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 other experts and friends in the field, Dr. Jeanne Palmer and Dr. Prithvi Bose. Please introduce yourselves. Dr. Palmer?
Dr. Jeanne Palmer:
Hi, my name is Jeanne Palmer. I'm a physician at Mayo Clinic in Arizona, and very happy to be here.
Dr. Raajit Rampal:
Prithvi?
Dr. Prithviraj Bose:
Hi, everybody. Thanks for having me. I'm Prithvi Bose at MD Anderson, Houston, Texas. I lead the MPN section there.
Dr. Raajit Rampal:
Today, we'll be discussing the treatment and management of myelofibrosis with three patient case studies, and our first installment will focus on the treatment of a patient with newly diagnosed post–polycythemia vera myelofibrosis. The case is a 71-year-old male with a 10-year history of polycythemia vera. The patient was managed primarily with hydroxyurea aspirin, and aside from pruritus, the patient had largely felt well.
Over the past 6 months, the patient noted progressive fatigue, drenching night sweats, and weight loss of about 15 lbs. Examination is notable for splenomegaly with a spleen of about 14 cm below the left costal margin. And imaging of the spleen shows the spleen is 3,000 cm3. The white count here is 18.5 with 6% peripheral blasts, hemoglobin 10.5, and platelets of 181. The bone marrow, of course, is performed and the marrow shows 90% cellular marrow with MF-3 fibrosis and 5% myeloid blasts.
Cytogenetics show normal karyotype, and the NGS panel is notable for a JAK2 mutation and an ASXL1 mutation. So the patient is given a diagnosis of post-PV myelofibrosis and by risk-stratification DIPSS, this is intermediate-2 risk disease. Guys, not a situation we see uncommonly, right? This is something that we, of course, deal with. And in thinking about this patient who we have before us, what are our goals in terms of the treatment plan for this patient and what are the major risks that you're worried about? So maybe, Jeanne, I'll start with you.
Dr. Jeanne Palmer:
Great, excellent. Yeah, this is a very common problem that we see in the clinic. I think when I approach these patients up front who have myelofibrosis, I break it down into two parts. Number one, what are the things in the short term that I need to do to try to make them feel better? And then number two, what are the long-term risks and the long-term planning with regards to transplant, et cetera?
In a patient such as this, obviously, with a spleen enlargement, he would likely benefit from a JAK inhibitor, and there are several that could be used up front. And then long-term, he's 71, hard to know how his performance status is, but this is somebody that we would be at least going through the process of figuring out whether he'd be a good transplant candidate.
Dr. Raajit Rampal:
Terrific. And, Prithvi, building off of that idea, if we think about the first goal of treating this patient, which is to make the patient feel better, but also to alleviate the splenomegaly, how do you think about which JAK inhibitors that we would use in the first-line setting, given that we now have multiple options?
Dr. Prithviraj Bose:
Yeah, exactly. Raajit. Obviously, a very relevant question these days and completely agree with Jeanne. We've got to think about short-term and long-term here. This is a patient that has some worrisome features. There's these 6% blasts that's never good. And obviously, spleen is enlarged, older patient, so transplant may be a little iffy, but certainly needs to be considered, of course.
So here, I think given that ruxolitinib has a proven survival advantage and is arguably the best drug for shrinking the spleen, and the anemia here is there, but not too bad, perhaps somebody that will tolerate ruxolitinib, perhaps with some anemia support. I think all things considered, I'd probably go with ruxolitinib.
Dr. Raajit Rampal:
I'll agree with everything. Obviously, we all would agree, we've got to first get the patient feeling better and get the disease under control. And assuming the patient's performance status is adequate, I think we would certainly consider the patient at least for a stem cell transplant. I guess getting to the question of first-line therapies, obviously, Prithvi, you've gone through ruxolitinib. We have, of course, momelotinib, for which there can be an anemia benefit, but as you're pointing out, this patient doesn't have a profound anemia to begin with.
