Updates in the Management of Myeloproliferative Neoplasms - Episode 6
Pankit Vachhani, MD, guides a discussion on the FDA approval of fedratinib and reviews how it has affected the therapeutic landscape for patients with primary myelofibrosis.
Ruben Mesa, MD, FACP: We had a new drug developed and approved in 2019. We’ve had an updated analysis that’s giving us a framework of the role of fedratinib in the frontline and second-line settings. Pankit, why don’t you share with us a bit? What do people need to know about fedratinib? What can help them when deciding, for that first time, to prescribe fedratinib?
Pankit Vachhani, MD: The initial trials of fedratinib actually occurred more than 12 to 13 years ago, roughly around the time when the COMFORT trials were occurring for ruxolitinib. The first trial, which was the JAKARTA trial, was a randomized study of fedratinib given at 2 different doses. There were 2 different cohorts. One took 400 mg; the other took 500 mg. Those groups’ reactions were compared against those given a placebo. To make a long story short, the primary end point—which was that spleen volume reduction of more than 35%—was comparable with what we saw with ruxolitinib in the COMFORT trials. The symptom burden decrease was also very comparable with that of ruxolitinib. That was in the first line setting where it was compared against placebo.
The second trial, JAKARTA2, started in 2011 but was put on hold in 2013 after cases of Wernicke encephalopathy came about. A case study has been done, published, and all put together. It focuses on the 8 cases of possible, probable, or definite Wernicke encephalopathy that were reported. Those 8 were out of roughly 700 patients from 5 to 9 clinical trials focusing on myelofibrosis and solid-tumor clinical trials. Of those 8, only 1 patient had a genuine definite Wernicke encephalopathy case. For the others, you could explain the findings using comorbidities or, for example, hepatic encephalopathy or brain metastasis related encephalopathy. Nevertheless, the JAKARTA2 study, which began in 2011, and was looking at fedratinib after initial JAK inhibitor failure, of ruxolitinib—that study had been put on hold in 2013. When the data were analyzed later, they were analyzed following protocol and later subsequently analyzed in 2 fashions. One was with the intention to treat protocol fashion. Then there was a reanalysis looking at only those patients who met the more stringent criteria for ruxolitinib failure: relapse, refractoriness, or intolerance. With that stringent criteria-based analysis, 79 patients were included.
Talking in terms of spleen volume reduction or symptom burden seeing a decrease of 50% or more, about 30% patients achieved those goals. What does this translate to for a practicing clinician? Well, the chosen dose is 400 mg daily. If you had to dose someone with fedratinib, that would be the starting dose, unless your patient has renal insufficiency, in which case, you’d lower the dose to 200 mg daily. For example, if you were using a concomitant CYP3A4 inhibitor like diltiazem, or any azoles, or clarithromycin, you would cut down the dose to 200 mg at the starting dose. The other point to keep in mind is that fedratinib is not just a JAK2 inhibitor but also a FLT3 inhibitor, alongside other proteins that get inhibited, like the BET family of proteins. Along with the FLT3 inhibition comes GI [gastrointestinal] toxicity. In the JAKARTA study, for example, about two-thirds of patients had nausea or vomiting. Most were grade 1 or grade 2 cases. Having these patients on antiemetics and antidiarrheal agents like Lomotil [diphenoxylate, atropine] or loperamide is crucial so that we don’t run into toxicities. As Dr Verstovsek previously brought up that, yes, we should be checking for timing levels and repeating these timing levels concurrently. That comes about because the FDA label has a black-box warning informing physicians and care providers to be cautious about when you get encephalopathy, to be cautious about checking the timing and repeating it. What I’ve found easier to do is check at baseline and just treat it concurrently with timing for patients who I have on fedratinib. That might be an easier thing to do than to keep checking, but maybe that’s just my way of doing things.
Ruben Mesa, MD, FACP: I agree with you 100%. You go into a CVS pharmacy and get vitamin D1; it’s $10 for 200 pills. It’s important, certainly, to check it at baseline and on occasion, but giving patients thiamine is a very low burden for them. There aren’t a lot of toxicities with it. I agree with you strongly: You give them those preventive medicines up front because once somebody has GI toxicities, getting them to feel better is always tougher. Give it to them up front. That way, they tolerate the medicine better. For many of them, we have been able to stop.
Transcript Edited for Clarity