The 2022 Tandem Meetings | JAK inhibitor selection & sequencing in myelofibrosis

In myelofibrosis, we are happy to have another JAK inhibitor approved and now we have on the market, in the United States, at least three different JAK inhibitors. So we can address that question that you’re asking me about. First of all, we can talk about which patient is the best patient for a particular JAK inhibitor. And then we can also talk about sequencing. We can use one after the other, after the other because there is no reason, whatever at all, to say that one cannot use one after the other. I want to highlight that because people usually assume that if one JAK inhibitor in a class doesn’t work, there must be a reason that would prevent the other JAK inhibitors not to work again. That’s not the case in myelofibrosis.

So let’s take a look at the frontline setting. We have a newly diagnosed myelofibrosis patient. And as we know, since 2011, ruxolitinib would be used in that setting, in people who have platelets above 50, and you would adjust the dose. Starting dose based on the platelet number. So five milligrams twice a day if the platelets are between 50 to 100, for example, and higher doses if the platelets are higher. Well, this is important because five milligrams twice a day is not a really very good dose of ruxolitinib. We know that, that dose does not provide optimal care for that patient in terms of decreasing the symptoms and decreasing the spleen. The goal of therapy is to go up on a dose from five twice a day, to ten twice a day, and higher because only then you can optimally take care of the patient.

Now in that setting, perhaps equally, you can think about fedratinib. Fedratinib is approved for frontline use in people who have platelets above 50. So it’s one or the other. But in particular, in patients who have lower platelets, you don’t dose adjust fedratinib. So you could say, perhaps in that setting, I should consider fedratinib. It’s simpler. There is no dose adjustments necessary. You do have to give prophylactic GI medications because there is some irritation of the GIs, like nausea and perhaps some diarrhea occasionally. But that doesn’t really affect the patient much. And you give people thiamine when you give fedratinib to prevent any distant possibility of central nervous system toxicity, but it’s relatively simple. So you have here an opportunity to better fit the patients, one way or the other, with your best choice. After that, you could choose fedratinib after ruxolitinib or ruxolitinib after fedratinib. In fact, there were studies done with fedratinib after ruxolitinib and about 30% of the patients have significant decrease in the spleen. We say, this is about 35% volumetric reduction or half by per patient and an improvement in quality of life, about 30% of the patients as well, roughly, have about half of the symptoms gone. So that is a full-fledged choice fedratinib after ruxolitinib.

And now you have a pacritinib approved about a month ago. And it is, on the label, a therapy for patients that have platelets below 50. Again, non-myelosuppressive characteristics of that drug is what is different than the others. Does not suppress the blood count. That’s why it’s approved in people with low platelets. 200 milligrams twice a day. You give it without much of a need for those adjustments. So dose intensity stays on throughout the therapy. And it’s very good, about 30% response rate, in spleen and symptoms. Certainly you can possibly envision that you can give it even in patients above 50, and certainly in patients in a second line setting in those that experience mild suppression from ruxolitinib or fedratinib and become cytopenic. This is perhaps a new word that we haven’t used much so far. Cytopenic patients, those with low blood cell count, particularly platelets, are a good candidate for pacritinib. And you can give it, no reason why not, after first-line ruxolitinib or fedratinib.