Q: What are the current approaches to risk stratification in patients with MPN, and how do you evaluate the response to therapy?

Treatment decisions in patients with polycythemia vera (PV) or essential thrombocythemia (ET) are based on the risk of thrombosis. Increased risk is associated primarily with older age and prior thrombosis, but other factors such as leukocytosis and somatic mutations (eg, JAK2, CALR) can be factored into these models. The models can also predict overall survival in individuals with PV or ET. Risk stratification in patients with primary myelofibrosis (PMF) is more challenging than in those with PV or ET. We have used the classic International Prognostic Scoring System (IPSS) and the dynamic IPSS (DIPSS) for many years. The DIPSS-plus model includes thrombocytopenia and cytogenetic components. Newer molecular models, such as the Genetically Inspired Prognostic Scoring System (GIPSS) and the Mutation-Enhanced International Prognostic Scoring System for Transplant-Age Patients (MIPSS70), are genetically based and particularly useful in patients who are stem cell transplant candidates. They do refine outcomes, but deciding which of the newer models to use can be overwhelming for community practitioners. The MIPSS70 and the MIPSS70-plus are geared toward transplant-age patients with PMF and integrate relevant clinical, cytogenetic, and mutation data. The GIPSS may enhance clinical prognostic models for PMF where it depends solely on genetic risk factors. With respect to post-PV and post-ET myelofibrosis, we now have a model that is helpful for predicting survival: The Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM). The MYSEC-PM incorporates the duration of myelofibrosis (ie, age at diagnosis) and other variables such as anemia, thrombocytopenia, and the presence of the CALR-unmutated genotype. The program is available online, and one can simply type in the variables and promptly view the results.

We should first consider the objectives of risk stratification in the various patient groups. Risk stratification is a different entity in patients with PV or ET compared with those with myelofibrosis. Risk stratification in patients with PV or ET relates primarily to the risk of thrombosis or bleeding. In individuals with myelofibrosis, either primary or post-ET or post-PV, risk stratification is truly related to survival. In both groups, risk stratification fails to fully account for disease burden; it does not tell you whether patients are really suffering from the disease or are having difficult symptoms. Thus, when I assess patients for treatment, I am mindful of both their risk of complications and their overall disease burden. In PV and ET, risk stratification is also based on clinical factors, including age, history of thrombosis, the presence of leukocytosis, and a range of intermediate genetic factors that are associated with cardiovascular and other risks. Risk stratification in myelofibrosis is more complex; risk stratification models, of which there are currently many, include a combination of clinical features, symptom severity, and myeloid mutation analysis by next-generation sequencing. In myelofibrosis, the MIPSS70 is the most recent variant in this group and is most impactful in terms of clinical decision making, as it relates to stem cell transplant, and less impactful in terms of deciding when to initiate or modify doses in medical therapies. With PV and ET, the thrombotic risk models do impact the decision to initially start cytoreductive therapy.

Risk stratification in patients with PV is based primarily on age greater than 60 years and previous thrombotic event. Contemporary risk stratification guidelines for patients with ET include the established factors (age >60 years old and prior thrombotic event) plus JAK2 mutation status, and they categorize individuals as being very low, low, intermediate, and high risk. JAK2 is the predominant mutation for PV and ET, estimated at greater than 90% for PV and 60% for ET. The IDH1 and IDH2 mutations predict a higher risk of transformation from PMF to acute myeloid leukemia (AML). We use the International Prognostic Score for Essential Thrombocythemia (IPSET) as an additional component to predict thrombosis risk when deciding whether to initiate cytoreductive therapy. The IPSET model includes age, prior thrombotic event, and JAK2 mutation status, as well as cardiovascular risk factors (diabetes, hypertension, and/or current smoking) that are independent predictors of thrombosis. For patients with PMF, the IPSS, the DIPSS, and the DIPSS-plus are being used routinely for risk stratification in academic and community settings. The MIPSS70 and the MIPSS70-plus are relatively new and will likely be used at academic centers first, but this type of model will likely become more widely utilized in time. I think that the DIPSS-plus model is likely the best for predicting the risk of transformation to AML in patients with PMF. The model predicts how long it would take 25% of patients in any particular risk group to progress to AML. Mutational analysis of the myeloproliferative clone may be used to identify molecular responses to targeted therapies in patients with PMF and other MPN.