Updates in the Management of Myeloproliferative Neoplasms - Episode 2

Therapeutic Decision-Making for Primary Myelofibrosis

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Key opinion leaders in the management of myeloproliferative neoplasms review factors to consider when selecting treatments for patients and highlight the role of fedratinib in the first- or second-line settings.

Ruben Mesa, MD, FACP: Srdan, as we’ve heard about the risk of premature death from myelofibrosis—it’s clearly a major concern, it’s clearly a burden these patients can face—how do you factor in these goals and the burden of disease as you try to come up with a treatment plan?

Srdan Verstovsek, MD, PhD: We all agree on the aspect of prognostication as valuable, particularly for patients who are justified to go with the transplant as an option. Pankit already outlined the value of prognostication; we do NGS [next-generation sequencing], for example, to refine it better for patients who are intermediate-1, for whom we’re not sure whether they should go with the transplant. The main reason to prognosticate is to get the patients to do the transplant. If they have a life expectancy of less than 5 years, you should suggest the transplant. Otherwise, to extend that train of thought to practical points—do I need to prognosticate every patient I see? If the patient is 85 years old, what’s the value of all this testing? You’re going to go by the symptoms.

That’s what you’re asking me, Ruben: What’s the next fork? The first fork is the prognostication for those for whom the transplant is an option. It’s not really for everybody. If the patient is also high risk by the standard IPSS without the molecular findings, do you really need to do the molecular findings to recommend transplant? That’s another topic. The first fork is for transplant-eligible patients. The second is, what’s the problem with the patient? The symptoms come as No. 1. I really applaud your efforts and your team’s efforts to develop the MPN10 [Myeloproliferative Neoplasm Symptom Assessment Form], the questionnaire that’s now incorporated in NCCN [National Comprehensive Cancer Network] Guidelines. It should be used in every practice to objectify those symptoms. If the symptoms are judged to be—and you have this semiobjective way of looking at those answers—bothersome for the quality of life of the patients, go ahead and treat the patients for the symptoms, whether they’re lower risk or higher risk. If they’re symptomatic, that’s the next fork. Then you go with JAK inhibitors to counteract the quality-of-life issues, to improve those and decrease the symptomatic splenomegaly. We have 2 aspects of those symptoms, I’d say. One is related to general myelofibrosis systemic symptoms. The other is symptomatic splenomegaly.

Ruben Mesa, MD, FACP: In the treatment guidelines, there’s the JAK inhibition as a positional frontline therapy, but there are also a couple of caveats of being able to selectively utilize hydroxyurea or interferon or some other therapies. I know that there’s probably more heterogeneity, particularly in countries where JAK inhibitors are very difficult for a patient to afford, particularly if it’s a self-paid system. Where do you see those other therapies coming in for managing myelofibrosis?

Jamile Shammo, MD, FASCP, FACP: The point about being able to afford or have access to JAK inhibition is important. I’ll tie that to a question about the assessment of symptoms, which is so important. Often, I get patients referred who have myelofibrosis, but they’re labeled as asymptomatic. How much time has anyone spent looking at the symptoms to truly understand how many symptoms they have? If someone has evidence of a myeloproliferative disease—perhaps early myelofibrosis—the goal is to control, to some extent, the counts and perhaps the splenomegaly that these patients are feeling on the exam. Maybe you’re not dealing with a lot of cytopenias. I’d see utilizing hydroxyurea to control myeloproliferative disease and splenomegaly in hematology for someone who may not have access to JAK inhibitors. The interferons have been utilized. Myelofibrosis is not the only MPN [myeloproliferative neoplasm] that has been treated as such. I’m an old-timer who—all of us are, except Pankit, perhaps—has used interferon in CML [chronic myelogenous leukemia], and it works. It takes a long time and involves a lot of pain, but with early stage myelofibrosis, it may actually be a reasonable choice for someone who doesn’t have access to this. I may even start to talk about anemia, but ultimately, this is a disease that’s characterized by progression. At some point, those patients will be experiencing symptoms and signs, and they will be requiring JAK inhibition. That’s my experience.

Ruben Mesa, MD, FACP: That’svery helpful. Srdan, we have fedratinib, which has been available to folks since September 2019. Many watching this perhaps haven’t had a chance to use fedratinib. What would you recommend to them in terms of which patient they should be considering for fedratinib? Should it be used in the front line or the second line? What situations should they look out for, in particular, when they don’t have a clinical trial as an alternative?

Srdan Verstovsek, MD, PhD: First, it’s very gratifying to see that we finally have more than 1 proved medication for patients with myelofibrosis. Although it’s a JAK inhibitor, it’s not identical to ruxolitinib. When we look at the face value of the benefits, they appear to be similar, in terms of controlling the systemic symptoms and that symptomatic splenomegaly. It’s a valid option in the frontline setting, particularly for patients with the lower platelets. You remember that the dosing of ruxolitinib for patients with platelets below 100 per mm3 is very low. It’s 5 mg twice a day. You are supposed to go up on a dose—maybe you can—to 10 mg twice a day, but hardly anybody can go higher. Therefore, you don’t get that good spleen control, and durability is very short. Perhaps, in that case, there’s a role for fedratinib, with no dose adjustment based on the platelet numbers. The majority of my patients—and those coming as referrals—are exposed to fedratinib as a second-line choice. If I’m aware and correct, that’s also included in NCCN Guidelines as a possibility because there’s good evidence that fedratinib, for patients previously treated with ruxolitinib, can control the spleen symptoms, and there’s no resistance to it. It’s not a class resistance. If you fail 1, you won’t do well on the other line—that’s not true. There’s no acquisition of mutations or anything like that that would lead to the lack of a possibility of treating patients with another JAK inhibitor after the first month. Most of the time, we use fedratinib in the second-line setting, with good control of the spleen symptoms.

Ruben Mesa, MD, FACP: That’s a very important point. Because of the pandemic, although I’ve had many trials open for patients with myelofibrosis, traveling has been difficult for many. For second-line therapy, though I might normally consider a clinical trial, I’ve been able to treat patients. Some did telemedicine with fedratinib, and there was success. Overall, it’s well tolerated. We use GI [gastrointestinal] medicines and prophylaxis: some Imodium [loperamide], some Zofran [ondansetron]. Most people really don’t need them or don’t need them for very long. I prescribe them thiamine—over-the-counter thiamine, according to the black-box warning, in terms of trying to avoid a very small risk of Wernicke encephalopathy. But it’s fairly easy to use. I’ve seen some really nice responses in individuals who had lost their benefit for ruxolitinib, and we’ve regained control of splenomegaly symptoms. It has been helpful.

Transcript Edited for Clarity