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 have them introduce themselves now. So Tony, can you go ahead and introduce yourself?
Dr. Anthony Hunter:
Yeah, thanks for having us today. So, Tony Hunter, one of the faculty members here at Winship Cancer Institute of Emory University here in Atlanta, Georgia.
Dr. Kuykendall:
And Steve?
Dr. Stephen Oh:
Yeah. Hello everyone. My name is Stephen Oh, I'm at Washington University School of Medicine in St. Louis, Missouri.
Dr. Kuykendall:
Awesome. Thank you guys for being with us today. So, today we're going to be discussing the treatment and management of myelofibrosis with three patient case studies. Our second installment will focus on a patient with myelofibrosis who develops anemia while on ruxolitinib. So, here we have a 75-year-old female who presents with night sweats, itching, and abdominal pain. She's diagnosed with primary myelofibrosis. Her hemoglobin is 10.1, platelet count 185, white blood cell count 9. NGS is done, that reveals the presence of a CALR mutation, as well as a TET2 mutation. A spleen ultrasound is done, shows a maximum spleen length of 22 cm, and an MF symptom assessment form total symptom score is performed, which shows a number of 42, so moderate to severely symptomatic.
So, she initially is treated with ruxolitinib, 15 mg twice daily, and responds well, with a 50% reduction in her spleen length by palpation, and she reports significant symptom improvement. Two years later, she presents now with progressive fatigue, her hemoglobin is down to 7.8, and her platelet count is 111. The night sweats, itching, and abdominal pain that she had are still well controlled on her ruxolitinib. So, a bone marrow biopsy is performed, and continues to show myelofibrosis without any increase in blasts. An NGS is done, which shows the acquisition of a new ASXL1 mutation, in addition to her previously demonstrated CALR and TET2 mutations. She was offered a transplant, but declines this on personal reasons, doesn't want to move forward with this. So, I'll start with you Steve. So, how do you go about approaching a patient with anemia that develops while they're taking ruxolitinib?
Dr. Oh:
Yeah, thanks. So, this is, I think, a relatively common scenario for patients with myelofibrosis who may begin treatment with ruxolitinib, and experience the positives, in terms of spleen and symptom benefit, and that may be maintained for an extended period of time, but eventually, the patient develops progressive anemia. So, we encounter this relatively frequently. And in terms of how to approach that, I think I would back up and say that one important point is to have the appropriate counseling with the patient when they first start ruxolitinib, in terms of what to expect.
As far as anemia, now in this case it's been quite some time since the patient started ruxolitinib, but again, I think setting expectations in terms of what is going to happen, what to expect with anemia, that it's not going to get better with ruxolitinib, and that in fact it's likely to get worse over time, whether that's early on in the course of treatment, or more so later in the disease course, which in that case, and in this setting, brings into question how much of this may be treatment related from the ruxolitinib, vs actually the progressive disease itself, and progressive anemia as a typical sequelae of that disease.
But back to how I approach this. So, I think you have a couple of options to consider in this kind of situation. One is to say, well the ruxolitinib is working well overall in terms of spleen and symptoms. In this case I believe that those aspects are relatively maintained, in terms of their responses. So you could say, "I want to continue the ruxolitinib ideally, and consider other options to address anemia." That could include ESAs, consideration of other anemia directed therapies, luspatercept, and things like that. Or you could say, "Well, can we consider another option that would entail switching off of ruxolitinib, so that we might be able to mitigate that anemia while maintaining ideally a similar degree of spleen and symptom benefit?" With one of the obvious choices in this case being momelotinib.
Dr. Kuykendall:
Yeah. So, I think obviously you mentioned a few things there I wanted to hit on. So, you started, "Hey, when we're dealing with anemia that occurs on ruxolitinib therapies, you probably should have that discussion before starting ruxolitinib, right? This shouldn't be a surprise to anyone that this does develop, especially a couple of years down the road, as we see in this case. And then I think when you're talking about approach from a treatment standpoint, you kind of talked about two main options. One, do you want to add on to the patient who's benefiting from ruxolitinib, or do you want to switch? Switch to another agent that still has the potential to retain some of those benefits, but may have additional benefits as well?
And we'll talk about those different options and some of the details of that in a moment, but I think one of the things I'd want to bring to Tony, and say is, Steve kind of talked about the idea of kind of ruxolitinib-induced anemia, vs anemia that can be expected with the disease. And I think that could be a challenge clinically sometime to differentiate, and sometimes we don't know. But I think, how could you differ? What are some clues that would make you think, "This is more related to the ruxolitinib, vs more related to the disease?" And the follow-up to that is, does it matter?
Dr. Hunter:
Yeah, it's a great question. I think Steve obviously alluded to some of this a little bit, is that we see this sort of on-target effect of anemia, in the majority of patients treated with ruxolitinib. And what you usually see is you're going to see a good drop in those patients in the first 8 to 12 weeks. And so, that's why it's important to counsel these patients early on, and sort of know to expect a little bit of that. You're going to see this drug-induced sort of drop in the hemoglobin, that generally, at least in that early part is going to kind of drop, and then hopefully stabilize for a while thereafter.
