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 in New York. And I'm pleased to be joined by my terrific colleagues, Dr. Jeanne Palmer and Dr. Prithviraj Bose. Dr. Palmer, please introduce yourself.
Dr. Jeanne Palmer:
Hi, I'm Dr. Jeanne Palmer. I am a hematologist at Mayo Clinic in Arizona.
Dr. Raajit Rampal:
And Dr. Bose?
Dr. Prithviraj Bose:
Hi, I am Prithviraj Bose from MD Anderson in Houston. I work in MPNs.
Dr. Raajit Rampal:
Terrific. Today we will be discussing the treatment in management of myelofibrosis with three patient case studies. Our second installment will focus on the treatment of a patient with myelofibrosis and anemia. To level set, K.L is a 56-year-old man who presents with progressive dyspnea on exertion. He had previously been very active. He notes unexpected weight loss of about 10 lbs and endorses early satiety. He notes left upper quadrant discomfort when exercising. In the examination of the patient's notable for splenomegaly at about 12 cm below the left costal margin. And the spleen volume is about 2,100 cm3. Blood counts demonstrate a white count of 4.3 with 3% circulating blasts, hemoglobin of 7.9, and platelets of 140. A bone marrow exam is performed and demonstrates a 70% cellular marrow with MF-3 fibrosis and 6% myeloid blasts. Cytogenetics show normal karyotype, and the myeloid NGS panel shows a JAK2 mutation and a U2AF1 mutation.
The diagnosis rendered is primary myelofibrosis and by risk stratification, this is a DIPSS+ high-risk patient and by the MIPSS70+v2.0, a very high-risk patient. Folks, again, a patient that is not uncommon in our clinical practice at all. Thinking about this patient on a high level, again, what is our goal for treatment of this patient, both in the short term and the long term? And what are the things that you are most worried about in terms of the patient's course in the short and long term? Maybe Dr. Bose, I'll start with you. What are your thoughts?
Dr. Prithviraj Bose:
Raajit, quite a few things concerning in this patient—a young patient, we definitely want to cure them. Overall survival is our overarching goal and we have a significant anemia. In terms of poor prognostic factors: less than 8 hemoglobin here, transfusion range, and then the U2AF1 mutation, which is not a good one to have. It is prognostically high risk as well as worsens the anemia. And then also the 6% blasts in the marrow is a little disconcerting, higher than what we would typically want in a chronic-phase patient. Quite a few things here. I think get them to transplant as soon and as safely as possible is the big picture of how I would look at it.
Dr. Raajit Rampal:
As you said, a very worrisome profile and high risk of progression. Jeanne, what are your thoughts about treatment approaches in a case like this? And I guess what are the things that you would be targeting to treat specifically?
Dr. Jeanne Palmer:
In this patient, I agree you really want to try to get them to transplant as quickly as possible, but even in the best circumstances it takes at least 4 to 6 weeks to get them to transplant. And in terms of treatment approaches, we could always try something like momelotinib, which may have a benefit on inflammation as well as having a benefit on the hemoglobin. Whether that response will be seen in a timely enough fashion to move forward with transplant is not clear, I don't think, plus getting the drug approved could take some time. That being said, especially if there look like there's going to be a delay, that might be a good approach for them.
If they do require packed red blood cells, I usually don't limit packed red blood cell transfusions due to concern over alloimmunization for transplant, especially with the number that this patient would need in the interim. And I would certainly try to keep them as functional as possible, maintaining a good performance status and sometimes that does require having a hemoglobin higher than 7, I usually try to keep them around 8. But I think in this patient it's really trying to optimize and expedite the timing of transplantation.
Dr. Raajit Rampal:
That being said, we had talked in a prior case about how do we optimize somebody for transplant. In a setting like this where the patient certainly has a markedly enlarged spleen, what is the threshold for transplant? What would you deem as good enough to get the patient to the transplant? Maybe Jeanne, I'll start with you.
Dr. Jeanne Palmer:
In a patient like this, especially who's younger, I probably would use higher-intensity conditioning. Even though I would prefer to have the spleen shrunk down to maybe less than 5 cm, ideally even get a complete spleen response, I probably would weigh that against the fact that I know that I can use a more intensive conditioning regimen, which definitely will help shrink the spleen as well. That again, using momelotinib in a situation like this I think is a really good option, especially if you can get it covered in a timely fashion, which has become easier these days. I would probably try to do that, but I may not be as stringent on getting that spleen response just because I know I can give some chemotherapy as conditioning that may help achieve some of that as well.
Dr. Raajit Rampal:
And Prithviraj, what are your thoughts about that?
Dr. Prithviraj Bose:
I think know Raajit is certainly no one right answer, but I think I would lean towards momelotinib as well in this patient, like Jeanne was saying. The hemoglobin is less than 8, and I'm likely to get into trouble with ruxolitinib if I try to use a high dose. And again, we know that the higher doses are more effective for the spleen and that has a survival correlation. But again, it is not easy to deliver the high doses in somebody who's starting out at 7.9. And I know that SIMPLIFY-1 told us that showed us that the two are equivalent for spleen in the front line. While there is more data over these 15 or so years with ruxolitinib, I think based on momelotinib's efficacy for anemia and its noninferiority for spleen in SIMPLIFY-1, I'd probably go with momelotinib in this patient.
