Inside the Clinic: Myeloproliferative Neoplasms: Current and Future Standards of Care - Episode 9
Stephen Oh, MD, PhD, highlights the role of transplant in myelofibrosis before Ruben Mesa, MD, discusses factors in selecting systemic therapy.
Stephen T. Oh, MD, PhD: Regarding consideration of transplantation for patients with myelofibrosis [MF] or MPNs [myeloproliferative neoplasms], first [I will state] the disclaimer that I’m not a transplant physician myself. There are a couple of ways to think about this. Of the available modalities to treat these patients, transplantation is the only option that has any prospect or realistic likelihood of attaining a long-term disease-free remission or even cure. In that sense, you could consider transplant as the goal for most patients with myelofibrosis. On the other hand, there are substantial, potential toxicities associated with transplantation. If we have more effective medical therapies that could eliminate or reduce the need for transplantation and the risk that comes with it, that could be the goal as well.
Keeping those points in mind, specifically considering whether a patient would be a candidate for transplantation, there are many criteria or factors to consider. One important overriding factor is that many patients with myelofibrosis, when they’re initially diagnosed, are at a relatively advanced age. Age itself doesn’t necessarily preclude transplantation, but in conjunction with other comorbidities, many patients with myelofibrosis are not eligible for transplantation. When you take those patients off the table, who’s left? Patients who tend to be younger. Age isn’t by itself a hard reason to say yes or no for transplant, but [it should be considered] in conjunction with a relatively healthy status and with more advanced or high-risk disease. In general, this includes patients with intermediate-2 or high-risk myelofibrosis and, in particular, those with high-risk mutations. Of course, if you were to look at patients who are already moving into the accelerated phase or blast phase from MF or another chronic MPN, those are the patients who would be prioritized for transplantation.
As far as bridging the transplants, this is mostly about timing, which I went over on the overall disease status. As far as who’s appropriate for transplantation, there’s no real proved bridging therapy going into transplants that’s routinely adopted. But there’s a continuing and evolving interest in the role of JAK inhibitors, such as ruxolitinib, in that setting. We commonly utilize ruxolitinib and other JAK inhibitors to treat patients with myelofibrosis. The obvious question is what to do with that going into transplant. Should we discontinue it, continue it, or resume it after transplantation? Keep in mind that there’s more experience with the use of JAK inhibitors, including ruxolitinib, as anti-GVHD [graft-vs-host disease] or prevention of GVHD in the setting of transplantation. There’s evolving and continuing interest in how to position these treatments in the setting of transplantation.
Ruben Mesa, MD: Coming up with a treatment plan for myelofibrosis is critical. It’s critical that we review the plan with the patient because how we respond to whatever path is chosen is important in terms of evolving and changing therapies, dose, and things of this nature. I begin with an accurate assessment of prognoses as well as disease burden. They both have implications in terms of choosing therapy. The first decision point is based on risk. The higher risk you are, the younger you are, the more fit you are, the more we consider whether we should go down a path of stem cell transplantation in the near future. Stem cell transplantation has a very different set of issues, risks, and potential benefits than medical therapy for MF, so it’s somewhat distinct. It’s a discussion that should be held early on, and it’s a continued discussion.
We probably transplant less than 10% of patients with myelofibrosis, but age and higher risk are factors. Even if transplant is decided, I recommend a sooner approach vs later approach. Even if I saw a patient tomorrow who I think should go toward transplant, there will be weeks, if not months, of testing that needs to occur in which the patient will need to consider the option and obtain a donor. Almost universally, that’s done in concert with the initiation of medical therapy to shrink the spleen, improve the patient’s performance status, possibly improve their cytopenias, and have them be in the best position possible for stem cell transplantation. With the majority of patients, we don’t start with transplantation because they’re older, they don’t want to move toward transplantation, or their disease isn’t immediately life-threatening. If the patient has a life expectancy of over 4 to 5 years, transplant is less attractive.
We stratify patients into 3 groups. First, low risk and asymptomatic. There’s fairly universal agreement that this is a group that we observe. There may be a role for long-acting interferons to help prevent disease progression in these folks. Above low risk and symptomatic, we start to get into JAK inhibition. We have 3 approved JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. [For patients who are] above low risk and symptomatic, low-risk symptomatic, and intermediate-1 risk and symptomatic, ruxolitinib has been approved and is a consideration in the front line for individuals with a platelet count above 50,000 per mm3. Fedratinib, approved in 2019, is a consideration in these groups. There are more data with fedratinib with intermediate-2 and high-risk [patients] given that it’s a more recent drug, but it can be used in the frontline or second-line settings.
We had pacritinib approved in February 2022, which is particularly helpful for individuals with cytopenic myelofibrosis—those with a platelet count of less than 50,000 per mm3. I look at whether that platelet count is under 50,000 per mm3 at the time of diagnosis or anywhere subsequent during the disease course. If either disease progression or because of undue toxicity from other medicines, pacritinib would be a consideration with a goal of improving splenomegaly and symptoms and being given at full dose.
As with any of these situations, patients are begun on a JAK inhibitor, but our work isn’t done. We monitor for response. Are we using an adequate dose? Is the patient achieving the response that we wish? Is there a significant reduction in the symptoms? Is the spleen significantly smaller? [We look for] a 50% reduction in the palpable component or more. Do they have toxicities, such as the development of transfusion-dependent anemia? Many things are evolving in terms of clinical trials, but for the majority of individuals who have FDA-approved agents in front of them, we think about ruxolitinib in the front line, perhaps fedratinib, and definitely pacritinib for individuals whose platelet count is less than 50,000 per mm3. If the individual had been on ruxolitinib but has an inadequate response or fails ruxolitinib, then fedratinib is a strong consideration. If they’re thrombocytopenic and they fail ruxolitinib, we use pacritinib.
Transcript edited for clarity.