Risk Stratification and Patient Classification for PMF

Aaron Gerds, MD, MS: There are a lot of different ways we think about risk for primary myelofibrosis. Most commonly, we think about overall survival. What is the average amount of time someone will live with this diagnosis? The concept is the more aggressive the disease, the more aggressive we should be with it in applying our therapies. Now, we can determine disease risk or average survival in a number of manners. We often use risk stratification systems. Now, unlike solid tumors, where you have an initial tumor, and then it travels to a distant nodal site as a metastasis, or even other organs, and the staging system is based on that, for blood diseases like leukemias, the blood is everywhere, including in myelofibrosis. We can’t necessarily have a stage system based on where the diseases travel, so we use these risk models. The most commonly used risk model is something called the Dynamic International Prognostic Scoring System, or DIPSS. It takes a number of clinical variables that you could easily get at any clinic visit, and you plug them together, and you get a score. And that score is associated with a median survival for that individual. The nice thing about this prognostic scoring system is it is dynamic, that’s what the D stands for, meaning that it can be used at any point along a patient’s disease course. Now, it doesn’t include very deep variables, such as cytogenetics, which we know are strong predictors of disease course and risk of progression. Moreover, it doesn’t include molecular information, such as the mutations that are inside the myelofibrosis cells. These models have been updated to the DIPSS Plus, which includes cytogenetic information, as well as this model called the MIPSS70 [Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients With Primary Myelofibrosis], which includes molecular markers, such as driver mutation status, and additional mutations, such as ASXL1, or TP53, and these other high-risk mutations. We take all these bits of clinical information together, and we try to think about what is the predicted overall survival for this individual going forward. Is it a very short period of time, say, less than 5 years? That would be on the higher end of risk. Or is it going to be longer than 5 years, which we would say is on the lower end of risk?

When we think about molecular status or mutations that are inside the myelofibrosis cells, first and foremost, it’s incredibly important for diagnosis. We like to identify that JAK/STAT driving mutation, the mutation that is driving that pathway, as part of this disease, whether we’re talking about JAK2, calreticulin, or MPL mutations. There is some prognosis within those. We know that patients with type 1 calreticulin mutations tend to do much better than patients with other types of mutations driving the JAK/STAT pathway in individuals with myelofibrosis. But what’s probably more important are the other mutations that we see inside these myelofibrosis cells. There are certainly some very high-risk mutations, like ASXL1, that predict for a more aggressive disease course over time, more likelihood for progression and those types of things, as well as mutations such as IDH2, where not only are they higher risk, but we also have now targeted therapies that could be applied in that patient’s treatment at some point in time. Thus, these mutations that we can get in these genomic analyses are incredibly important for diagnosis, prognosis, and now even treatment.

Symptom burden assessment is a big piece of what we do every day in the clinic. It often drives our treatment. A lot of times, you may have a patient with some middle-of-the-road-risk disease, or even low-risk disease, where you may not think you can improve things too much with a JAK inhibitor otherwise, but boy, they’re symptomatic, and starting a JAK inhibitor may make them feel a lot better. That can really drive your treatment. In checking symptom assessment, I think a lot of people just ask the questions, “Well, how are you feeling? Do you have any night sweats? Do you have anything else going on?” But I tend to use the MPN-SAF [Myeloproliferative Neoplasm Symptom Assessment Form]. It’s a validated tool to measure not only the types of symptoms the patient is having, but their intensity, and kind of measuring that clinic to clinic to clinic while they’re on a treatment or even on observation. You can see if they’re getting worse or getting better by simply looking at the numbers that are recorded. This has been validated in a number of studies, as well as used commonly in clinical trials.

Transcript Edited for Clarity