And then over time, in a patient like this, when you're seeing this anemia that's developing a couple of years down the road, otherwise well controlled, maybe that clues you in, maybe this is a little bit more of a disease-related sort of progression, or disease-related anemia that's sort of developing over time, vs just purely a drug-related change, where you've been on this stable dose for a long time, and hopefully saw some of that effect early on. So I think that's one aspect of it, is just the clinical situation.
And then to go along with that, are you seeing other signs of change in the disease? Are you seeing worsening leukocytosis? Are you seeing thrombocytopenia develop in this patient? Right? They developed a new ASXL1 mutation, so you've had some molecular evolution with a new high-risk mutation that may sort of explain some of this change, as well. So, I think a number of these things are all sort of what you're trying to look at to sort of get a little bit of an idea about whether that's more drug-related, is it disease-related? But again, there's no perfect test. We don't have a lab test to say, "Hey, this is ruxolitinib anemia vs this sort of disease-related anemia." Maybe Steve can find that in the lab for us. Yeah.
And then like you said, does that distinction really even matter? I mean, I think to some degree, yes. We talked a little bit about right about, obviously anemia is a strong prognostic factor in myelofibrosis, and maybe drug-related anemia doesn't have quite that same impact as we've seen some of the COMFORT studies, and things, as sort of true disease-related anemia. Regardless, you still have to treat what's in front of you, so you're still going to have to practically deal with that, whereas in some cases, maybe it doesn't matter quite as much about in some practical situations what is driving it, vs how you're going to manage it, is maybe more important.
Dr. Kuykendall:
Yeah. Kind of a follow up to that differentiation, or the distinction between disease-related anemia, if you have a patient who develops anemia similar to this patient, so a true drop, I think they started in the 10s, going down into the 7s, and this is a few years after starting therapy, is your general approach to rework the disease up? Are you getting a new bone marrow biopsy? Are you getting another NGS panel? What's your approach to this? I think everyone's a little bit different.
Dr. Hunter:
Yeah. I do think anytime you've seen sort of a reasonably significant clinical change, where maybe you're going to think about changing treatments, maybe you're worried about disease progression, it's very appropriate to repeat a marrow, look at molecular features. Again, you saw evolution in this patient for example. So, I do think that's appropriate, and I think patients ask a lot, "How often do I need a bone marrow biopsy?" And my usual response is I don't do serial bone marrow biopsies at some set interval, just to sort of monitor things. I do them when the clinical need arises, when we think we're going to do something with that information or need some information to sort of explain things for us. And so, that's sort of the way I think about it.
And I think in a patient like this, where 2 years out they've been doing well, and now you're seeing changes in the counts, appropriate sort of time to sort of reevaluate the disease from that standpoint. Obviously always get the low-hanging fruit too, right? Look at things like iron deficiency, and any other sort of non-direct disease related causes of anemia, because those things certainly come up in patients with number comorbidities and things like that going on as well.
Dr. Kuykendall:
Yeah, I think that's a good point that you bring up at the end, as far as making sure you're not ignoring other reasons for someone to become anemic. Obviously it's more likely to have a common reason for anemia than an uncommon reason. So, certainly kind of looking into those other factors that could be easily corrected and normalize things. So, Steve, coming back to you here. So, in this case, so if you had a preference, would you continue this patient on ruxolitinib, and add something to that initially, or would you make the switch?
Dr. Oh:
Yeah, so I think in this situation, it really comes to, in a lot of ways, practical aspects, and also patient preference. If, let's say you were considering adding ESA, or luspatercept, is it going to be inconvenient for the patient to come in to receive those treatments? Would that be administered by your treatment center, or would it be local, and how can that be arranged? Some patients would say they'd rather keep with something that's worked well for them overall for the extended period of time, and add that new agent to it, whereas others might say, "No, I don't want to add on another type of treatment, and if you can give me another oral medication instead maybe that would be my preference."
So, I don't think there's one right answer here, and certainly in many cases we might cycle through a couple of different of these paths to find one that might be the most beneficial. But, I think certainly a strong case to be made here, that consideration of changing to momelotinib, and with the expectation that we can maintain a similar degree of spleen and symptom benefit, while potentially mitigating to at least some extent that anemia would be a very reasonable course of action.
Dr. Kuykendall:
Gotcha. All right. So, now I'm going to kind go rapid fire between... Back and forth between both of you to say, let's say we switched this patient to momelotinib, and they're going from, we said initial dosing was 15 mg twice daily, so we're assuming they're still on the same dose, and assuming we're switching directly to momelotinib, how do you think... Tony, you go first. How would the spleen be impacted? What would you expect? What's your general feeling?
Dr. Hunter:
In a patient like this, who's still been responding, you're switching to momelotinib, which was shown to be relatively comparable in spleen responses, I would expect pretty stable disease from that standpoint, as far as hopefully maintain spleen response. Probably not a huge change overall, and this is a patient who's still responding from that sense in spleen right now.
