Fedratinib for Primary Myelofibrosis

Harry P. Erba, MD, PhD: We now have a second FDA-approved drug, fedratinib, in myelofibrosis. I’m going to turn to Ruben to discuss the clinical trial data, and then I’m going to ask Srdan to talk about, since they’re both indicated in the first-line setting, how you choose between these 2. Let’s start with Ruben.

Ruben A. Mesa, MD, FACP: There are 2 main studies. First, the pivotal study, which was the JAKARTA study that looked at 2 different doses of fedratinib: 400 mg and 500 mg versus placebo. It showed without question vast superiority in terms of control of spleen and symptoms. To remind folks again, this was several years ago, so this was concurrent during the approval time of ruxolitinib. This is a different study from what might have been done if it was much more recent.

It clearly showed benefit, without question. Adverse effects included some GI

adverse effects, potential for cytopenias, and in a small number of individuals, a neurological adverse effect that was potentially related to Wernicke encephalopathy.

A close look at that still puts that somewhat in question, but the agent is approved with a black box warning to monitor and replace thiamin before patients begin on the therapy and monitor for Wernicke encephalopathy. It functionally should not be a large issue in that this was a rare adverse effect and should be prophylaxed with thiamin. That is the basis of that frontline approval. The delay in approval was in resolving this whole issue of thiamin, Wernicke encephalopathy, as well as the drug development pipeline and delay.

There is also second-line data with a second-line trial led by Dr Harrison from the United Kingdom, myself, and many of our colleagues who we’ve recently updated at ASH and EHA, and it was recently published. That found a good 30% to 35% response rate for spleen and symptoms in the second-line setting for individuals who had failed ruxolitinib by relatively rigorous criteria in terms of resistance or intolerance. It was clearly active in the second-line setting for people who had failed ruxolitinib.

We’re pleased to see the commercial availability of a second agent, and it’s certainly something people should be considering for their patients who have failed ruxolitinib, for whom you do not have a good alternative clinical trial to consider. Fedratinib is approved and is an option for these individuals.

I will make 1 comment on dose as well. In the pivotal study, there was both the 400-mg and 500-mg dose. The 400-mg dose was felt to optimize efficacy, and there was more toxicity in the 500-mg arm, so 400 mg is the dose.

Harry P. Erba, MD, PhD: Krisstina, the other toxicity is GI toxicity with diarrhea. Is there anything special you do or tell your patients?

Krisstina Gowin, DO: Absolutely. Setting the stage for the potential adverse effect of diarrhea as a toxicity so they’re anticipating it is extremely important. Then do coadministration with some of our great antiemetics, which we now have available.

There is subduraconin, which is oral, which I have been using particularly for patients who have a history of being sensitive to medications and are potentially at high risk for significant nausea, but diarrhea is a problem as well. Managing the symptomatic diarrhea with Imodium, Lomotil, I have even gotten some GI input for patients who potentially may need more advanced therapies for managing the diarrhea.

Transcript Edited for Clarity