytopenias, presence of anemia, thrombocytopenia are a big factor in selecting some of these newer JAK inhibitors, I think. And so, certainly the presence of symptoms, splenomegaly, cytopenias. Beyond that, I think it's important we're not just treating numbers on a page. So, a patient's preferences are important. Certainly, obviously, this patient wasn't really interested in proceeding with transplant right away, so that's certainly a factor. What's the fitness of the patient? What are their treatment goals? What are their comorbidities? Certainly all factor in sometimes to how we're going to at least initially think about treatment in these patients.
Dr. Kuykendall:
Yeah. So, I think you mentioned... You hit on a lot of things. It really is an individualized discussion with each patient, even just preferences, throwing options out there, and describing the pros and cons of each thing. And sometimes patients may say, "Well, based on that, this is how I feel, or this is the specific kind of goals I'm going for." That shared decision making. Right? All right, so you kind of told us what you'd think about all the different things you'd factor in. So, I'll rely on Steve to tell us, how's he going to treat this patient? Let's make a decision. Unfortunately we can't ask the patient right now what they want to do, but let's say, if you're the patient, and you're the physician, now you're sharing that decision with yourself, what are you thinking here?
Dr. Oh:
Yeah, I think this is a really good example. I think that the constellation of features in this case is a very typical presentation for a patient with myelofibrosis, meaning they have a variety of symptoms, they have some degree of splenomegaly, they have some degree of cytopenias, and that leaves you with a couple of different options for initial treatment amongst the JAK inhibitors. But I think the most obvious ones to consider for this patient, for initial treatment would be either ruxolitinib, or momelotinib.
And as Tony was mentioning, in some ways it was simpler if we go back a few years, because we had the one choice, ruxolitinib, and so it would be essentially straightforward, that that would be almost certainly your recommendation for first line treatment. And I think in many cases like this, that would continue to be my recommendation, because I would expect that the patient would experience significant symptom improvement, they would have improvement in their splenomegaly, and the symptoms associated with that, and any degree of cytopenias that could be worsened by ruxolitinib, we will sort of take that with ruxolitinib because it's a trade-off with those other benefits.
Now it's become more complicated with... In a good way, with the other options, including momelotinib. So, here now in this case we think about, well the patient has baseline anemia, hemoglobin 8.5, platelets are okay, but they're a little bit on the lower side. If we were to fast-forward in a case like this, if we had started the patient on ruxolitinib, inevitably their platelets are going to drop, at least to a certain extent, their hemoglobin is going to at least drop a little bit and maybe stabilize. And that may or may not result in whatever dose we start with, that there may be some dose reduction required for the ruxolitinib.
Now again, regardless, the patient may experience significant symptom and spleen benefits, so that may be overall a good choice. But, thinking about momelotinib now, we have another option, where we would also expect symptom and spleen response, but we would not as much expect a worsening of anemia. In fact, we might see an improvement in anemia, at least to a certain extent, and less of an effect on the platelets overall as well. So, it's a balance between, or a trade-off between these different considerations, and I think certainly a case could be made to either start with ruxolitinib, but consider a switch to momelotinib if the cytopenia has become limiting, and/or actually consider momelotinib upfront, because of the cytopenia, specifically the anemia in this patient.
Dr. Kuykendall:
Yeah, I mean I think you pulled up a lot of good points there. So, obviously these frontline patients with more moderate anemia, where that hemoglobin's in a range where you're concerned that if you start them on ruxolitinib, it may drop them into needing transfusions, they present a challenging case, and I don't know if we know exactly the right approach, or which is optimal, or if there is one. I think they're both options right now. If we try to look back, we had a clinical trial, SIMPLIFY-1, that compared momelotinib and ruxolitinib head-to-head. But the question I'd pose to you, Tony is, is this a trial that you can look at, given the fact that in that trial most patients actually had hemoglobins greater than 10? It was like about 70%, 75% were really not that anemic, right? So, can you draw on that trial? Or are you looking at something else to make that decision?
Dr. Hunter:
Yeah, I mean, I think we still need to use the data that we have, and that's sort of what we have to best make decisions. I think in reality, the patients we treat in practice, many of them aren't going to fit into these clinical trial criteria in reality. And so, I think it's something to draw on. Like you said, it's not necessarily exactly like a lot of the patients on that trial, and you saw in that study very comparable spleen reduction, maybe a little bit less symptom benefit from momelotinib, but then to counteract that, a little bit more positive impact on anemia. So, I think this is especially that moderate anemia range, like Steve mentioned, I think this is where that shared decision making comes into play, I think, about what's going to be the best option.
And I think there are practical considerations sometimes for these sort of things too. I think an older patient, cardiovascular comorbidities, maybe they're not going to tolerate anemia quite as well, vs a little bit young, healthier patient who's doing fine with their hemoglobin of 8.5. I think for those of us that treat patients at big centers, like most of our cancer centers, is that I have patients that come from four hours away. So, if they need to come in for once a week to get a blood transfusion potentially, is going to be a little bit more impactful than a patient who lives right down the street, and maybe is going to be easy to pop in, and get counts checked. Sometimes those practical considerations are really important in treating patients, as well, and will factor in to the decision-making here.
Dr. Kuykendall:
Yeah, I think that's a great point. So, with that I'll say, I mean we have a couple of key clinical takeaways from this case. We know that momelotinib is approved for patients with myelofibrosis and anemia, and it's agnostic to line of therapy, which is why we're talking about does it make sense in the first line, or second line. Momelotinib was shown to be non-inferior, like you said, to ruxolitinib in terms of spleen volume reduction in the SIMPLIFY-1 trial. Anemia and thrombocytopenia are common reasons for dose reduction and treatment discontinuation in patients treated with ruxolitinib. So it's something that we're factoring into our initial decision making.
And baseline anemia has not really been shown to impact spleen responses to ruxolitinib. However, baseline anemia and anemia that develops on therapy may impact overall outcomes. And so, I think it is something that we need to take into account, but we do know we can still get good responses, at least in terms of spleen responses in patients treated with ruxolitinib who are anemic.
So, that brings us to the end of this case. Please see other segments for further discussion about the latest research in myelofibrosis, or ascopost.com. Thank you guys so much.
