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Managing Accelerated- and Blast-Phase Myeloproliferative Neoplasms

Posted: 4/4/2024

This is Part 3 of Addressing Unmet Needs in Myelofibrosis, a three-part video roundtable series. Scroll down to watch the other videos from this roundtable.

 

In this video, Drs. John Mascarenhas, Gabriela Hobbs, and Abdulraheem Yacoub discuss the management of accelerated- and blast-phase myeloproliferative neoplasms. The patient is a 57-year-old man with primary myelofibrosis diagnosed 5 years ago. He is receiving ruxolitinib at 10 mg twice daily with good spleen and symptom control and RBC transfusion every other month. Complete blood count reveals WBC of 19 × 109/L, hemoglobin 8.1 g/dL, platelets 120 × 109/L, 11% blasts, and many nuclear RBCs. His spleen is 5 cm below the left rib and nontender on exam. A bone marrow biopsy reveals 30% cellularity, an increase in atypical megakaryocytes in tight clusters, grade 3 myelofibrosis, and 5% blasts by IHC. Next-generation sequencing reveals JAK2 V617F 45%, U2AF1 23%, and TP53 15%; karyotyping shows a 1q minus and 17p deletion.

 

In the conversation that follows, the faculty review the three phases of myelofibrosis, the treatment options for advanced-phase myeloproliferative neoplasms, and whether the percentage of blasts in the bone marrow or peripheral blood affect a patient’s eligibility for transplant.



Transcript

Disclaimer: This video transcript has not been proofread or edited and may contain errors.

