An expert oncologist overviews quality-of-life data and considerations in treatment sequencing in myelofibrosis.
Aaron Gerds, MD, MS: The approval of ruxolitinib for the treatment of myelofibrosis was a pivotal moment in the way we think about designing clinical trials for patients with cancer in general. Again, it was a key instance where patient-reported outcomes, quality of life metrics, and symptom burden metrics were used as a foundation for approval as opposed to response in terms of remissions or survival. It was an important moment in clinical trial development and regulatory approval for agents. Ruxolitinib, through improving symptoms and spleen size, did lead to significant quality of life improvements, and that’s been shown in a number of analyses of the COMFORT studies. Analyses of the JAKARTA studies likewise show that when we shrink spleens and improve symptom burdens, people’s quality of life improves significantly. It’s the same for pacritinib, and now momelotinib as the development in momelotinib continues.
It makes sense though. If we’re shrinking spleens, and improving symptom burdens, you would think that would ultimately translate into a quality-of-life improvement. But I want to make a key point here, that patient-reported outcomes are not necessarily quality of life and vice versa, and symptom is not quality of life, so you have to assess that with a separate metric. Nonetheless, it does make sense that when we do improve the symptom burden in these patients, their quality of life also improves. I think that is a key piece of the treatment thoughts when sitting down with a patient and saying, “Look, this medication not only can make these symptoms better and hopefully translate into some survival advantage for you, but also it will quite frankly improve your quality of life.” I think that’s what patients are asking for. They not only want therapies that can make them live longer, but therapies that are going to make them live better.
In patients with myelofibrosis not previously treated with a JAK inhibitor, we have a lot of work to do. We have 3 approved JAK inhibitors, which all have data in the frontline setting. We will hopefully soon have another JAK inhibitor in momelotinib approved, which also has data in the frontline setting. How do we sort all this out for a patient with myelofibrosis, either newly diagnosed or recently diagnosed, who needs therapy? I think we can start working piece by piece. Ruxolitinib has been around the longest, of course, and has the longest follow-up data, and I think has the most comfort level in use. So we start with ruxolitinib as our guidepost in thinking about this. Pacritinib has certainly carved out a niche in patients with thrombocytopenia, so certainly when someone needs initial therapy with a JAK inhibitor and has a platelet count of 50,000 or less, you would consider pacritinib because you can deliver a full dose JAK inhibitor, yet not totally trash the counts. The benefit of pacritinib has been demonstrated in a number of studies in patients with cytopenic myelofibrosis, so kind of carving out that group of patients. I think in patients who have very intact bone marrow function, meaning they’re not anemic nor have significant thrombocytopenia, ruxolitinib still is the go-to therapy. Certainly, for someone who has a platelet count greater than 100,000 and is not anemic, you would consider ruxolitinib.
As of today, the gray area, I think is a patient with platelet counts between 50,000 and 100,000. There are some data supporting the use of fedratinib in this place, but also fedratinib does have a more difficult adverse effect profile to deal with compared to ruxolitinib. You’re unlikely to give full dose ruxolitinib in those patients where we think they may have the most benefit. You could consider pacritinib in that case. The PERSIST-2 study included patients with platelet counts up to 100,000 so there are plenty of data there, but the challenge is that the label specifically discusses severe thrombocytopenia, patients with platelet counts less than 50,000, so there may be difficulties in getting that drug approved in that space. Certainly, you could try lower doses of ruxolitinib based on the dose adjustments in the package insert in that population, but again, you’re less likely to get responses, and they may need to move on to second-line therapy.
I think momelotinib could potentially slot into that place. Again, we talk about anemia in patients with momelotinib, but the MOMENTUM study and other studies have included patients with platelet counts as low as 25,000. Subanalysis of that shows in fact, we can deliver full-dose JAK inhibitor therapy with momelotinib in patients with platelet counts between 50,000 and 100,000. Also, in patients who have anemia, and who need JAK inhibitor therapy, ruxolitinib is likely to make that anemia worse, as does fedratinib. We would certainly think about momelotinib in that instance, for a patient who needs a JAK inhibitor who is also anemic. You can start to think about where we would parse out these 4 different JAK inhibitors based on platelet counts and anemia at the time when they need to start a JAK inhibitor.
In medicine, there’s often a lack of logic. For people like myself who are almost pure empiricists, that’s OK. When we look at the JAKARTA-2 data, we see that patients who had previous exposure to JAK inhibitors have good responses to fedratinib, another JAK inhibitor. It doesn’t make sense if you give a JAK inhibitor and then another JAK inhibitor, why would you have a response? But these JAK inhibitors are different. Moreover, when we look at retreatment with ruxolitinib, we also see responses. We know that interruptions of JAK inhibitors can allow time for responses to occur again. In those studies, we looked at patients who had ruxolitinib for a long time, took a holiday for various reasons, and then came back to ruxolitinib, and we saw similar response rates in the retreatment with ruxolitinib. There’s something inherent about switching JAK inhibitors or taking a break and coming back to JAK inhibitors that allows for responses to be regained. There is enough circumstantial and prospective data to suggest that sequencing JAK inhibitors makes sense in some vein. Again, it shouldn’t make sense biologically, but certainly in the data we do see that reflected, so we can think about sequencing JAK inhibitors.
Often when we have a patient who has more proliferative myelofibrosis, when platelet counts are preserved, for example, who was treated with a JAK inhibitor like ruxolitinib in the frontline setting, we can think about fedratinib in the second-line setting. In patients who developed thrombocytopenia on ruxolitinib, we can think about pacritinib as shown in the PERSIST-2 trial. Even with momelotinib, a burgeoning JAK inhibitor, if you will, the MOMENTUM study included patients previously treated with a JAK inhibitor, mainly ruxolitinib, who went on to have successful treatment responses with momelotinib. There are plenty of data to suggest that sequencing JAK inhibitors makes a lot of sense. Like in the frontline setting where we’re going to have to parse out all these different JAK inhibitors, we’re going to have to do so as well in the second line.
Transcript edited for clarity.