Ruxolitinib for Patients With Primary Myelofibrosis

Ruben Mesa, MD, FACP: We’re in an era in which there are the greatest number of phase 3 trials ever for myelofibrosis. It’s not even close, in terms of the amount of clinical investigations being done for these patients. I’m deeply excited about that; the more options, the better. It’s heterogeneous, so we’re going to learn a lot. But before we get to the drugs in the pipeline in those trials, let’s take a deeper dive into the 2 drugs we have approved: ruxolitinib and fedratinib. Srdan, I’ll turn to you. Clearly, you’ve been at the forefront. Many of us have contributed, of course, but you’re knowledgeable regarding the development of ruxolitinib in the treatment of myelofibrosis. Many, I hear, have poorly heard parts of this story. What do they need to know about ruxolitinib in 2021 as it relates to dosing or low platelets? What’s a good response? What’s not a good response? What's your elevator speech for your trainee at The University of Texas Health San Antonio MD Anderson Cancer Center, who’s asking the ruxolitinib guru, “What should I know about ruxolitinib for myelofibrosis”?

Srdan Verstovsek, MD, PhD: Jamile had a very good introduction, explaining what we should be aiming for with ruxolitinib and JAK inhibitors. What we learned over the last 10 years—since it was approved in 2011—is that earlier intervention with a very good dose matters. What I’m talking about is that we should focus not only on the improvement of quality of life, which is very valuable. We talked about what the guidelines would say; first, we consider the transplant. Then we consider the symptoms. You want to improve the quality of life. You can improve the quality of life within 4 to 6 weeks through the optimal way, with a relatively lower dose of ruxolitinib: 10 mg twice a day. The durability of the response and the life extension that we’re certainly seeing quite often with ruxolitinib depends much more on the degree of spleen response. For the spleen response, you need a higher dose. You start with a lower dose—this is the case with the patient that has a low platelet count. To answer your question at least partly, you start with a lower dose or a lower dose because patients have anemia already. You should optimize this dose in terms of the dose escalation to the maximum safe amount to get that spleen as small as possible, which would transfer and improve durability and life extension.

Rather than thinking about immediately changing, if the response is not good with the low dose already, how can you optimize the therapy further? You can optimize it with earlier intervention. For the patients who are, based on MPN10 [Myeloproliferative Neoplasm Symptom Assessment Form], sick enough already, you didn’t recognize it just by asking questions. You now have a questionnaire to utilize. You would say that early intervention will make them feel better sooner. They are less anemic and less thrombocytopenic, so you can give them a better dose. That earlier intervention is easier to manage; patients get a better response, and that response lasts much longer. That’s what we learned over 10 years: when optimizing the therapy, starting low is fine as long as you go up. An earlier intervention gives you the opportunity to maximize the benefits before thinking about changing, and I’m happy that there are options to change. Let’s not just be overly complacent and say, “We have another drug we’ll change.” Why don’t we optimize all these options and start by optimizing the therapy with ruxolitinib in front line? Then think about momelotinib, fedratinib, and others?

Ruben Mesa, MD, FACP: It has really been an amazing period of time in many ways. You and I remember well—as does Jamile—what myelofibrosis treatment was like pre-JAK inhibition. We had incredibly cachectic patients with massive splenomegaly. They had almost a gray pallor. You could tell who the patient with myelofibrosis was in the waiting room without looking at the chart. There was a look, a hollowness to the muscles, and that has decreased dramatically in the era of JAK inhibition, with individuals clearly living longer. I just saw an individual who started when ruxolitinib was commercially approved. That patient has been on it since—over almost 10 years for an individual who probably had a life expectancy of 2 to 3 years when we started. Earlier intervention clearly matters.

Transcript Edited for Clarity