Dr. Raajit Rampal:
Welcome to The ASCO Post Roundtable Series on Optimizing Management of Myelofibrosis: Balancing Watchful Waiting and Early Action. I'm Dr. Raajit Rampal from Memorial Sloan Kettering Cancer Center, and I'm joined by two terrific friends and colleagues, Dr. Jeanne Palmer and Dr. Prithviraj Bose. Please, Dr. Palmer, tell us about yourself.
Dr. Jeanne Palmer:
I'm Jeanne Palmer. I am a hematologist at Mayo Clinic in Arizona.
Dr. Raajit Rampal:
And Dr. Bose.
Dr. Prithviraj Bose:
Hi, I'm Prithviraj Bose, Department of Leukemia at MD Anderson. I focus on MPNs.
Dr. Raajit Rampal:
Terrific. Thank you both for being here. So today we'll be discussing the treatment and management of myelofibrosis with three patient case studies. Our third and final installment will focus on the treatment of a patient on active treatment for myelofibrosis.
So C.R. is a 76-year-old female who was diagnosed with myelofibrosis after presenting with profound fatigue, drenching night sweats, and early satiety. At the time of diagnosis, her spleen was about 7 cm below the left costal margin and about 1,100 cm3 on imaging. Her initial bone marrow demonstrated MF-2 fibrosis and 2% blasts and hypercellularity. And the NGS panel showed a CALR reticulin type I mutation, an ASXL1 mutation, and an NRAS G12D mutation. White count initially was 22,000, a hemoglobin of 9, and platelets of 90.
So the decision was made by the treating physician to start the patient on ruxolitinib at 5 mg twice daily and up titrate to 10 mg twice daily. And over this time, the patient's symptoms improved, and the spleen volume decreased. So three months after starting ruxolitinib, the white count was now 11, hemoglobin 8.5, and the platelets were 85,000.
Five months after starting ruxolitinib, the night sweats began again, as does the early satiety. The spleen now shows a modest increase in size on palpation, and the white count is now 28,000, with a hemoglobin of 7.5 and the platelets of 65,000. The treating physician reduces ruxolitinib to 5 mg twice daily, and the spleen further increases and the symptoms worsen.
So a situation that of course we often see, right? We have a nice initial response, and then the response is not sustained. So in a patient like this, and I'll start here with Jeanne, what are the thoughts going through your head about where this disease may be going, and how are you going to evaluate it?
Dr. Jeanne Palmer:
Well, first of all, I'm not really happy with where the disease is going. To see a loss of response to ruxolitinib that quickly definitely suggests a more aggressive disease, despite the fact that there's the CALR reticulin mutation. And so in this patient, I think even though they're 76 and they're a little bit on the higher spectrum of age for transplant, I would really think, is this patient somebody who could undergo transplant? Because there are definitely 76-year-olds out there who have a very good performance status, low comorbidities, and if we were able to identify a good donor and stuff, I would still consider for bone marrow transplant. So that would be one thing I would be thinking about with this patient.
Now in the event she wasn't a good transplant candidate, this is certainly somebody I would consider switching to a clinical trial if available, because ideally that would be where we would want to go. But if a clinical trial was not available, we'd be thinking of one of the other JAK inhibitors, such as something like momelotinib or pacritinib, based on the anemia as well as the low platelets.
Dr. Raajit Rampal:
Mm-hmm. Great. And, Prithviraj, what are your thoughts about that?
Dr. Prithviraj Bose:
I agree with Jeanne that this is overall not going well. The counts are not where you want them to be. They're precluding a good dose of ruxolitinib, and that's the key issue here. We are not being able to deliver the dose of ruxolitinib that we associate with good efficacy. So certainly we could do momelotinib or pacritinib. The counts are, I think, low enough that both are reasonable, and there's significant anemia, and the platelets are close to 50. So we could certainly do those things, but then also investigational, because again, there are some high-risk features here. The CALR is, of course, a good mutation to have, the type I, but then there is ASXL1, which is certainly not so good.