Dr. John Mascarenhas: Welcome to the ASCO Post Roundtable series on Addressing Unmet Needs in Myelofibrosis. I'm Dr. John Mascarenhas. I'm a Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, and I'm really glad and happy to be joined by my colleagues and friends, Dr. Gabriela Hobbs and Dr. Abe Yacoub. And I'll let each one introduce themselves. Dr. Gabriela Hobbs: Hi, I'm Gaby Hobbs. I'm an Assistant Professor at Harvard Medical School in Boston and the Clinical Director of the Leukemia Service. Nice to be with you today. Dr. Mascarenhas: Thanks for joining us. Abe? Dr. Abdulraheem Yacoub: Hello. Thank you for the invitation. My name is Abdulraheem Yacoub, I'm a Professor of Medicine at the University of Kansas and I specialize in myeloid neoplasms and MPNs. Dr. Mascarenhas: All right, fantastic. So we have a terrific assortment of experts in the field and we're going to be discussing the treatment and management of myelofibrosis. In this final installment, we're going to focus on managing accelerated- and blast-phase MPN. So this is case 3, and this is Mr. DT. He's a 57-year-old gentleman with primary myelofibrosis that was diagnosed 5 years ago. He's receiving ruxolitinib at 10 mg twice daily with good spleen and symptom control, and receives a red cell transfusion of one unit about every other month. The white count is 19,000, hemoglobin is 8.1, platelets are 120,000, and on manual review of the peripheral blood smear, there's 11% blast. That was confirmed by flow cytometry that showed, again, 11% blast. And there's a lot of nuclear red blood cells. So he's got a leukoerythroblastic blood picture, and on exam his spleen is 5 cm below the left costal margin, but nontender on exam. So the first question I'll pivot to Gaby. What are the three phases of myelofibrosis? Maybe give us a sense of what we're thinking about in terms of phases. Dr. Hobbs: Sure. So myelofibrosis, like chronic myeloid leukemia, is thought of as a triphasic disease where it starts out in this chronic phase where usually we don't see increased blasts and usually patients have less cytopenias, although not always. Patients can then progress through this kind of intermediate stage called accelerated-phase disease, which is really kind of an in-transit stage where the blasts are increased between 10% and 20%, not quite meeting criteria for blast phase. And then anything over 20% would be considered blast phase or blast crisis or similar to acute myeloid leukemia. I guess when thinking about those three conditions, it's important to note that there's really no biological marker that separates accelerated phase from blast phase. This is kind of an arbitrary definition that we've made for MPNs in the same way that we've made for myelodysplastic syndrome. So I think, for me, accelerated-phase patients are really somebody that just kind of raises a lot of red flags as somebody that's not likely to be in a stable condition for a long time. Dr. Mascarenhas: Okay, excellent. Yeah, so it is really a continuum. It's not necessarily discrete phases necessarily. And Abe, in this patient who's on ruxolitinib and feels well, and let's say the spleen is pretty well controlled, but has 11% blasts in the peripheral blood. What would be your next steps in the workup and management? Dr. Yacoub: So this is an unfortunate progression of myelofibrosis. Unfortunately, patients with myelofibrosis within chronic phase usually go through a progressive phase of myelofibrosis and they benefit from JAK inhibitors as their line of therapy. That's really the classic presentation and management algorithms we have for myelofibrosis. Patients who are accelerating through increasing blasts are actually transforming into a different neoplasm that is more immediately life-threatening and, predictably, going to progress into the blast phase or acute leukemia equivalent. And those patients would require a different path and they would require a different therapy that is not necessarily JAK/STAT pathway inhibitor–based, and they would require more disease-directed therapy. So once a peripheral blood blast identified as increased, that is an automatic pull for restaging of the disease. This would require a bone marrow examination, re-evaluation of the karyotype, re-evaluation of clonal evolution by mutational analysis and really, a serious look into the transplant candidacy for these patients if that had not been done before. Dr. Mascarenhas: Okay, excellent. Let’s say in this case, we repeated the bone marrow biopsy, and the bone marrow biopsy shows 30% cellularity, an increase in atypical megakaryocytes, both in tight clusters, it's MF grade 3 (MF-3), can't obtain an aspirate for obvious reasons. And by what we have in immunohistochemical staining from the marrow shows about 5% blasts. JAK2 is 45%, U2AF1 is 23%, the dreaded TP53 is 15%, and it is noticed on karyotyping that there's a 1q minus and a 17p deletion, and I know Gaby's already nervous about those findings. So what do you do? How do you incorporate or integrate that data into treatment decision? Gaby, what do you think? Dr. Hobbs: Yeah, you're right. I am definitely very, very concerned about this patient. For sure, in patients with myelofibrosis that are in an evolution, sometimes we see the peripheral blasts come up and then they go back down again. So it's sometimes hard to know, really, what to do with those elevated circulating blasts. But in this case, more than the blasts, I'm really concerned about the mutations that they have and in particular the TP53 mutation, which really portends a worse prognosis, and like I mentioned before, this is a person that's likely to evolve and so really needs to meet with a bone marrow transplant specialist, get typed, and really consider a transplant sooner rather than later. I think that the most difficult decision in this case is how do you treat them right now? Can you make an impact on their transplant outcomes by trying to lower these mutations, and do we have available therapies that can do that? This may be a person that would benefit from hypomethylating agent therapy, to try to make an impact on that TP53 mutation in particular. And then the question is do you continue the ruxolitinib if they're having symptomatic benefit from it? So trying to do those two together may be the right approach for this patient before transplant. Dr. Mascarenhas: Okay, excellent. So you touched on hypomethylating agents, and there's a lot of data that we don't have time to review in detail today that would suggest that induction chemotherapy like we typically use, for example 7+3 for our de novo AML patients probably is not the best approach here unless it's followed immediately by a transplant. So we often do pivot to hypomethylating agents and we do have data, for example from our MPN-RC 109 study, which was a multicenter perspective study in which many of you have participated in, which show that the addition of decitabine at the traditional 5-day 20 mg/m2 every 4 week schedule, has a median survival of about 9 to 10 months. And it's just important to put into context, the median survival for patients who effectively have blast-phase disease is about 3 to 5 months. I show one slide here to just impress upon the listeners that those patients who have P53 