Fedratinib, certainly, we have data from JAKARTA that that could be a suitable first-line option here, of course, with the caveats of GI toxicities and Wernicke’s encephalopathy, but these are things, of course, that can be dealt with. And I think we would agree that pacritinib, in this case, is probably not warranted given that the patient's platelet counts are preserved. So, if we are all to agree on ruxolitinib as our first-line therapy for this patient, how would you approach dosing with the idea that we know that anemia and thrombocytopenia are going to be side effects that are on target and that we will have to deal with? How would you approach dosing? Jeanne, I'll start with you.
Dr. Jeanne Palmer:
In these patients, I'm usually somewhat conservative and start them at 10 mg twice a day, recognizing that they probably will drop their blood counts and hopefully this can mitigate a significant drop. As we know, there is evidence that indicates higher doses are more effective in spleen size reduction. So this would be somebody, if they tolerated it, especially if I wasn't able to achieve a good spleen response, I would try to push that dose up. But given that anemia and thrombocytopenia, in particular, are more profound, especially during the first few months of therapy, I usually would start at a lower dose.
Dr. Raajit Rampal:
And, Prithvi, how about you? How would you approach dosing in this patient?
Dr. Prithviraj Bose:
Of course Jeanne makes a great point and the hemoglobin is 10.5, you don't know what it's going to do when you start the ruxolitinib, but again, like Jeanne already alluded to, ruxolitinib is a dose-dependent drug and its survival benefit is also dose-dependent via the spleen. The better the spleen response, the better the survival, and the spleen response is dose-dependent. So that is a discussion I would have with the patient that, "Maybe let us go with package insert dosing based on the platelets."
Sorry, I forget what the platelets were, but 15 or 20 mg BID based on the platelets and support the anemia with other drugs. Again, I want to go back to what Jeanne said, this can be tough. In these patients, perhaps what we learned from the REALISE trial where you start lower, like she said, 10 mg BID and then go up, that could be very reasonable too. I think it's a discussion I would have with the patient and see what their tolerance is for the anemia.
Dr. Raajit Rampal:
Excellent points by both of you, and I think for the audience listening, maybe the way to put this into summary is to know that we will see treatment-emergent effects like anemia and thrombocytopenia. And the question really becomes how are you going to mitigate that risk? And as Dr. Palmer has talked about, doing a dose-escalation study for which there is data from the realized study is a reasonable thing, but the key with that strategy, of course, is to remember to dose escalate and not get stuck on a dose. We want to optimize the dose because, as I think everyone has talked about we, that really correlates with patients doing well long-term.
And to Dr. Bose's point, if one is going to start with the package insert label dosing, then being mindful of introducing on drugs to support anemia early on is a thing of paramount importance in trying to make sure that the patient is able to deal with the first couple of weeks or months of therapy. Moving on, we've talked about stem cell transplant, so if the patient did elect to proceed with a stem cell transplant, and let's assume this patient is a candidate, what degree of disease control do we need to achieve? If we think about AML, right? In AML, it's obvious, we want the patient to ideally have MRD-negative disease, depending on the genotype before they go into a transplant. Of course, that's not something we can achieve in myelofibrosis, but the question still remains, how much control do you need to have before you go in? I will start with Dr. Palmer, our transplanter here, for comments.
Dr. Jeanne Palmer:
In terms of, again, timing for transplant, there are some information that we do not have on this patient, but if we decided that the patient is indeed going to go to transplant, in this situation, I would probably try to get the spleen under control, get a good spleen reduction, and then bring them to transplant once we have the maximum spleen response. I think this provides them with the best opportunity for good long-term survival. Usually, it's about 2 months, we try at minimum, to give ruxolitinib or a JAK inhibitor prior to proceeding with transplant.
