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Recognizing the Role of Hematopoietic Stem Cell Transplant in Myelofibrosis

Posted: 4/4/2024

This is Part 2 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 role of hematopoietic stem cell transplant in patients with myelofibrosis. The patient is a 64-year-old woman with CALR-mutated primary myelofibrosis, diagnosed 8 years ago, who started receiving ruxolitinib 2 years ago for worsening weight loss and increasing splenomegaly. She is recently retired, active, and has three living siblings in good health. Her spleen is nonpalpable on exam. Complete blood count reveals WBC of 8 × 109/L, hemoglobin of 8 g/dL, platelets of 56 × 109/L, peripheral blood blasts of 1%. Cytogenomic labs reveal 46 XX with deletion 20 q, and next-general sequencing of peripheral blood shows CALR mutation 45%, ASXL-1 19%, and EZH2 5%. Her dose of ruxolitinib is lowered to 5 mg twice daily due to her decreasing platelet count and easy bruising, but she has never required RBC transfusion.

 

In the conversation that follows, the faculty discuss the prognostic factors in the first 6 months that predict overall survival in myelofibrosis, factors to consider when determining whether a patient is a candidate for stem cell transplantation, and the available treatment options for patients with worsening splenomegaly and thrombocytopenia while receiving ruxolitinib.



