Differentiating and Switching Between Agents in Myelofibrosis

Andrew Kuykendall

Natasha, can you tell us what's unique about the mechanism of action of momelotinib or pacritinib that differentiates them from ruxolitinib or fedratinib?

Natasha L. Johnson

Sure. Pacritinib and momelotinib both target ACVR1. That's a really hot topic right now, and people want to know more. ACVR1 was not a focus in the pacritinib trials, and its inhibition was highlighted as a potential benefit later on. ACVR1 leads to upregulation of SMAD2/3 signaling, which in turn increases hepcidin levels and iron-restricted anemia; patients with myelofibrosis often have elevated hepcidin levels leading to a sort of anemia of chronic disease. Inhibiting ACVR1 reduces SMAD signaling, thereby reducing hepcidin levels and allowing for better iron utilization and better functional erythropoiesis.

Andrew Kuykendall

These targets are important for two factors you've already mentioned: one, differentiation or unique efficacy profile, in terms of ACVR1 or toxicity profile, and two, noting that maybe FLT3 has some role in efficacy too. FLT3 upregulation is really important in myeloid diseases, as it may be associated with disease progression. We haven't really figured out if that matters so much for our JAK inhibitors, but it may, and it certainly seems to play a role in toxicity and gastrointestinal side effects. Fedratinib and pacritinib—both FLT3 inhibitors—tend to cause more gastrointestinal side effects than momelotinib and ruxolitinib, which don't hit FLT3.

But ACVR1's unique, right? Momelotinib is an ACVR1 inhibitor. This is going to allow for better utilization of iron and anemia benefits. In the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials, we saw better rates of transfusion independence, decreased transfusion burden, and even increased hemoglobin levels in patients who were transfusion-independent at the start of the trials. So this was always a hallmark of momelotinib—one of the things that set it apart and really encouraged researchers to continue developing this agent.

The interesting thing is that, recently, pacritinib has also gone back and shown that, lo and behold, it’s a potent ACVR1 inhibitor as well. This was not something that was talked about a lot during the initial development of pacritinib—it largely rested on the fact that it was a selective JAK2 inhibitor. It also hit something called IRAK1, which is this NF-kB target that may be associated with cytopenias as well.

And in examining trial data further, we've seen lower rates of transfusion independence with pacritinib compared to best available therapy as well, suggesting that perhaps it has similar benefits in terms of anemia. This conclusion is a little bit tougher to draw, because we haven't looked at it prospectively in all these trials, but certainly it may be that this is an agent that we can use for anemia as well. That brings me to this next question: Now that we have these two agents that we can use in the presence of cytopenias, which patients are you going to switch from ruxolitinib?

Natasha L. Johnson

That's a good question, and I don't think the answer is easy. You’ve really got to be looking at the whole patient. How well are they really doing on ruxolitinib? What is the benefit that they're getting from it, and what are their blood cell counts? For example, if we have a patient who because of more profound anemia can't receive optimal dosing and is on a lower dose of ruxolitinib, and who is experiencing a high symptom burden and not feeling well, I would consider switching them to momelotinib. With momelotinib, this patient could likely be on optimal dosing to provide better spleen and symptom improvement without causing them to develop worsening anemia or become transfusion-dependent.

Another example that comes to mind is a patient who is on maximum dosing of ruxolitinib but has moderate anemia, with hemoglobin between 10 and 11 g/dL, and is still experiencing significant disease- and spleen-related symptoms. This is a patient I would consider switching to momelotinib to try to get a better response on spleen and symptoms. In my opinion, it's taking the whole patient into account. Of course, we have many patients who are on ruxolitinib and danazol at the same time and it's not really doing anything for them, or they're on erythropoiesis-stimulating agents with ruxolitinib and that's not benefiting them, so those patients are good candidates for a switch to momelotinib.

