Determining Treatment for MF And Upfront Therapy Options


A group of experts explain how to determine treatment for each patient with MF, as well as upfront therapy options.

Ruben Mesa, MD: Let’s pivot a bit toward the therapy of myelofibrosis [MF] and, at the current time, we have a few tools in the toolkit and many more in development that we’ll be speaking of. We have, obviously, stem cell transplantation which we’ve discussed. It can be curative. Certainly, allogeneic stem cell transplant has been curing therapy for myeloid disorders now for many years with important nuances in terms of whom to treat. We’ve had a JAK [Janus kinase] inhibition now proved over 10 years as a cornerstone of therapy. We have a variety of things that we might use in a supportive mode. Hydroxyurea to control leukocytosis and, in certain circumstances, erythropoiesis-stimulating agents to help to improve anemia. But let’s get a bit more into just some of the high-level information regarding these different therapies, and then we’re going to dive a little bit deeper into how they might interplay. So first, Angela, maybe just at a high level, we’ve had now ruxolitinib [Jakafi] approved for more than 10 years. Why is that drug approved? Whom do we use it in now in 2022?

Angela Fleischman, MD, PhD: Today, it’s a little bit difficult to think back into the pre-JAK inhibitor era. But many myelofibrosis patients do have quite enlarged spleens which are bothersome to them and have a very severe symptom burden. Now, those people can be helped immensely by JAK inhibitors. We know that JAK inhibitors reduce spleen size and improve symptoms. So those are needs that are clearly important for MF patients and can be addressed by JAK inhibitors. The need of anemia and other cytopenia in myelofibrosis is more difficult to address with JAK inhibitors and, in some cases, the currently approved JAK inhibitors may actually worsen anemia and thrombocytopenia. So I think it’s important to have a frank discussion with a patient with myelofibrosis in terms of what do they feel their greatest needs are? What do they feel their problem is? And what do they want fixed? Because if their primary problem from their perspective is their anemia, then at the present time, maybe a JAK inhibitor is not quite the best option for them. I think it’s important to clearly communicate with the patient what JAK inhibitors can and cannot do.

Ruben Mesa, MD: That’s a very, very important point. Jamile, we’ve had rux [ruxolitinib] 10 years, improved spleen symptoms, maybe improved survival. It’s been helpful. And now since the fall of 2019, we’ve had fedratinib [Inrebic] approved as well. Whato we think about fedratinib? How do we use that drug?

Jamile Shammo, MD, FACP, FASCP: Fedratinib is presumably a more JAK2-specific inhibitor and has been evaluated in several trials. And the indication is for both frontline because the JAKARTA trial was a double-blind, placebo-controlled study in treatment-naïve patients that were randomized to either placebo or 2 different doses of the drug. So that’s 1 trial that demonstrated the efficacy in spleen volume reduction and improvement in total symptom score. And also, there was another trial, the JAKARTA2, where the same drug was evaluated. It was a phase 2 open-label study in relapsed/refractory MF patients that had previously been treated with ruxolitinib. And there, the initial data suggested over 50% responses, but then a reanalysis, because of the inclusion criteria that was, sort of, I should say different from what people would normally utilize for describing rux [ruxolitinib] failures. They were reanalyzed, demonstrating that you could actually have 35% response rates, spleen volume reduction, and improvement in symptom score with re-treating patients with this particular JAK inhibitor. So essentially, we have an alternate option that is FDA [Food and Drug Administration]-approved at the moment, and I’m sure there are many more that may be on the way.

Ruben Mesa, MD: Very helpful. And I know we saw this year that fedratinib, the longer-term safety from the current FREEDOM studies, suggested GI [gastrointestinal] toxicity that was manageable and observation for decreases in thiamine that could be corrected, and no cases of Wernicke encephalopathy. Any patients that you’ve had on fedratinib, anything special that you do for these folks? Do you start these drugs ahead of time? How do you monitor that thiamine piece?

Jamile Shammo, MD, FACP, FASCP: I’m glad you brought that up, Ruben. Because obviously, in the initial trials, there was no mitigation strategy for nausea, vomiting, diarrhea, and that was actually 1 important aspect and some patients had to come off the study because of GI side effects. But mitigation strategies by educating the patients, making sure that you address and prepare them for how to deal with the symptoms of diarrhea and nausea, which can affect up to 20%, certainly would help improve those symptoms. And in terms of thiamine deficiency, I check it on every patient I have, though I’m not going to be waiting for the results. I typically would treat them accordingly but monitor the level moving forward. And I’m curious what you think, but I tend to think that perhaps the deficiency may have been induced by the cachexia that came with the disease that was not controlled and perhaps dietary restrictions, if you will. I mean like people who aren’t able to maintain their dietary because of their massive spleens, etc.

Ruben Mesa, MD: I don’t think you’re incorrect. I think now as we look, it’s pretty clear that a lot of patients sometimes have fairly modest thiamine levels pretreatment. And maybe this pushes them over the edge, but they’re not necessarily starting with robust levels. I’ve taken a fairly proactive approach with the patients that I’ve put on commercial fedratinib. Thiamine is cheap. They can go to CVS, they can get 100 pills for like 10 bucks, so I largely have put people on it. It’s a minor matter and the study would suggest that monitored, it’s really not as big a deal. It’s a black box warning, but again, 1 that is relatively manageable.

This transcript has been edited for clarity.

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