Dr. Kuykendall:
All right Steve, you're up next. What would you expect to happen with their symptoms? So, overall their symptoms have been relatively stable, although fatigue has worsened.
Dr. Oh:
Yeah, so I think from here, I would draw in part from the SIMPLIFY-2 study, which was in some respect a switch study, where patients went directly from ruxolitinib to momelotinib. So, with that in mind, and knowing that the symptom response generally was maintained, that is what I would expect here by switching to momelotinib.
Dr. Kuykendall:
Yeah, certainly that was probably the most exciting thing out of SIMPLIFY-2 was that patients switching over had this kind of comparable improvement in their symptoms when that was actually what held them back in SIMPLIFY-1. So in the second line, there may be certainly a benefit in switching to momelotinib there, maybe different mechanisms of symptom improvement. All right, you're next, Tony. What would you expect in terms of the anemia? I mean, this would be the reason we'd switch over, right? Hemoglobin decreasing.
Dr. Hunter:
Exactly. Yeah. So this is your main reason for change. So, certainly the hope here is that you're going to see some hemoglobin improvement over time. And certainly, if you look at some of the data from MOMENTUM and other studies, you can see that anemia improvement hopefully relatively early on in the first 8 weeks or so. And so, hopefully that's something you're going to see relatively early on. But certainly that's the hope here, is you are going to see some anemia benefit or anemia improvement in this switch. Yeah.
Dr. Kuykendall:
Yeah, I think the best data doesn't really apply to this, but when SIMPLIFY-1, when everyone was kind of randomized to momelotinib vs ruxolitinib, and then after 24 weeks those that were on ruxolitinib switched over to momelotinib, you could see this kind of rapid improvement back to baseline in those patients. Now, that was clearly more treatment-related anemia, right? Because we're talking about that first 24 weeks. Now, when you're years down the road, it's not clear if that necessarily is the same thing you'll see, but I would expect, as you mentioned, to see some improvement there with anemia. And then Steve, I'll let you talk about platelets. What do you think would happen with the platelets? They only dropped to 111, but would you expect any change there?
Dr. Oh:
Yeah, I would expect that there'd be some rebound in the platelets, that they would come up a little bit, particularly if you're coming from a dose of 15 mg BID of ruxolitinib. So, they're not going to return to normal necessarily, but I would expect that they would increase a little bit. And I would also just reinforce with the anemia aspect that that jump in SIMPLIFY-1 with the crossover was relatively early, and not exactly the same as this situation. So here, what I would say is in my experience, after momelotinib was approved, if anything the expectations from both sides, patient and provider, were perhaps, in my experience, a little bit too unrealistic, in terms of what degree of anemia to expect. So, here, understanding that it's been an extended treatment period with ruxolitinib, this degree of anemia is at least partly, if not primarily driven by the disease itself, I would dial back the expectations in terms of what degree of anemia improvement to expect.
Dr. Kuykendall:
So, expecting maybe more stabilization in terms of that, than necessarily rapid rebound, like we saw in SIMPLIFY-1.
Dr. Oh:
Yeah.
Dr. Kuykendall:
Yeah, I think that makes sense. And then lastly, Tony, quality of life, what do you think? Overall beneficial? Same? What do we think?
Dr. Hunter:
Yeah, I mean I think we both, or have all said, I think the hope is that sort of spleen and symptom response is going to stay fairly steady, and that maybe you get at least some anemia benefit. I think in this case, the biggest thing that's sort of worsened from a symptom standpoint was fatigue, not surprisingly, with the drop in the hemoglobin. So, I think if all else considered equal, and our sort of assumptions are correct, that hopefully you get at least some modest benefit with maybe some improvement in at least the fatigue that's related to anemia. I think fatigue's really tough. There's so many things that impact fatigue, and it's not all driven by just anemia. So I think, I have patients where sometimes you get that hemoglobin bump, they feel no better from fatigue, and it sort of just shows that there's other disease related, and life related factors. So, I think that can be a little bit of a wild card from that standpoint, but hopefully at least a modest benefit.
Dr. Kuykendall:
Wonderful. And again, that's our goal, is quality of life, at the end of the day, that's what we're hoping to accomplish with these folks. So thank you guys for that. So just some key clinical takeaways. So, really the MOMENTUM study is what ultimately got momelotinib over the hump, and led to its approval, in addition to the data that was already created with SIMPLIFY-1. But this study demonstrated that momelotinib was superior to danazol, actually, as an active control in achieving symptom and spleen responses in patients with myelofibrosis who were anemic and had previously been treated with ruxolitinib.
Anemia that occurs during treatment with ruxolitinib may convey a poor prognosis, and something that we certainly need to take into account as we're monitoring patients, and anemia during ruxolitinib therapy may be related to treatment or underlying disease, as we talked about, though this distinction can be difficult to determine.
So, that brings us to the end of this case. Please see the other segments for further discussion about the latest research in myelofibrosis or visit ascopost.com. Thank you, guys.
