Case Studies in Myeloproliferative Neoplasms - Episode 10
Jamile Shammo, MD, reviews prognostic models in myelofibrosis.
Jamile M. Shammo, MD: Now that the diagnosis has been made, there have been multiple prognostic models to estimate survival and help determine whether transplantation may be a reasonable option, because it continues to be the only curative modality for this patient population. Perhaps the most widely utilizable scoring system until the last decade was the IPSS [International Prognostic Scoring System], which was initially published in 2009. That utilized 5 different parameters: age of 65, hemoglobin less than 10 g/dL, white blood cell count above 25 per mm3, blast count of over 1%, and presence of constitutional symptoms. Each parameter was 1 point. If you applied our patient’s parameters, you end up with 4 points, which automatically puts him at a high-risk disease. That takes you to the highest possible category with an estimated median survival of about 2.3 years.
It turns out that when you do the IPSS at the time of diagnosis, it’s helpful in estimating the survival changes from low-risk at 11.3 years to 2.3 years, but then as the patient lives with this entity for several years, they may develop things like anemia and perhaps thrombocytopenia. Their prognosis might change depending on those poor prognostic futures that would evolve over time. Then the concept of a Dynamic International Prognostic Scoring System [DIPSS] became important, and therefore the DIPSS was developed the following year with emphasis on the development of anemia. Some of the statistical analysis demonstrated that there was much more importance that was placed on the development of anemia with a hemoglobin below 10 g/dL, so that was given 2 points in the DIPSS. There are 3 groups with variable median survival.
The following year, various parameters were found to be of importance and were added to the DIPSS+. The complexity continues to occur, and this, too, is dynamic. The unfavorable carrier type is included. The development of transfusion dependence is important prognostically. Having a low platelet count—below 100,000 per mm3—is also given a point. This can be utilized at any point in time. The DIPSS+ has 4 different points going from 15.4 to 1.3. Those are all parameters that you could use when you are evaluating your patient for a consideration for transplantation. If you were wondering what the unfavorable carrier type is, you can see it here. It’s the complex carrier type, or 2 single abnormalities, including the following cytogenetic abnormalities.
Because we are in the molecular age, the molecularly inclined International Prognostic Scoring System has been developed. This came out of a collaboration between the Mayo Clinic and the Italian group, as has been the case for many years. They evaluated a large cohort of patients who had myelofibrosis [MF]. All those patients happen to be below age 70. The idea is identifying patients who may be fit for transplant, and looking at certain variables with multivariate analysis continue to hold their statistical significance. By adding certain clinical variables and looking at data that is gleaned from NGS [next-generation sequencing], which is something we’re all utilizing in clinical practice, you see the hemoglobin below 10 g/dL, white blood cell count, platelet count, blast, constitutional symptoms, as well as myelofibrosis CALR, absence of CALR type 1, which by the way is the 1 that presumably is associated with the better outcome.
High molecular risk is the presence of any mutation in any of those categories or the presence of 2 high-molecular-risk mutations. It gets 2 points. Essentially, you may end up with 3 by applying those points. You essentially had 3 different risk categories, and you’ll see the difference in median overall survival depending on the score you get. If you end up with a patient who has a very high-risk score—50% of those people will not make it up to perhaps 2 years—then you can certainly justify a stem cell transplantation in this patient population. This is a reasonable inclusion of the molecular data that we have in a prognostic scoring system that has clinical data for that purpose. I’m curious to hear your thoughts about the outcome of stem cell transplantation. It’s always a huge point of discussion with patients. It’s the only curative treatment option for this patient population. Perhaps better selection of this patient population is always key moving forward.
The next prognostic model actually was made for the patients who developed myelofibrosis from ET [essential thrombocythemia] and PV [polycythemia vera]. Without laboring the point, it separates patients into 4 prognostic groups, which is important when you have some patients who have evolved from ET or PV.
Ruben Mesa, MD: These tools are quite helpful. They clearly overlap to a great degree. But fundamentally, there end up being 3 groups however we define them. We have the groups with a short survival: a year or 2 with pretty aggressive disease. We have those who are the long-lived patients with MF. We all have some patients who have dramatically long survivals with decades of disease. Then there is 1 group in the middle. Prithviraj, how big is that first group? That really high-risk group may be a bit more likely to travel to see you and your colleagues at [The University of Texas] MD Anderson [Cancer Center] with all your trials and options of that nature. How big is that group? What are the drivers of that group that are likely to go over to AML [acute myeloid leukemia]?
Prithviraj Bose, MD: In my estimate, that group is about 10% to 20%. That is the really high-risk group: patients with adverse carrier types, things like monosomy 7 and 11q23, complex carrier types, things like that. Of course, there are also the mutations that all of us have been talking about: ASXL1, SRSF2, and multiple others. Among them, U2AF1 is a relatively new kid on the block. All those are risk factors. There are some classic risk factors as well: anemia transfusion dependence and then the blast count of 10% to 19%, which is your accelerated phase. They obviously have a very high risk of transformation to AML. Finally, low platelets, less than 50 per mm3, is a very high-risk category.
This transcript has been edited for clarity.