Disease progression in myelofibrosis can manifest in many different ways, whether it be increased clinical symptoms, spleen progression, or an evolution to an accelerated or blast phase secondary acute myeloid leukemia (AML). In addition, some patients develop underlying progression without obvious clinical signs. Thus, recognizing disease progression in all its forms is an important part of optimal disease management and patient outcomes.

It is important to define what is meant by disease progression, as this can mean different things for different patients with myelofibrosis. When a patient progresses, it could mean that their symptoms are no longer under control or are getting worse, the spleen is getting worse, they are becoming more transfusion dependent or cytopenic, or they are actually progressing to accelerated or blast phase disease. These are some major parameters that I think about with respect to disease progression in myelofibrosis, but it is important to understand that these are not independent events. It is not uncommon for people to have symptom progression and spleen progression concurrently. So, one must be aware of the landmarks of defining successful disease control to understand what it means to have disease progression.

The outcomes for those with myelofibrosis that progresses are not great. For example, if you look at patients who have disease progression on ruxolitinib and go off therapy, the prognosis is historically poor. Whether that changes in the modern era of having multiple JAK inhibitors available is not yet clear, but any type of progression can potentially be associated with a poor outcome. Switching to newer available therapies may mitigate the progression to some degree, but we do not yet entirely know the answer to that question.

Anemia and thrombocytopenia are clearly becoming some of the most important clinical features that we see in patients with myelofibrosis. JAK inhibitors work by slowing down the influence of the driver mutations in patients with myelofibrosis. For those with polycythemia, it can be useful to give them a drug that slows down not only a mutant JAK but also a wild-type JAK. However, when patients with myelofibrosis start to become sclerotic and can no longer conduct normal erythropoiesis, then the benefits from JAK inhibitors are likely going to be limited.

It is important to remember that the studies conducted for the initial US Food and Drug Administration (FDA) approval of JAK inhibitors were done in patients with higher-risk disease who were more genetically evolved, which led to the initial FDA approval for higher-risk patients with intermediate-1 and intermediate-2 disease. But many patients who stay on therapy longer have lower-risk disease. For example, based on the results of the RESPONSE study, patients with polycythemia who are refractory to hydroxyurea can then receive ruxolitinib, and these patients tend to stay on the drug longer.

This begs the question of whether we need to treat people earlier. You cannot give these agents to all patients because they do come with side effects, and there are long-term risks associated with therapy. Therefore, an important area of research is to identify early on the patients who are going to develop high-risk disease. If we could identify which patients are going to develop high-risk disease, those are the patients for whom it would make sense to keep their disease from becoming more genetically evolved, if possible.

For patients with myelofibrosis, disease progression really occurs on a continuum, and patients can progress in different ways. As Dr Rampal mentioned, for some individuals, this can mean progression of their underlying symptom burden, while, for others, it can mean progression in terms of their spleen volume. Further, in some patients, progression can also present as evolutionary disease to accelerated or blast phase secondary AML, which is often refractory to modern therapies, and the outcomes can be pretty dismal without transplant. Thus, being able to recognize progression is important for so many reasons.

While we have multiple JAK inhibitors that we can utilize, responses are often not complete, and sometimes the progression of disease to AML while on therapy can be missed. Although progression to AML often comes with warning signs and symptom burden, many times it does not. We have seen patients who have maintained the usual disease response criteria of spleen and symptom burden control but still developed increasing blast counts in the peripheral blood while receiving ruxolitinib for chronic phase myelofibrosis, which suggests an evolution to AML. We have even had several patients who developed extramedullary leukemia. In many of these cases, it was not evident to the patients that they were doing poorly and were progressing in their disease because they continued to feel pretty well on ruxolitinib.

The JAK inhibitors are great therapies, but they are not really anticlonal drugs. Even at higher doses, they do not demonstrate the ability to induce a remission of leukemia. So, there needs to be a lot of attention focused on making sure that a patient’s peripheral blood blast count is not rising as an indicator of an eventual progression, even when they are clinically doing well on a JAK inhibitor. We need to acknowledge that, while we have had patients who were successfully treated with ruxolitinib for a decade or even longer, it is not a drug that reliably halts disease progression. By 3 years of therapy, half of patients will have discontinued ruxolitinib, so it is important to recognize that the vast majority of individuals will not take ruxolitinib for the duration of their lives.