Dr. Raajit Rampal:
Great. Excellent thoughts from everybody. Obviously we want to cure the patient. That is the goal here and getting to transplant is the way we do that and some optimization it sounds like is what we would all do, but with a limitation because we need to get to transplant ultimately. A question that comes up from time to time is we know from other diseases, MDS being the best example. Perhaps when somebody has long-term red cell transfusion dependence, we often do use iron chelation, but the data in myelofibrosis is not so clear. I guess the question here is if the patient were to become red cell transfusion dependent, and let's assume that going to transplant gets delayed for whatever reason, is there a reason for iron chelation in a case like this or in general? Prithviraj, what are your thoughts about that?
Dr. Prithviraj Bose:
Great question Raajit. I don't know that there is one correct answer. We have not been big users of iron chelation at MD Anderson, but I am aware of some data that showed I think an improved event-free survival. I'm not opposed to it if the ferritin is greater than 2,500. They've had... What is it? 20 to 40 units, something like that. I know this is of course a naive patient, but I'm not opposed to it. I don't use it a lot, but it would be okay.
Dr. Raajit Rampal:
And Jeanne, how about you in the context of transplant specifically?
Dr. Jeanne Palmer:
I don't use a lot of iron chelation, especially pretransplant, just because of some of the side effects. It can increase the creatinine suggesting some impact on the kidney. And interestingly, with regards to the ferritin, although initially there was a study that suggested a higher ferritin may impair transplant outcomes when they actually went and looked at ferritin vs, say for example, iron based on MRI, the ferritin is actually not as predictive as looking at the iron load based on the liver MRI. It's not something I generally would do and hopefully, especially given the fact that you can use so many different types of donors these days with haplo, mismatched, unrelated, et cetera, most people should be able to make it to transplant before they would hit that point of needing 20 units of packed red blood cells, which is generally when we start to think of it. The good thing about doing a transplant is when somebody's hemoglobin normalizes, if they still have a high ferritin, you can do phlebotomy actually after the transplant and really reduce that ferritin level fairly well.
Dr. Raajit Rampal:
Excellent, great points by both. This is a question I think that certainly comes up a lot in referral cases. Let's assume that the patient gets started on momelotinib and you know what? They're having a reasonably good response. The hemoglobin has now come up to, let's say 9 to 10, patient feels much better, the spleen has shrunk. Obviously the genetics are still concerning, but how do you now think about the timing of transplant and now the patient is functioning, is back to normal life activities. How do you have that discussion with a patient and how do you think about it internally? Maybe Jeanne, I'll start with you.
Dr. Jeanne Palmer:
Actually, I had a case like this where a patient had pretty bad anemia. We were all set to go to transplant. She started momelotinib, her hemoglobin came up, she's like, "I feel great, I'm going to go on a trip to Japan." And she came back and she's like, "I don't actually even want to go to transplant now." And I really tried to convince her she had very high-risk molecular markers. And I feel like even though we can improve the anemia with momelotinib, that doesn't take away that upfront anemia, which does carry a poor prognosis, especially aligned with the U2AF1 mutation.
Whereas a patient like that, I might say, "Hey look, if you really want to take that trip to Japan that you've looked forward to go for it. I think Japan's a fantastic place to visit, but I also don't think that should be something delayed." Now, fortunately, ultimately a few months after the patient came back, she said, "Actually, I think I will go forward with transplant." And we transplanted her and she's doing fabulous now. But it is something that even if they've had a good response to it, especially with high risk mutations, I generally encourage them to move forward with transplant with a good response.
Dr. Raajit Rampal:
And then if they can sneak in a trip to Japan, even better. Prithviraj, the same question. This is a situation which it's a good problem to have, but we run into the situation quite a bit.
Dr. Prithviraj Bose:
Absolutely. This comes up a lot because since we are all clinical, we are asked this a lot by patients, "What's coming down the pike? Are there potentially curative drugs?" We've talked about mutant selective drugs, Mutant CALR for example, new generations of JAK inhibitors, stuff like that. There is a lot to talk about, but I do remind them, and I'm sure we all do here, that we still have the four JAK inhibitors. That's all we have approved. We do not know about what's going to happen with these newer drugs. And the four JAK inhibitors are not curative. They have brought dramatic benefits to patients, but they're not curative and transplant is the only known cure. This patient is 56, they have some high-risk features. I would not wait. I would transplant them at their best response again.
Dr. Raajit Rampal:
I think to wrap this segment up, I think we're all very much convinced by the genomics and what the genomics tell us about prognosis, which is I think in many ways inescapable and knowing that our treatments have efficacy but have limitations on efficacy as Dr. Bose just said, important considerations.
I think the key clinical takeaways here that again, the treatment of patients with myelofibrosis needs to be individualized in the main symptoms and signs requiring treatment should be considered. Anemia remains a major unmet need and there are numerous approaches to anemia. We've talked about momelotinib in this segment, but obviously other drugs like ESAs, luspatercept, have been used. And finally, one thing to consider, which we didn't really get too much into today, is the impact of anemia. And we know we have the RR6 model. For our audience, this is something that gives us insight into how a patient's prognosis is affected by treatment with ruxolitinib. And one of the key things from the RR6 model is that patients who have transfusion-dependent anemia, it has a negative prognostic impact on a patient and something that we need to be mindful, even if we are making some headway in a patient's clinical course, that remains a detriment in terms of prognosis.
To conclude, 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.
