Targeting JAK2 in Myeloproliferative Neoplasms - Episode 8

Targeted Therapies for Myelofibrosis

A discussion of JAK inhibitors, risk models, quality of life, splenomegaly, and other issues in treating patients with MF.

Srdan Verstovsek, MD: In the treatment of myelofibrosis—that is the most difficult to manage of the MPNs [myeloproliferative neoplasms]—there is certainly a major change in the management of myelofibrosis with the application of the JAK2 inhibitors. If we are talking about treatment for PV [polycythemia vera] in the second-line setting, a quarter of the patients or perhaps more, would need something beyond this frontline therapy of hydroxyurea. With ET [essential thrombocythemia], there is a similar situation. Regarding myelofibrosis, I think we can say that development ofJAKinhibitors is earth-shaking for the outcome of these patients. I think you would agree with that statement.

Andrew Kuykendall, MD: Yes, it has completely changed the game for, as we said, these salvage approaches. We have gone from sometimes very gruesome approaches of taking people’s massively enlarged spleens out to now being able to provide a pill that, for the vast majority of patients, is going to improve their spleen size just by taking it twice a day. I imagine it is a pretty big change for patients.

Srdan Verstovsek, MD: Yes, and again, it is active regardless of mutational status and whether you have primary myelofibrosis, or have it secondary to PV or to ET. The benefits are seen across the board to a similar extent, and on average, from clinical studies, for about 3 years, and a good proportion of the patients have that benefit prolonging their life. I think the evidence, particularly over the last couple of years, speaks to that prolongation of life as a benefit that we did not really imagine because we were talking about controlling the symptoms and the spleen. Now, we are looking at the Medicare database and the SEER [Surveillance, Epidemiology, and End Results] database; we have all these large, federal databases that are suggesting people actually live longer.

Andrew Kuykendall, MD: It is really encouraging, obviously. That is the goal of all these medications, to have people live longer and live better. For ruxolitinib, we knew people were living better, but there is good evidence that people are living longer, too. As someone who has closely reviewed the COMFORT trials, it is almost hard to understand how there was a survival benefit when patients were allowed to cross over after 6 months, and most patients did. It reinforces the benefit of getting these patients on ruxolitinib earlier, if they are appropriate candidates for it. There is clearly a benefit to getting treated earlier. To show a survival benefit in a study that allows crossover after 6 months is challenging to do, but when it is shown, it shows the benefit of early initiation.

Srdan Verstovsek, MD: The early initiation, I think, is one of the key factors for achieving that longevity because if you are introducing the therapy late, you are facing patients who are very debilitated, who particularly have anemia and thrombocytopenia that affect the delivery of the therapy. Early intervention is needed even when patients are not extraordinarily sick, especially those who have an indication for therapy with symptomatic splenomegaly and general systemic symptoms. If they do not have excessive anemia or thrombocytopenia, your management will be easier; you can get a better dose of ruxolitinib and a better chance for extensive improvement of the patient’s metabolism, function of the organs, performance status, and spleen size, making the spleen as small as possible.

The analysis of the benefits stretch from, you have a high albumin, high cholesterol, your weight goes up—I think that is a very well-known patient complaint, gaining too much—but performance status improves, kidney function improves, and the spleen is much smaller. Then, people can sustain life with much better quality for much longer, and I think that is the goal of our efforts today, versus 10 years ago. We would say, “Do not wait. Early intervention matters. You will make people happier sooner. Why do you need to wait for people to be dying?” Intervene early, and that will translate, as you optimally treat the patients with the safest, highest dose to decrease the spleen as much as you can, to life extension. I think that is something we need to strive for, to be widely accepted, to up the bar from quality of life improvement to life extension.

Andrew Kuykendall, MD: I definitely agree. I think the one thing we focus on is the survival benefit, as was seen in patients who were eligible for the study, patients who had big spleens. I think there is a lot of discussion around what really constitutes a symptomatic spleen. Sometimes patients do not know, or physicians do not know, but a big spleen is usually symptomatic. I had a recent patient I saw in the clinic who had a spleen that was extending past his belly button, but he said it was not causing him any symptoms. He did not really understand why he was having increased urinary frequency, or frequent diarrhea, or why his kidney function was going up, but he said the spleen that was across his midline was not symptomatic. I think we probably waited a little too long to treat a patient like that; sometimes just asking a patient if they are symptomatic or not probably is not right. These big spleens, once they are 5 cm, or palpable under the rib, usually cause some degree of discomfort, even if it’s minimized by patients.

Srdan Verstovsek, MD: You extended this discussion to proper assessment of patients. We should be asking questions or utilizing what we were saying before when discussing ET and PV; we need to be assessing the quality of life with the proper questionnaire, which should become part of the electronic medical record, so we can respectively follow the quality of life as the patient answers those questions. You have a point from 0 to 100, and then you can track it like you tack the CBC [complete blood count]. Unfortunately, we do not have anything like that for the spleen itself. These are the limitations of what is happening right now, but with education, I think the assessment of patients’ quality of life and early intervention through recognition of the bad quality of life sooner rather than later will be ultimate goal. There are studies, as you know, done with low-risk patients, we still go by the risk of dying, but low-risk patients should not be symptomatic. They are, though, if you ask the questions, right? You have to ask the questions, and that is why the NCCN [National Comprehensive Cancer Network] guidelines say that, for even lower-risk patients, if they are symptomatic—which is the key—you need to ask the questions. There is a role for ruxolitinib.

Andrew Kuykendall, MD: If you are ever wondering what the flaw is in using risk models for determining treatment withJAKinhibitors, splenomegaly is not included in any of the risk models. That is one of the main reasons we are using those drugs. Low risk, high risk, whatever risk it is—if they are symptomatic based on the symptom score or they have problematic or bigger spleens, then they are candidates, and they can benefit from these drugs.

Transcript edited for clarity.