Several risk assessment scoring systems have been developed to help with risk stratification for patients with myelofibrosis. There are several factors, such as specific genetic mutations, that can help identify patients with the highest risk for progression to acute myeloid leukemia (AML) and thus can be useful for developing targeted treatment regimens.

The clinical presentation of myelofibrosis can come in a variety of shapes and sizes. There are patients with more proliferative myelofibrosis who have symptoms and splenomegaly but a lower risk of transformation. Others may be at high risk of transformation or are in the process of transformation with an identified genetically evolved disease, and still others have prefibrotic myelofibrosis that may be associated with a longer disease-free survival. Patients can present with a range of signs and symptoms that can be quite variable, and we have learned over time how to use these signs and symptoms to predict how these individuals may progress in their clinical course and, more recently, how to adjust their therapy.

The myeloproliferative neoplasms community has developed several commonly used prognostic scoring systems: first the International Prognostic Scoring System (IPSS) and then the Dynamic IPSS (DIPSS), followed by the DIPSS-Plus. Whereas the IPSS is recommended for risk stratification at the time of diagnosis only, DIPSS is validated for the prognosis of patients anywhere in the disease process, so it is a valuable tool in that regard. The DIPSS-Plus incorporates additional key risk factors, such as thrombocytopenia, cytogenetics, and transfusion dependence, that we have learned are valuable and add more granularity.

Now, with the use of next-generation sequencing and the risk of molecular medicine, we have developed the IPSS-molecular (IPSS-M) in myelodysplastic syndrome, which incorporates a variety of mutations. While there is a little less granularity in myelofibrosis, we do know that there are several high-risk mutations, such as ASXL1, EZH2, SRSF2, IDH, U2AF1, and TP53, that confer a less favorable prognosis. This has led to the creation of probably the most important and reliable prognostic scoring system in myelofibrosis, which is the Mutation-Enhanced IPSS 70-plus version 2.0 (MIPSS70-plus v2.0).

Even though I may clinically feel that I have a good sense of where a patient may be, I still go through the exercise of obtaining a patient’s prognostic risk score to see if my impression of their disease state matches with an objective score. And I do this knowing that their risk score might alter my approach to treatment if the patient has terrible symptoms that I have to address but they do not have a lot of the high-risk features that put them at an increased risk for transformation to AML and death.

Risk assessment can also be useful for assessing whether to move more quickly toward offering allogeneic stem cell transplantation. We do not want to miss an opportunity to take a high-risk patient to transplant because, once they develop post-myelofibrosis AML, their transplant success rate decreases and their 2-year survival drops, dramatically. Similarly, we do not want to expose a low-risk patient to all the associated risks of transplantation when they may have done well for a long time with a JAK inhibitor or another therapy. Improving our ability to predict this relationship and to better identify those patients at highest risk is a continued area of active research.

An important consideration with respect to allogeneic stem cell transplantation in myelofibrosis is that patients with proliferative disease may do better with myeloablative conditioning regimens. However, most centers do not consider it safe to use myeloablative conditioning regimens for patients who are older than 55 years unless they are particularly fit. Likewise, the window for an allogeneic stem cell transplant may start to close for patients who are in their late 60s and 70s. For these individuals, it is important to look at the highest risk factors, such as the presence of an ASXL1 mutation, which may be associated with an increased risk of transformation to AML. That is an objective genetic feature that increases my likelihood of recommending earlier transplantation. Transfusion-dependent anemia is another risk factor that I highly consider because we want to make sure that we get those patients to allogeneic transplantation before they develop iron overload.

No matter what the prognostic information tells us, it is important to remember that we are dealing with human beings. Patients have lives they want to live and individual considerations, and, regardless of how high their calculated risk of developing AML is, they may refuse treatment for personal reasons (eg, they may have a child graduating from high school and want to get them off to college before they undergo the rigors of an allogeneic transplantation). As clinicians, we respect and incorporate those considerations into our recommendations as we help our patients navigate this challenging disease.