Targeting JAK2 in Myeloproliferative Neoplasms - Episode 2
Dr Verstovsek and Dr Kuykendall discuss the limitations of past treatments for MPNs.
Srdan Verstovsek, MD: Where are we with the new therapies, the targeted therapies looking at the underlying abnormality, which is hyperactivity of the JAK-STAT pathway in particular, so JAK inhibitors? To give us a sense as to where we were and where we are, I should say that for ET [essential thrombocythemia] and PV [polycythemia vera], and maybe you will join me in discussing myelofibrosis, in the past [therapies] for ET and PV were nonspecific. We had chemotherapy agents, from melphalan to busulfan, radioactive phosphorus, then hydroxyurea, and finally, some interferons. None of these were really attractive. We now know much about them, some are really toxic, like alkylating agents. We do not use them much at all.We were left basically with hydroxyurea in most of the cases—maybe anagrelide 20 years ago for ET; interferon was in and out with new some preparations, but they were never fully approved. Now we have a different spectrum of therapies for ET and PV. What was the state of myelofibrosis treatment in the past?
Andrew Kuykendall, MD: Myelofibrosis is a disease that is, as we said, more severe, more serious than ET and PV from a prognostic standpoint. Median survival is somewhere around 6 years on average for these patients. Obviously, that differs based on a lot of different factors, but largely, when treating myelofibrosis, you were extrapolating from our treatments for other diseases and trying to take care of whatever aspect of the disease you possibly could. Certainly, transplant has long been a possibility for patients with myelofibrosis, but the truth of the matter is that very few people are able to get a transplant and have that option. Whether it is due to comorbidities, age, or different factors, it is just not a realistic possibility for the vast majority of patients.
Besides that, we were trying to control numbers—whether it is hydroxyurea—stemming from what we know from ET and PV, looking at immunomodulatory, IMiD, agents like lenalidomide or thalidomide for improving anemia in patients with myelofibrosis. There is radiation of the spleen, doing splenectomies. This is really an all-hands-on-deck salvage approach to try to get some benefit. The diversity of issues the patients were having called for a variety of different solutions. Frankly, none of them are great solutions, which is why the emergence of JAKinhibitors has been so profound.
Srdan Verstovsek, MD: Yes, I absolutely agree; what struck me is that there are these efforts to prognosticate in terms of who will die sooner or later, that is the sad part of it. The prognostication efforts have evolved so much that we have so many prognostic scoring systems. But after all that, precision in saying, “Oh yes, you have a life expectancy of less than 5 years; you should go for the transplant,” eventually benefits so few patients. Less than 10% of patients actually go through the transplant procedure itself. A lot of effort and lots of testing is done to examine mutations, the bone marrow fibrosis grade, and cardiotropic abnormalities. They are put together sometimes in a complex way to prognosticate, but at the end, there is a little disappointment, I should say, that all these efforts are not really leading to more patients getting to the transplant because of difficulties going through the [procedure]. The mortality rate is still pretty high.
Andrew Kuykendall, MD: Yes; I think we spend a lot of time creating these prognostic models, and at the end of the day, they are very useful for identifying transplant candidates. I think, in the future, we will come up with better ways. In addition to prognostic modeling and coming up with survival expectations, at least what they have done, in my opinion, is identify factors and features of the disease that are very important. These are things that matter when they come up. We often order these mutation panels, and they give us 54 or 98 or 100 and however many genes back, and you look at that and there may be several abnormalities. But whether those matter is not clear. I think one of the things the prognostic modeling has done is shown us that when certain genes are mutated, in myelofibrosis specifically, that is something to take into account and to realize the disease has the potential to do things that maybe it is not showing externally. It is a limitation, but hopefully it will pay dividends later.
Srdan Verstovsek, MD: This is a really good point because any knowledge is good knowledge. There is some evidence, and we may touch upon this later, that some of these mutations, for example, do influence the outcome of therapy with JAK inhibitors. Genetic complexity may have an influence, and we may talk a little later about what to do with the patients while they are on therapy with JAKinhibitors. We will discuss how to assess the likelihood of losing response or progression, and that is coming from this extensive testing and developing prognostic factors for transplant. It is a good [adverse] effect, if you like, that we learned more than we expected from this type of testing.
Regarding the NCCN [National Comprehensive Cancer Network] guidelines, the last 2 versions over a year, year and a half, have simplified, in a way, the prognostic scoring systems, not in terms of which prognostic scoring systems to utilize. There are many different ones, and they are kind of complex, but they have allowed us to say there are 2 groups of patients in terms of prognostication: lower risk and higher risk. Patients who are at a lower risk are traditionally low and intermediate 1, but they lump them together in the NCCN guidelines because they have a better life expectancy than 5 years, and they should be treated in the same way for the symptoms of myeloproliferation, for example. The higher-risk group of patients—intermediate 2 or high risk—are basically treated in the same way, right? You treat them for symptoms in the spleen, or for anemia, maybe even in combination with different medications after the first question about a transplant or no transplant. That aspect, at least, of the guidance has been simplified. The goal is the transplant decision, yes or no, and then you move on to symptoms, yes or no. I think that is more evidence of the evolution of how we look at the treatment of patients with myelofibrosis in particular.
Transcript edited for clarity.