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 Mount Sinai in New York, and I'm really happy to be joined by my two colleagues and friends, Dr. Gabriela Hobbs and Dr. Abe Yacoub. I'll let each one introduce themselves. Gaby? Dr. Gabriela Hobbs: Hi everyone, my name is Gaby Hobbs. I'm the Clinical Director of the Leukemia Service at the Mass General Hospital in Boston, and I specialize in the care of patients with myeloproliferative neoplasms. Dr. Mascarenhas: Welcome, Gaby. Abe? Dr. Abdulraheem Yacoub: Hello. 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, welcome, and thanks guys for joining me today. Today, we're going to be discussing the next case in the series, and this is the treatment and management of myelofibrosis. Case 2, this is Ms. MK. She's a Caucasian 64-year-old woman with a calreticulin mutated primary myelofibrosis diagnosis that was made about 8 years ago. She was initially started on ruxolitinib approximately 2 years ago in the setting of worsening weight loss and increasing splenomegaly. The local physician had obtained an ultrasound that showed about 20-cm spleen length. Just to give the audience a sense, a normal spleen is about 13 cm. Her past medical history is notable for hypercholesterolemia and gastritis. She's on ruxolitinib at this point, 5 mg twice daily. Omeprazole, atorvastatin, and zolpidem to sleep. She recently retired from teaching, but she's very active and she loves doing Zumba three times a week. She has three living siblings that are all in good health. Again, she's 64, CALR-mutated MF on low-dose ruxolitinib and has available siblings. On exam, spleen is not palpable. Her white count’s 8,000, her hemoglobin is 8, her platelets are 56,000. The blast in the peripheral blood smear are 1%. Cytogenomic labs are sent off, and she has a 46 XX with the deletion 20q and sequencing shows, from the peripheral blood, CALR mutation 45%, ASXL-1 19%, and EZH2 5%. So the dose of ruxolitinib had been dropped to 5 mg twice daily due to decreasing platelet count and easy bruising, but no massive bleeding, no massive GI or epistaxis. And she's never received or required a red blood cell transfusion. In this case, and maybe I'll start with Gaby, what additional information might be important for deciding on what to do in this scenario? Dr. Hobbs: Definitely highlights some of the many challenges of taking care of patients with myelofibrosis that have had this diagnosis for many years. So in terms of additional information at this point, I'd like to know is she a good transplant candidate? And are her siblings matched to her? As we know that patients for myelofibrosis, specifically, that have a matched sibling usually have better outcomes that those have unrelated donors. Those would be the first two pieces of information that I would want to have as I think that she is definitely at a point where transplant should really be a consideration, if it hasn't been already. Dr. Mascarenhas: And Gaby, you've done a lot of work on the role of transplant and how it integrates into the care of our patients, and I think this is a great case to highlight, and I want to specifically know is, when would you have referred this patient to your transplant colleagues, just even for the evaluation? Would it have been at diagnosis, would it have been when she was maybe optimized on ruxolitinib or would it be as she's beginning to "fail" or perhaps not succeed as much? Dr. Hobbs: Yeah, what a great question. I think probably the hardest part of taking care of patients with myelofibrosis is deciding when is the right time for transplant. In this patient, it really highlights how long these discussions can take place because she's been living with myelofibrosis for many years and obviously has been doing relatively well, has not needed transfusions, and she had been doing okay presumably on ruxolitinib. And so although I generally say that my answer would be if a patient with DIPSS intermediate-2 or greater, if I meet a patient like that, I would usually refer them to transplant at that point, because I know they're going to need a transplant. In practice, that's also really difficult because these conversations can then last for many years. So I would say if that person wasn't referred to transplant initially or when they became that higher-risk patient, certainly at this point, when a patient is found to have several different risk factors that make me really concerned, the ASXL-1 mutation, the dropping blood counts, and having to reduce that ruxolitinib dose are three things that would really make me concerned. I would say if this person has not seen a transplant doctor yet, now is really the time to do that. Dr. Mascarenhas: Excellent. And Abe, I'm going to ask you a question that's a little bit off-center from this discussion, which is I think important to hit on, is this patient's CALR mutated. Knowing that information, let's say from the beginning, would that have influenced your decision-making in terms of the use of a JAK inhibitor? Are your expectations different? Dr. Yacoub: Good question. To start with, the driver mutation in general has not been predictive of response to JAK inhibitors, particularly ruxolitinib is a JAKSTAT pathway inhibitor, and it's equally effective regardless of the driver mutation. So whether patients are JAK2-mutated or have other driver mutations or no known driver mutations, that was not predictive of response or lack of response. So that would not necessarily be, not in 2024, a therapeutic decision-maker for us in terms of that. What strikes me is that, historically, we have identified CALR-mutated patients are the more favorable patients who are likely going to have a more indolent disease and they're going to have longer journeys with their disease and less risk of progression. Unfortunately, this is not the story or the narrative for this individual patient. She obviously has clonal evolution, she has abnormal karyotype, she has high-risk mutations, she has cytopenic phenotype, and she's unable to tolerate an effective dose of ruxolitinib that is associated with a clinical benefit of survival. So judging by her course, she's not really behaving in a favorable way, which is, again, going back to Gaby's point, sometimes it's not just the initial risk, it's really the evolving risk based on how patients fare with therapy might hinge us towards escalating care for these patients. Dr. Mascarenhas: Abe, that's a great response. I want to just have a sense from you, what is the optimal dose of ruxolitinib? She's on 5 mg, twice a day. What would you say is the minimal effective dose that you ideally want patients on? Dr. Yacoub: 10 mg twice a day of ruxolitinib is the least dose that has been statistically superior to placebo in the comfort studies. And anything less than that is probably not effective. And now, 2 years on therapy and patients are unable to escalate to more than 5 mg twice a day, that is not a successful therapy. I think this is definitely time to switch or to change course. Dr. Mascarenhas: All right, excellent. And this is a nice way to transition to prognostication on ruxolitinib. And of course there's the RR6 model, which you can just find online and then plug your patient's information in. And that was a model that was developed by our Italian colleagues that looked at a series of over 200 patients in their Italian database that received ruxolitinib with a diagnosis of myelofibrosis. And with statistical analysis, they determined three independent prognostic factors in the first 6 months that influence survival. And that's ruxolitinib doses less than 20 mg twice daily, red cell transfusion requirements at baseline, 3, and 6 months, and then a spleen length reduction by palpation of less than 30% at 3 and 6 months. And you can add these points up, and there are three risk categories with survivals that are associated with them. And that has been