Case 1: Initiating Therapy for Myelofibrosis


Srdan Verstovsek, MD, PhD: We’re going to move on to talk about therapies. It was a very nice review that Dr Komrokji gave us on the possibilities of what to utilize in our patients with myelofibrosis. Do all the patients require therapy? Is that ultimately what happens in everybody? Prithviraj, what is your take here? How do we go about the therapy? Should we treat everybody at the time of diagnosis, or shall we wait? When is the time to intervene if not right at the beginning?

Prithviraj Bose, MD: We would love to have a drug that really reverses the natural history of the disease and one that can fundamentally reverse the disease process. Unfortunately, we don’t have that. So, I think it’s appropriate to observe as Rami was saying earlier, in a patient who is asymptomatic, low risk—I think I would favor observation. I would start ruxolitinib in patients who are symptomatic and have substantial splenomegaly certainly, because the drug provides some undeniable benefits in those regards. I would probably not start it purely because of its survival improvement. Again, going back to what Rami was saying earlier, we completely believe that it improves survival in patients who require it. So, for patients who are symptomatic, who have big spleens, it really reverses their symptoms; it makes them feel better, eat better, be more energetic, etc. Perhaps it has an indirect effect on survival, which has really been shown in the long-term follow-up of the COMFORT trials. So that is there, but I would use it for symptoms and spleen, and that’s the drug I normally would start with. Regarding what percentage will ultimately require therapy, I don’t think we quite know that percentage, but I think eventually, it will be everyone.

Srdan Verstovsek, MD, PhD: In terms of initiating therapy on time, how would we go about defining when is the right time? We have a questionnaire that we all hopefully use, which is the MPN-10 questionnaire, to objectivize the quality of life of the patients and see how bad the quality of life is, which may help us define the timing of introduction. We can certainly measure the spleen by palpation, ultrasound, or CT [computed tomography] scan. I don’t think we use MRI [magnetic resonance imaging]. When is the best time or should we talk about utilizing the therapy early on to prevent the progression in a way, or to have the prolongation of life early? Andrew, what’s your take on that?

Andrew Kuykendall, MD: I think it’s a great question because I don’t think we know the answer exactly. I think we have bits of information that give us a better feel for that. But what we know about ruxolitinib therapy is we saw the waterfall plots that Rami presented from the COMFORT studies, and virtually everyone who is on that, so they got some degree of benefit. While it might not have reached the 35% threshold to call it a swimmer plot, virtually everyone got some improvement in their spleen volume.

Multiple studies have been looking at what predicts response versus nonresponse, and things that predict a less-than-adequate response or less of a response would be more molecularly complex disease, larger spleens, and those are things that happen throughout the course of the disease and happen in the later stages. So by holding off on therapy, it may be that we’re allowing some of these factors to arise that prevent the response, so we’re getting the best response we could.

We know that patients maybe earlier on in the disease course, with a spleen that’s not massive—with maybe just a JAK2 mutation and not a significant complex molecular profile—maybe those are the ones who are more likely to benefit, and we can acquire that response early on and prevent it from getting to an area where we’re not able to get that. But I think that’s a challenging question, to know the right time to start a therapy in someone. Oftentimes, I’d say that you can talk to a patient and patients will tell you, based on their quality of life, when is the right time to start a therapy. But it’s a challenging discussion.

Srdan Verstovsek, MD, PhD: No question about it. It does seem, as you mentioned, that early intervention in terms of management is preferred because it’s easier to manage possible adverse events with anemia and thrombocytopenia if you start earlier in patients who do not have already significant anemia or thrombocytopenia. You have to account for the ultimate goal, which should be the decrease of the spleen to the larger degree that was, as Rami showed, connected with the prolongation of life. So, we should choose earlier intervention in not-so-sick patients, easier management, better dose of ruxolitinib, better spleen response, and perhaps then prolongation of life.

Just to conclude, 1 more question before we finish discussion of this topic. Rami, you had mentioned the role of interferon in myelofibrosis. Where do you see the role of interferon to move from JAK inhibitors to another possible therapy, perhaps earlier on in the disease management?

Rami Komrokji, MD: Obviously, interferon has been around in different versions and tested over many years. There is probably now approval for the newer formation, the ropeginterferon in Europe for ET [essential thrombocythemia], mPV [mean platelet volume], and myelofibrosis basically that have been studied, suggesting that interferon could alter the natural history of the disease, lead to reversal of the fibrosis or molecular responses. However, those were smaller studies, and the major limitation in most of those studies has been the toxicity and the patients not being able to stay on interferon for a long time to observe that benefit. Typically, it needs a couple of years of treatment with the interferon-based regimens to see some benefit.

So, in my opinion, based on the data, it’s that subset of patients that are early on in the disease, that they don’t have extensive fibrosis yet. They are younger, they are into that low, maybe intermediate-1 risk disease, that could benefit from interferon treatments. I typically would discuss a pegylated interferon like Pegasys or if there was a trial with ropeginterferon, in younger patients, early on in the disease, not much symptomatic. Once the patients have massive splenomegaly or constitutional symptoms or profound cytopenias, I typically have not observed clinical improvement or responses with interferon. So I think if one is going to think of interferon-based therapy, it should be done early on in patients that have lower-risk disease, not extensive fibrosis—not that high-symptom burden.

Srdan Verstovsek, MD, PhD: Very good. I will agree from my clinical practice, it’s the same type of experience, perhaps in the highly proliferative early phase where we need to control the blood cell count, it’s much better than in the later phase.

I thank you all very much for a lively discussion on the variety of the topics on myelofibrosis and thank you all for participating. We’re going to move on with the second case.

Transcript edited for clarity.

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