Treatment Strategies for Primary Myelofibrosis

Srdan Verstovsek, MD, PhD: In 2019, fedratinib was approved and then incorporated into the national guidelines, these are the NCCN [National Comprehensive Cancer Network] guidelines. It was listed as a drug that can be used in the frontline setting, as is the case with ruxolitinib. It was also listed as the drug that can be used after ruxolitinib, in a second-line setting. Now, the new updates from this year say that you can do it the other way around. If you start with fedratinib, you can use ruxolitinib. If you start with ruxolitinib, you can use fedratinib. There is clarification to say there is no particular order. We have utilized ruxolitinib most of the time as standard practice for the last 10 years as the first choice, then fedratinib second, but you can do it either way around. An additional clarification, which I think is actually the most important part of the update in April 2021, is a listing of luspatercept, which is the anemia drug, as a possibility based on an ongoing phase 2 study, in patients who are on JAK inhibitors and anemic. About a third of the patients had benefit in improving their anemia parameters. That listing of luspatercept as a choice is a major one in the guidelines because we don’t have anemia drugs to use. We utilize prednisone, danazol, and perhaps thalidomide; none of these are very effective. None of these are really approved. Now, luspatercept is a choice. Again, it’s not approved, it’s in a phase 3 randomized study for possible approval as we speak. But it’s a welcome addition of an anemia drug that may help patients in this particular aspect of their problems.

The JAK inhibitors would be standard practice for lower- and higher-risk patients if they are symptomatic. Symptomatic means either symptomatic organomegaly, or general systemic symptoms related to myelofibrosis that I described earlier, like night sweating, low-grade fevers, itching, bone aches and pains, and body wasting. These are general problems that come from inflammation that comes from the disease. Proliferation causes a big spleen, and that can be affected by the JAK inhibitors. For JAK inhibitors for the spleen and symptoms, you would treat the anemia, which is present usually in the high-risk patients, with anemia drugs. Many times, a combination of the 2 together. Then in patients who are progressing to acute leukemia, if the blasts are increasing, you treat with hypomethylating agents. These are limited choices that we have. Out of those, only the JAK inhibitors ruxolitinib and fedratinib are really approved, they’re full-fledged drugs for myelofibrosis. Others are not approved and have a limited ability to help our patients.

Aaron Gerds, MD, MS: For a patient with primary myelofibrosis, or post-ET [essential thrombocythemia] or post-PV [polycythemia vera] myelofibrosis, really, we think about 2 things. One is disease risk. And the other though and probably more important, is how they’re feeling, or what do they have going on in terms of symptoms and spleen size? The main tool we have in clinic these days, in terms of FDA-approved and regulatory-approved medications, are JAK inhibitors. These JAK inhibitors are really good at shrinking spleens and improving symptom burdens. Thus, if a patient has a significant symptom burden, as measured by the MPN-SAF [Myeloproliferative Neoplasm Symptom Assessment Form], or has significant splenomegaly, or both, I think starting therapy with a JAK inhibitor is really important. There are some other instances where we might think about other treatments. If a patient is anemic to the point where they may need transfusions in the near future, or are already getting transfusions, we will often think about agents that can improve the state of their hemoglobin levels and avoid transfusions going forward. Those drugs often include things like erythropoiesis-stimulating agents, newer drugs like luspatercept, or other oral agents like danazol. There are also some data for a class of medications called IMiDs [immunomodulatory imide drugs], including thalidomide and lenalidomide, in that space to improve anemia in these folks. Thus, that’s kind of almost a special instance outside the general thinking about high-risk disease, or even lower-risk disease with significant spleen sizes and symptom burdens.

For primary myelofibrosis and post-ET and post-PV myelofibrosis, the 2 drugs that have regulatory approval are ruxolitinib and fedratinib. Both are JAK inhibitors. A lot of their action is through inhibition of JAK1 as well as JAK2. The 2 drugs have a little bit different off-target effects. We think about FLT3 inhibition with fedratinib and some other cytokine inhibition with ruxolitinib. But they are of the same class, and we expect similar results with this class of medications, namely the ability to shrink spleens and improve symptom burdens. Outside of that, any therapy use is really off-label at this point. If we’re using an agent to improve anemia, say again, an erythropoiesis-stimulating agent, danazol, an IMiD, or luspatercept, it would be off-label. Thus, certainly, there is a dire need for new medications, new therapies, and new approaches to therapies in this patient population.

Transplantation, to date, is the only thing that has shown curative potential or the ability to put a person in a remission and have that remission maintained for a long time without additional therapies. We really think about transplantation in patients who have higher-risk disease. What it kind of boils down to, and I think the European guidelines put this quite nicely, is if using our prognostic models, or your clinical acumen, if you think a patient’s average survival is less than 5 years, indicating pretty high-risk disease, then you would consider transplantation in someone like that individual. Then you would say, “Well, are they well enough to go through a transplant? What would be the potential complications?” And we start thinking about that. If a person has a predicted survival longer than 5 years, then they may not benefit from transplant at that time, and you might want to delay transplant until something changes. Say they’ve been on a JAK inhibitor, and the JAK inhibitor’s no longer working, or their counts are fine now, and then several years from now, their counts are not fine, say they become thrombocytopenic or anemic, and then maybe you would want to transplant then. But really, we think about that in terms of survival. There was a really nice analysis just published, a collaboration between a number of MPN centers, as well as the CIBMTR, the Center for International Blood and Marrow Transplant Research, which is a large transplant-based database, where they were looking at patients who were treated with transplantation and those who were treated with nontransplant therapies and kind of compared the two based on disease risk. It was clear that the high-risk patients and intermediate-risk patients benefited from transplantation, where the low and low-intermediate patients really did not benefit from transplant. Actually, transplant was somewhat detrimental at that point. Thus, it kind of re-emphasized what we all intuitively know about who should get transplant and who should not, at least those patients with myelofibrosis.

Transcript Edited for Clarity