The Role of Fedratinib in Myelofibrosis

Transcript:

Harry Erba, MD, PhD: What’s new this year in the management of myelofibrosis in the United States is the FDA approval of fedratinib with a very broad indication of treated, previously treated, or previously untreated patients with intermediate and high-risk myelofibrosis. Moshe, you did some of the initial work with fedratinib. Why don’t you talk to us about the road to FDA approval for that drug?

Moshe Talpaz, MD: We worked with fedratinib for more than 10 years. We really participated with it from the phase I, and the overarching statement would be that it is not a bad drug; it is a good drug. The second statement I would make is that it’s not as good at symptom control as ruxolitinib is. It doesn’t have the same percentage. It’s more like 30%, and maybe 1 of the reasons is it perhaps has no adverse effects. Especially in the first month or 2 of treatment, it has no gastrointestinal [GI] adverse effects like nausea, vomiting, and diarrhea, and that may count toward the positive symptom effect.

The third point is that I have been impressed with its effect on splenomegaly, which exceeds that of ruxolitinib. A good example is we have done a limited phase II study testing 3-dose level to the extent—if I recall, it was 300 mg, 400 mg, 500 mg, and found that 40% of the patients who were “resistant” to ruxolitinib responded with the spleen response almost equal to the same numbers that you get frontline with ruxolitinib. That was an impressive number. To an extent, it confirmed in the larger studies that were done with fedratinib, and I give credit to Celgene Corp for now going back, reanalyzing the status, and being extremely conservative with their analysis. They still had a nice 30% response in this population of patients. Many of them were totally resistant to ruxolitinib.

It has probably a superior effect as far as spleen control. Catriona Jamieson and I published a paper in which the argument was that it also reverses fibrosis in a substantial number of patients, whereas control of fibrosis was restricted to a rare and small number of patients with ruxolitinib. Now, with a word of caution, this has to be proven prospectively in an organized study. I wouldn’t like to overread into it, but I’d like to see a study. I do have patients who have improvement in fibrosis, no question about it, but this is anecdotal. This is not a solid basis for argument.

Two more scientific arguments. One argument is the claim to fame that it’s not a JAK1 inhibitor; it’s a JAK2 inhibitor. So maybe it has fewer immunosuppressive effects. The second argument is more like my argument, the fedratinib is a multikinase inhibitor. No drug in the world is a pure kinase inhibitor that inhibitors only 1 kinase. This 1 happens to inhibit many, and it’s very possible that many of its effects are not a function of just inhibition of the JAK2 kinase but also other kinases. That has to be studied a little further.

Generally speaking, it adds to the armamentarium of drugs. It’s a JAK2 plus drug, and it clearly has a role not only in patients that are resistant to ruxolitinib but also perhaps in patients who do start with some very large spleens. It may be a superior drug in these patients. We will identify eventually the niche of which 1 of these drugs.

Harry Erba, MD, PhD: As we remember the COMFORT-I study, it did not require a JAK2 mutation. About 75% had a JAK2 mutation, and so we couldn’t sort out the benefit of the drug in JAK2 mutated or unmutated. I’m not a statistician, but when I look at the waterfall plots, it seemed to me that there were more patients with a JAK2 mutation who had splenic size reduction than JAK-negative patients.

Mary Frances McMullin, MD: There are not a preponderance of JAK2 patients to go into those trials as well.

Harry Erba, MD, PhD: Yes.

Mary Frances McMullin, MD: It didn’t have to be.

Moshe Talpaz, MD: The prevailing claim is that they’re all the same. As far as the response, it doesn’t matter if it’s calreticulin, JAK2, or MPL, they all respond equally, or prognostically they are not exactly the same. But MPL is considered the worst disease, a more serious disease. To what extent is this confirmed? We just go with this statement as it goes along without actually confirmation? I don’t know.

Robyn Scherber, MD: Along those lines of being potentially good in patients with lower blood cell counts, Claire Harrison, is presenting here at ASH [American Society of Hematology Annual Meeting & Exposition] that there’s a specific analysis of fedratinib with patients between 50,000 and 100,000 cells/mm³.

Moshe Talpaz, MD: You’re correct.

Robyn Scherber, MD: Yeah, symptom and spleen response. It does bring in the question of, would you think about starting with fedratinib frontline rather than ruxolitinib?

Moshe Talpaz, MD: Robyn, you bring up a very important point. Is it less myelosuppressive as far as the platelet effect and the anemia than ruxolitinib? It has to be looked at carefully.

Harry Erba, MD, PhD: What are the downsides of starting with fedratinib in terms of toxicities? Mary Frances, what do you think about that?

Mary Frances McMullin, MD: My experience is going back to the trials and the number of patients on the whole who tolerated it very well. I gather that a lot of them will have a lot of GI toxicity, particularly in the first month or 2. In fact, there’s advice now provided to anticipate this problem and give them antiemetics and advise them on antidiarrheals up front.

Harry Erba, MD, PhD: John, he didn’t talk about Wernicke encephalopathy.

John Mascarenhas, MD: Maybe because there’s not much to talk about. There was a concern early on that led actually to the halting of the clinical development when it was under the control of Sanofi Aventis because of 8 cases of Wernicke encephalopathy. When the dust settled and those were really evaluated in rigorous fashion by independent committee, it was probably more like 1 case. There really hasn’t been a lot of literature that would support. I personally checked thiamine vitamin B₁ levels in my patients with myelofibrosis. I don’t see thiamine deficiency. I’ve not seen Wernicke. I do pay attention to it. There is a black box warning now, so the advice is to check thiamine levels before and then every 3 months while on therapy. The reality is it’s probably cheaper just to put someone on a multivitamin and send them on their way. It wouldn’t persuade me not to prescribe the drug.

Transcript Edited for Clarity