validated in the Moffitt cohort of 40 patients, but may provide physicians with an opportunity to determine whether an outcome measure that really matters significantly, which is survival, is perhaps compromised. And maybe what we were alluding to in a previous discussion is, when is the optimal time to refer to transplant? So Gaby, I'm going to head back to you. Let's say this patient, if you plug in the data, is about intermediate risk score. And let's say the median survival there might be around 5 years. And of course, as I say this, I always think, as Abe pointed out, is these things are medians. They don't really tell the patient what to expect. So you can tell a patient, "You have a favorable CALR mutation," and then the patient could behave like this, and that doesn't go always with the narrative, as Abe pointed out. But let's say by statistical analysis and projections, the survival might be limited to 5 years. In this patient who's got myelofibrosis on this reduced dose of ruxolitinib and is 64 with, let's say, good performance status. Gaby alluded to that. She's doing Zumba three times a week and then she's got these three sibs that are in good health, that she has relationships with, and are... That's also important. That sometimes is forgotten is the actual having a relationship with a sibling that would then result in the ability to gain access to peripheral blood stem cells. Gaby, let's say in this case, A, do you use the RR6? And B, does it help you make a decision in this case? Is it helpful? Dr. Hobbs: I would say the RR6 is a helpful model. I would say that probably the more helpful model for this particular case is really just the traditional MIPSS. What really concerns me most in this case is not so much what the RR6 model tells me. Certainly, that's instructive to know, because she's on a really low dose of ruxolitinib and if she's not transfusion-dependent, she's probably going to be soon. What really concerns me about this person is that she has these high-risk mutations and has more than one of them. She has the ASXL-1 mutation and the EZH2 mutation. Both of them are high-risk mutations. So even if the patient had the CALR mutation initially, which predicts a more indolent course, now, like Abe mentioned, she has clonal evolution with these two mutations. And so I would say, like I mentioned before, if this person hadn't been referred, the transplant, now is really the time. I think sometimes it's difficult to know. The person is doing pretty well, they don't have a lot of symptoms, their counts are borderline, and so it's really difficult to make that decision to say, "Now we're going to pull the trigger and you should go to transplant." For me, this case is more straightforward, where I would say now is really the time to get things moving and make sure that we get this person to transplant before their disease progresses or gets worse or they start to require blood transfusions. Because really once you get into requiring transfusions, things get a little bit more complicated and may worsen transplant outcomes. I would say my number one priority now, regardless of what risk score we want to use to tell this person that their disease is now not what it used to be in terms of probably having lower-risk disease, transplant should really be at the forefront of our discussion with this person, to happen in the next couple of months. Dr. Mascarenhas: Excellent. And as you pointed out, if we go beyond this RR6 model on the first 6 months of ruxolitinib and you use scoring systems like the MIPSS-70, the patient is high risk. If you use the myelofibrosis transplant scoring system, which is geared to helping that discussion with the transplant about the transplant option, in terms of the pros and cons, the high-risk 5-year survival for the MTSS would be about 50%. And in this patient's case, she has one sister who's a 10 out of 10 match, and she has three unrelated 10 out of 10 donor options available. So she does have donor options, she's in good performance status. She is inclined to do a transplant. Patients that look great on paper and have donor options but are absolutely not inclined to do transplant, so it's a no go. So I think that's an important other consideration. Both of you covered really nicely what's the optimal time for transplantation. And it's usually, I think, before it gets too late is the answer. It's often hard to convince someone to move to transplant when they're really doing well on a JAK inhibitor and they're engaged in life and doing Zumba and then you're telling them "We'd like to move you forward with transplant." But that's probably the ideal time to really start having those discussions. But the question I have for Abe is, in this case, let's say the 10 out of 10 sister is going to be the donor and it's going to take about, let's say 3 months to get the whole thing together. But during that period, the patient's having worsening splenomegaly on ruxolitinib and this lower platelet count, would you just hang tight? Or what would you do in that interim period before conditioning for transplant? Dr. Yacoub: Yeah, and that's actually, it's a very good point. How do we optimize her disease control and symptoms while we're waiting for a transplant to happen, which in this case it is likely going to happen within a few months. This is almost one of the classic indications in which switching therapy to other JAK inhibitors to optimize response and improve cytopenias is indicated. Of the JAK inhibitors that are approved, pacritinib has been particularly studied in this setting, and particularly in patients after ruxolitinib therapy with therapeutic phenotype and seems to be right on level for those patients in order to improve their symptoms, functionality. Although this patient is doing well, but she could also benefit from... Anemia benefit from pacritinib in this setting. So this would be a situation in which switching to pacritinib as a bridge to transplant would be a reasonable option. Dr. Mascarenhas: Excellent. I think we covered this case pretty well and I just want to summarize the key clinical takeaways from this case, which is ruxolitinib dose should always be optimized, and we really use spleen reduction as the clinical biomarker for optimizing and maximizing the effect of the JAK inhibitor. But thrombocytopenia, that can be both disease- and therapy-related, will frequently limit the dosing of ruxolitinib. And Abe pointed out that if you don't get to at least 10 mg twice daily, you're really probably not garnering the optimal benefit of ruxolitinib. We have pacritinib now, which is a JAK2, IRAK1, ACR1 inhibitor, and that's a great drug for this cytopenic or thrombocytopenic population in particular. Fedratinib is also a great second line agent for platelet counts greater than 50,000, as Gaby had pointed out, to salvage spleen. And I think I would try to optimize JAK inhibition in route to a transplant to optimize the outcome there. One can use the RR6 model to provide prognostication after 6 months of ruxolitinib treatment, from a survival perspective. And allogeneic transplant remains the only curative option. It's really important to make sure patients are aware of that, that the discussion that takes place. A benefit was really only observed in those patients who are higher risk, usually intermediate-2 or high-risk patients, and the MTSS can help guide discussions with the patient. So we do have these tools to help the discussion along, in making the decision between a transplant as a potential cure in these patients. Because although the JAK inhibitors are really great additions to our treatment armamentarium and address a lot of the unmet needs, ultimately survival is only impacted in the most meaningful way if someone is able to get a transplant. 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.

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