But again, achieving an optimal spleen response, I think, really does generate a benefit, not just from the spleen itself, but from the overall suppression and some of that inflammation going on. So that would be generally how I'd approach it. Now, in terms of the blasts, at 6% blast, this is not something I think needs a special attention prior to moving forward with transplant. If the blasts were above 10%, between 10% and 19%, that becomes somewhat questionable of whether you would use something like a hypomethylating agent up front or not. There's some data from Europe suggesting that it's not needed. It's generally something I do, especially if I think the patient will tolerate it. But in this patient, I think once you achieve a spleen response, I'd move forward.
Dr. Raajit Rampal:
Great. No, important points because it's hard to know where you need to start off before you launch the transplant. So along those lines, obviously, Jeanne has hit on some of the measurable things, but then the question is both medical and philosophical, which is, what is the right timing from the patient's perspective? Because in so many cases, patients feel better when they start therapy, but how do you then say to somebody or convince somebody it's time to go to transplant? So, Prithvi, how do we address this very difficult question?
Dr. Prithviraj Bose:
In this patient, like I said at the beginning, the 6% blasts worries me. Our group had previously demonstrated that if your blasts are between 5% and 9%, the outcome is more similar to that of accelerated phase, 10% to 19%, than it is to that of chronic phase. So that certainly makes me nervous, but like Jeanne said, I don't think I would do anything special for it.
I think the spleen needs to be shrunk and ruxolitinib does that as well as any other drug. And again, dose dependence is important, which is why I think here I would want to get that spleen down as quickly as I can, perhaps support the anemia as we alluded to already, and take them to transplant. As far as a optimal size, of course, I would look to Jeanne. I don't transplant myself, it's whatever Dr. Popat at our place is happy with.
Dr. Jeanne Palmer:
Yeah, I don't think there's an optimal size. There's some data suggesting when the spleen is greater than 15 cm below the left costal margin that that may impact outcomes. And ideally, the better the spleen reduction, probably the better the outcomes. But I don't think we have clear data with, let's say we get them to 2 cm below the left costal margin vs 5. Less than 5 would be, I think, the minimum that I would try to achieve.
Dr. Raajit Rampal:
And along the lines of trying to measure where we are, how would you best monitor progress? So making this a more granular question, do you get serial imaging of the spleen to ensure that you're actually getting the spleen size reduction or do you rely on the physical exam? Is there a role for serial bone marrow biopsies? This is a question that I think we often hear from referring patients. How do you approach serial monitoring? Go ahead, Jeanne.
Dr. Jeanne Palmer:
I usually see how my exam is. If my exam is consistent, I'll do maybe an image up front and I say, "Well, geez, the spleen is 27 cm," and I feel their spleen of 15 cm below the left costal margin. I'll feel fairly confident that my physical exam is probably going to reflect what's going on. There are the patients who have a spleen, maybe that's more posterior, that I'll do an exam and I will definitely not appreciate the full amount of the spleen, in which case, I think serial monitoring is important with imaging. And in terms of which type of imaging, I think ultrasound. There's no radiation, it's quick and easy to do. I don't repeat bone marrow biopsy. I do right before the transplant, but it's not something that I feel strongly needs to be repeated in patients. I think the peripheral blood gives us a very good amount of information. So putting patients through an unnecessary procedure may not be needed.
Dr. Raajit Rampal:
Fair enough. Prithvi, what are your thoughts about that?
Dr. Prithviraj Bose:
I'll just add that I think we want to transplant them at best response, and that's not well-defined, but I wouldn't do anything extra beyond what Jeanne said, just serially, see what the exam tells us, maybe an ultrasound, and not wait unnecessarily and just take this patient to transplant when we think they've gotten their best benefit from the JAK inhibitor.
Dr. Raajit Rampal:
All outstanding points. Maybe just to summarize for our audience the key clinical takeaways. So the treatment of patients with myelofibrosis really needs to be individualized and the main symptoms and signs requiring treatment should be considered. The FDA-approved JAK inhibitors have different efficacy and side-effect profiles, and that really should be considered when making treatment decisions.
And finally, as we've talked extensively about in the last few minutes, the transplant really remains the only curative therapy, and the timing of transplant needs to be carefully considered when making a treatment plan for the patient. 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.
