Case 1: Fedratinib Treatment for Myelofibrosis

Rami Komrakji, MD: Now, recently, a second JAK2/FLT3 [Janus kinase/fms-like tyrosine kinase 3] inhibitor, fedratinib, was approved by the FDA based on 2 trials, the JAKARTA, that was an up-front study, and the JAKARTA2, that looked at patients after ruxolitinib failure. In the JAKARTA study, patients were stratified as intermediate 2 or high risk, and randomized between fedratinib at 2 different dose levels—the first being placebo; this led to the approval of this drug in this population. Fedratinib has a little bit of a different profile: It’s a JAK2/FLT3 inhibitor, with a toxicity profile a bit different from ruxolitinib.

When we look at the response rate in those patients treated with fedratinib at the 400 mg level, 36% of those patients achieved the primary endpoint which is a 35% reduction in spleen volume from baseline at 24 weeks. When you look at those patients that had platelets between 50 to 100 x 109 per liter, the response rates were similar—around 36%—and then around 1/3 of the patients had symptom improvement.

So regarding what we expect in terms of adverse effects, because of the FLT3 inhibition, we do observe more GI [gastrointestinal] toxicity. Those patients will have diarrhea, nausea and vomiting; that’s typically manageable in most of the patients. The rate of anemia and thrombocytopenia, when you look at the numbers, look equivalent or similar to ruxolitinib; however, one has to keep in mind that the study allowed patients below a platelet count of 100 x 109 per liter, with more cytopenia. So there is probably less—a little bit of cytopenia observed with fedratinib compared to ruxolitinib in those patients.

The fedratinib has a black box warning of Wernicke encephalopathy (WE). Originally, this was a valid concern; however, over meticulous review of those cases, it turned out that only a few handfuls, 3 cases or so, were true Wernicke encephalopathy. In many cases, this had been linked to thiamine deficiency—patients having nausea and vomiting, which leads to dehydration and malnourishment. Typically, we do check a baseline thiamine level in all of those patients, and we would consider thiamine replacement prior to starting fedratinib. It is an option for patients that may have borderline cytopenias, to consider in the up-front setting, and it’s an option for patients after ruxolitinib failure.

Transcript edited for clarity.