So here, depending on what we are trying to achieve, one might think of different investigational drugs. For example, with imetelstat, we have a suggestion of overall survival, improvement, but perhaps not that good for spleen. So I think that is how I would think about my different trials. Nuvisertib is great for symptoms, not as much for spleen. So just examples to show that... I think I would look at what is the main thing I'm trying to achieve for this patient. Obviously survival is always number one, but then what are the more immediate issues as well as I try to pick a trial.
Dr. Raajit Rampal:
So all terrific points, and we are fortunate now to be in an era where we have options. I think that is a very different world from pre-2018 where we had one option at that point. But keeping in mind that, of course, we're all based in referral centers, and a lot of MPN is, of course, taken care of in the community, and for the sake of our audience, in an era where we have multiple JAK inhibitors, how do you think about whether or not the next right step is to just try a different JAK inhibitor vs going down the route of an investigational therapy? Obviously this is part philosophical, but I think it's important for our audience to hear this discussion. Prithviraj, how do you think about that?
Dr. Prithviraj Bose:
Yeah, Raajit, I don't think there is one correct way of thinking about it. We know that momelotinib, pacritinib, particularly in this patient's case where we have a cytopenic phenotype, so fedratinib not as much in the discussion here, but certainly those have good efficacy in the second line. We know from MOMENTUM, SIMPLIFY 2, and then the pacritinib trial that they certainly work. I think what we don't know as well is what is the durability? Are we having an anti-clonal effect? And this is 76-year-old patient; if we are thinking of prolonging survival here without transplant... Of course, transplant, if it is reasonable, should be considered.
But if we are thinking of not doing transplant, then perhaps some of the newer drugs, the investigational agents that have shown promise at a biological level... Imetelstat is one example. Of course, the trial is randomized, which creates its own issues, but then those things have appeal there. We don't have any data, but we have an exciting agent from Ajax, the type II JAK2 inhibitor, which is able to, at least in the lab, overcome resistance to the type Is. These things do come to mind. I think if I have a trial, I would probably pursue a trial, but again, it would have to fit the clinical needs of the patient.
Dr. Raajit Rampal:
Jeanne, how about you? How do you think about this?
Dr. Jeanne Palmer:
Well, I think the participation in the clinical trial is always fantastic, but you also have to take into account the patient's preferences and also logistics. I've had patients who live very far away. Depending on how frequently they would have to come in, whether it's a pill or an infusion, these things all may impact how the patient is going to do. At the end of the day, we know that this patient has a higher-risk disease, and so do they want to spend the time that they have left traveling to go get a clinical trial option every other week or not may impact some of their decision-making. The way I look at it is if it's a possibility that they could participate in a clinical trial if they live locally, if it doesn't put undue financial stress on them, I think it always is great and I certainly encourage patients to do so. But sometimes it's just not going to work based on logistics and finances, et cetera.
Dr. Raajit Rampal:
And I think these are all great points because there isn't one approach, and it really is about, I think, what we have in terms of options, what we think the likelihood of success is with a conventional option, and I think a really great point by Jeanne, which is we have to think about logistics. Because it puts the patients through quite a bit to go through a trial, but sometimes it is our best option.
So our key takeaways here is that, as was mentioned, there is data to support other JAK inhibitors in the post-ruxolitinib setting. And of course, we have fedratinib, we have pacritinib, we have momelotinib, all of which have second-line data. But of course, the one thing we didn't touch upon is transitioning from one JAK inhibitor to another. That has to be carried out carefully.
And I think, as I'm sure our panelists would agree, especially when tapering down ruxolitinib, it's really important for our audience to know that we have to go in a gradual manner, and sometimes we do end up overlapping one JAK inhibitor and another. But it's important to realize that the onset of efficacy can take time with non-ruxolitinib JAK inhibitors. And so there should be an expectation set with patients that there may be a period of time where symptoms are not as well controlled before they become better controlled. And of course, there's no standard current way to approach this, I would say, but it is something that needs to be considered carefully. And finally, one has to think carefully about the possible benefits of switching to an alternative JAK inhibitor vs an investigational agent, I think, as Dr. Palmer and Dr. Bose have very nicely laid out.
So this 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.
