A Look at Fedratinib and the JAKARTA Trials

Srdan Verstovsek, MD, PhD: Fedratinib was approved in the United States as a therapy for patients with myelofibrosis based on the JAKARTA study. This study was done many years ago and compared fedratinib—at the dosage of 400 mg a day in 1 arm and the second arm 500 mg a day—with placebo. The placebo-controlled, randomized study with 3 arms, 400 mg a day was chosen for approval as a recommended dosage. It’s 1 dosage. You start it regardless of the platelet number, unlike ruxolitinib.

The results, in terms of the efficacy in controlling the spleen and symptoms—remember, these are the benefits of the JAK inhibitors—are similar to what we have seen with the studies that led to approval of ruxolitinib. You can say that efficacy is about the same. Of course, we don’t have a study that compares 1 with the other head-to-head, but the face value of the results, in terms of controlling spleen symptoms, is about the same.

The drug is approved for patients with intermediate-2 and high-risk myelofibrosis, and that is what is in the NCCN [National Comprehensive Cancer Network] Guidelines for utilization of fedratinib. Everybody starts with 400 mg a day, no matter what the platelet number is. Dose adjustments are not often needed. Obviously, there is a possibility of anemia, much less thrombocytopenia, as is the case with ruxolitinib. In terms of myelosuppression, fedratinib and ruxolitinib are similar. You may need to decrease the 400 mg daily dosage of fedratinib to 300 mg or even 200 mg in case of excess myelosuppression. Medication is given as 4 pills of 100 mg each, so one could modify the dosing.

The adverse effects are different. This is the difference between ruxolitinib and fedratinib. If it’s similar in myelosuppression, then it’s dissimilar in the causing nausea, vomiting, and diarrhea. Fedratinib is a FLT3 inhibitor and inhibits another factor. That is not important for myelofibrosis, but the class of drugs—the FLT3 inhibitors—causes nausea, vomiting, and diarrhea. That is a low-grade problem in about two-thirds of the patients on the JAKARTA study and requires—in my own practice, this is what we do—giving patients antinausea medication, so they don’t stop the therapy unnecessarily, because nausea happens at the beginning when you prescribe it. With that, people stay on the therapy.

One more factor here is different. Fedratinib appears to inhibit uptake of thiamin, a vitamin from the gut into the body. That, possibly, leads to low levels of thiamin the body, which is the cause for neurological toxicity, called Wernicke encephalopathy, and a black box warning for use of fedratinib. There is 1.3% chance of a possible neurological toxicity and long-term Wernicke encephalopathy. What does this mean? One needs to measure thiamin before giving fedratinib, supplement it if it’s low, and measure thiamin periodically during the therapy with fedratinib. That’s about toxicity.

JAKARTA2 was a nonrandomized, open-label, phase 2 study in the second-line setting. Reanalysis of that study showed efficacy in the second-line setting after ruxolitinib of about 30%, which is important. That’s why in my practice we use fedratinib in the second-line setting more than in the frontline setting.

In my practice, fedratinib has a role. In the frontline setting, it has a minor role because the efficacy of fedratinib—based on studies that led to its approval compared with a study that led to the approval of ruxolitinib—appears to be the same. There is a little issue with some low-grade GI [gastrointestinal] toxicity, for which I usually give antinausea medications, for example. And there is a need for monitoring thiamin level because of a very low risk of having Wernicke encephalopathy as an adverse effect through low levels of thiamin that may happen in the body of the patients while on fedratinib.

This is all manageable. But after ruxolitinib, we don’t have much to do offer our patients. JAKARTA2 was an open-label, phase 2 study in the second-line setting, and it was published last year after reanalysis of with the scrutiny of which patients were enrolled and what were the benefits, provided a compelling reason to utilize fedratinib in a second-line setting. Overall response rate in controlling the spleen was about 50% and about the same for the symptoms.

We utilize fedratinib, in patients who are not doing well anymore on ruxolitinib, as a second-line choice for people with a big spleen, who have a bad quality of life and still relatively decent bone marrow reserve, because it does cause a degree of anemia and thrombocytopenia. In that setting, which would be maybe up to half the patients in a second-line setting, fedratinib has a very good established role.

Transcript edited for clarity.