mutations, and of course we can have a discussion about whether it's one mutation or multiple hits in this patient, patient had a mutation and a deletion of 17p, so has multihit P53, at least in our analysis, the combination of ruxolitinib and decitabine seen to correct the negative impact of P53 mutation on outcome. Of course, we had a discussion previously about the role of transplant, and Gaby pointed out, very importantly, I think the only potential for someone like this to really have a meaningful extension in survival would be a transplant. But ideally we do try to reduce the burden of disease going into the transplant. So often a hypomethylating agent like decitabine, in combination with ruxolitinib for example, could be used to achieve that. We are exploring the use of IDH inhibitors, and IDH1 and 2 inhibitors probably happen in about, collectively, 20% of patients with advanced-phase disease, and it's a marker of advancing disease and disease evolution. There's been a number of studies that would suggest that venetoclax does not appear to improve overall survival in this patient population. I think this is a really interesting finding that perhaps, unlike de novo AML, we don't necessarily see that improvement in survival outcomes with venetoclax added to treatment regimens for MPN-related leukemia or blast-phase disease. One question I have for Abe is, for you in your center, does the percentage of blasts either in the bone marrow or the peripheral blood smear matter for the determination of transplant? Do you have to have them eradicated from the peripheral blood? Do they have to be below a certain number? Does it make a difference? Dr. Yacoub: So yeah, it's a very good point, and again, we understand that this patient's life expectancy without a transplant is by all measures short and measured in months and one year survival would be even unexpected with medical therapy. So this is a situation where a serious consideration of transplant is absolutely necessary for these patients, even with lesser control of their disease. The other factor here is that in patients with MPN in blast phase, even if you achieve a response with their bridging therapy, they're not going to achieve a remission. They just might revert to a chronic phase of their MPN and they probably will continue to have residual disease. So this MRD-negative status is not something that we can even achieve. So with those limitations, we understand that some disease control before the transplant is better than no disease control before the transplant. And that's really the only guidance, is that this disease might be better than completely uncontrolled frank leukemia status going to an allo, but in achieving a complete remission is also almost unrealistic in those patients. So the maximum disease control before a transplant, and usually there are other medical reasons to factor in the transplant, whether there is an available donor, whether there's actually a clinical trial that can be used as a bridge to that. I would like to emphasize that probably those patients need to be managed at a tertiary center in which a lot of these options in clinical trials are available. So this is definitely a case where probably should be referred to a center with higher volume transplant with skills in transplanting patients with MPNs. Dr. Mascarenhas: Very well put. And I'm going to ask Gaby a very straightforward question. What percent blast do your transplanters want to see when you hand that patient with myelofibrosis over for their conditioning regimen? Dr. Hobbs: Good question and not that straightforward. I mean I think they like to see less blasts. Like Abe said, we realize that we're not going to get MRD-negativity with these patients. I would say that they do like to see them get cytoreduced. In this case, I would say that that's an easier goal to accomplish because the blast percentage is really not that high and it's just 5% in the bone marrow. But like you know, there haven't been studies really demonstrating a benefit to getting patients to transplant without any blasts or in remission in this specific scenario, this accelerated-phase scenario, with improved outcomes with transplants. I would imagine that as our therapeutics improve, it makes sense that if you lower the level of those mutations and get those patients closer to an MRD-negative state, that they would do better. But oftentimes these diseases are so difficult to handle pre-transplant that it's difficult to have that higher bar of an expectation to get these patients into better remission before transplant. Dr. Mascarenhas: All right, excellent. So I think we've highlighted for the listener that these patients are obviously challenging to manage. They're heterogeneous, they're not uniform in the way they present and behave. They're often molecularly complex. They often harbor these mutations like spliceosome mutations, U2AF1 or P53 mutations that would suggest that outcomes are going to be rather poor and that even treatments for those in those settings can be limited, including transplant. And there are centers that really think twice about transplanting a multihit P53-mutated patient because the outcomes can be quite poor. I think the other point that is elucidated, which highlights an unmet need, is there's lack of data that clarifies what is the optimal or maximum amount disease burden reduction that's required. And if blasts or the surrogate for it, is it less than 10%, 5%, no percent in the peripheral blood and bone marrow? That still remains somewhat unclear, and for sure is variable depending on where you practice and the expectations of the transplant team. Again, to summarize our clinical takeaways for this case, advanced-phase MPN is associated with poor outcomes, and induction therapy alone does not meaningfully improve outcomes. So if you've got this MPN blast-phase patient, particularly if they're not a transplant candidate, I would not give 7+3 to that type of a patient. I do think that the decitabine-based therapies do afford better tolerability. Patients can remain ambulatory and they are a mechanistically rational approach that has data for improved survival, but often can be used as a bridge to transplant. Adding venetoclax may improve response rates, but there's really no data that suggests that it improves overall survival. So I don't typically add it unless I'm really trying to rapidly cytoreduce to get someone immediately to a transplant. Again, I know we've said it multiple times, I'll say it again. Transplant really remains the only option for significant survival benefit in these patients with advanced disease, if they are transplant-eligible, and of course, that's the minority of patients. So that really highlights the unmet and urgent need for better therapies for our patients with MPN accelerated and blast-phase disease. And to Abe's point, that's why these patients really should be, whenever possible, referred to a tertiary care center with expertise in this area and clinical trial options. 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. I want to thank Gaby Hobbs and Abe Yacoub for joining me in this series and I appreciate your participation and thanks for joining us.

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