Andrew Kuykendall

I think there are two things that sometimes are interrelated that you need to think about. One, I think the slam-dunk patient is the one who is transfusion-dependent, who is on a low dose of ruxolitinib, and who has benefited from ruxolitinib to some degree. We've already talked about the importance of full-dose ruxolitinib in terms of achieving maximal spleen responses, the challenges in achieving that due to cytopenias, and the potential of using an agent that could actually improve transfusion requirements—such as momelotinib and maybe pacritinib. The patient who's on suboptimal doses and is requiring transfusions is the one who I think we feel like we can switch over very comfortably.

I always harken back to the RR6 model that was developed a few years ago, which looked at patients who were treated with ruxolitinib to try to determine what factors seemed to predict or correlate with worse overall survival. The three factors that identified patients who were at risk for worse overall survival were: transfusion dependence; suboptimal spleen response, defined as less than 30% reduction in palpable spleen; and suboptimal dosing of ruxolitinib (less than 20 mg twice a day). Patients who have more than one of those factors—those are patients I think we can switch over very comfortably.

If patients are very thrombocytopenic, certainly pacritinib could be an option. The MOMENTUM study did enroll patients with platelet counts all the way down to 25,000/μL, so momelotinib may be an option in the thrombocytopenic patient population as well. There is probably a little bit less data there than we've seen with pacritinib, which I think is the slam dunk. The other ones you mentioned are more gray areas. We currently have patients who are still symptomatic on good doses of ruxolitinib and who have mild anemia. The question is: Are you going to get better symptom benefit if you switch to momelotinib? I don't know; these are complex patients. It could be these symptoms are from some other pathway that's not going to be touched by momelotinib, but I do think that for patients who are having inferior quality of life despite being on a maximum dose of ruxolitinib, we should consider an alternative JAK inhibitor approach or clinical trials in that setting. We owe it to the patients to try to give them the best quality of life.

Andrew Kuykendall

If and when we do decide to change from one treatment to another, practically, how do we do that? Especially taking into account that, most of the time, we're changing from ruxolitinib to something else, and we know that patients who immediately discontinue ruxolitinib often have a withdrawal syndrome or worsening of their symptoms. Sometimes it can even be as severe as having a cytokine-release syndrome that necessitates hospitalization. So, Natasha, how do you handle that? How do you transition?

Natasha L. Johnson

First, it’s like what you said earlier—it's about educating patients upfront to know not to abruptly stop taking ruxolitinib. We see that happen; they might have lost a grant and can’t get the refill so they've stopped taking it and feel horrible. It’s very important to let them know upfront: do not stop taking this medication because of the possible consequences, and if they have any issue getting the drug, to let us know so we can provide financial and copay assistance programs.

Aside from that, when we are making the switch, ruxolitinib has a much shorter half-life than fedratinib, pacritinib, and momelotinib, and therefore, we need to overlap JAK inhibitors for a short period of time. There's not very clear guidance on that, but the way that we do it is maybe for 5 to 7 days, you’ll overlap ruxolitinib with the new JAK inhibitor. If they’re on the optimal 20-mg twice-a-day dosage, we may cut that in half and tell them to take 10 mg twice a day for about 5 days, at which point they can stop and continue on the new JAK inhibitor.

Andrew Kuykendall

That's kind of been our approach. I don't think there's a right answer, and I think we're all searching for it, but we do worry that some of these newer drugs that have longer half-lives may take some time to get into the system. If we immediately stop ruxolitinib prior to starting them, there may be some symptoms that emerge in that window and overlap. The one thing I'd advise not to do is allow a 14-day washout, despite this being used in MOMENTUM and JAKARTA-2. That is not clinically something that we practice, correct?

Natasha L. Johnson

That is correct. A patient will feel horrible.

Andrew Kuykendall

I think that was really studied for trial purposes, to see the independent impact of a JAK inhibitor on spleen size in patients who were JAK inhibitor–naive, but it’s not something we would do in clinical practice.