Risk, Prognosis, and Nontransplant Options in Primary Myelofibrosis


Ruben A. Mesa, MD, and Srdan Verstovsek, MD, PhD, provide insight on the disease burden and prognostic scoring of primary myelofibrosis, as well as options for nontransplant candidates.

Ruben A. Mesa, MD: Let’s switch gears and focus on myelofibrosis. Individuals with their first diagnosis of primary myelofibrosis and those who have evolved from polycythemia vera [PV] or a central thrombocythemia are patients with post–ET [essential thrombocythemia] or post-PV myelofibrosis [MF]. As we had discussed with polycythemia vera, we need to be mindful of both disease burden and risk. The disease burden is a little different from what we had discussed with polycythemia vera. They can have enlargement of the spleen. Unlike polycythemia vera in MF, splenomegaly is quite prevalent, and sometimes it is dramatically enlarged and can cause a range of difficulties: early satiety, pain, catabolic impacts, etc.

Second, [there is] an impact on the [blood cell] counts. The counts can be low. In primary myelofibrosis, most individuals have anemia. If they have post-PV myelofibrosis, they certainly have had a clear decrease in their erythrocytosis. They can have leukocytosis. They may have thrombocytopenia. They can have risk of vascular events, but that is less common than you might find with P [polycythemia] vera or ET. They also have a risk of progression toward acute leukemia.

Myelofibrosis is a life-threatening condition to a much greater degree than we anticipate with earlier MPNs [myeloproliferative neoplasms], such as polycythemia vera.

Because of this and the heterogeneity of prognosis, there have been many efforts to try to create prognostic scores for managing patients with myelofibrosis. With the historical prognostic scores looking at survival of the DIPSS [Dynamic International Prognostic Scoring System] and DIPSS plus probably being looked at most around the world. I have you pull these up in terms of creating the scoring, but they’re based on largely clinical information: age, anemia, leukocyte count, elevation in the blasts. These are clinical features not too dissimilar from prognostic scores we use in MDS [myelodysplastic syndrome] or the old scores in CML [chronic myelogenous leukemia].

The DIPSS plus includes features such as karyotype—an abhorrent karyotype is a higher risk—and then more modern criteria, such as the MIPSS [Mutation-Enhanced International Scoring System] or MIPSS70 [Mutation-Enhanced International Scoring System ≤70 years], that incorporate new molecular findings. They largely incorporated all those other findings—blood counts, age, symptoms—but also include genetic changes. One is the realization that CALR-mutated patients vs JAK2 or NPL likely have a better prognosis. Two is that individual additional somatic mutations have been associated with higher-risk disease, specifically ASXL1, ECH1 and ECH2, IDH1 and IDH2, and multiple additional somatic mutations that add risk.

People ask how can you remember all these scores, how you use them. Fortunately, you can find them online. For MIPSS70, just type that into your web browser and it will pop up. You can put in the clinical variables and get that information.

Where do we use these prognostic scores? They can help you to find a survival, from as poor as a year or a year and a half to a life expectancy well in excess of a decade. They make the most impact in terms of our decision-making regarding pursuing stem cell transplantation. With individuals who have a life expectancy likely under 5 years and are good transplant candidates, we should think about transplantation as an earlier option. For individuals who lack those features, we potential put transplant on the back burner. There is undoubtedly much about MF and prognosis for us to learn.

Srdan Verstovsek, MD, PhD: Transplant is always an option for a patient with myelofibrosis when they have a shorter life expectancy. Transplant is always an option for patients with myelofibrosis, but only for those who have a higher risk of dying, because you have to justify risk of transplant procedures that come with some mortality, unfortunately. You must justify that procedure as reflected with the expectation of their life with the disease is. Utilizing prognostic scoring systems, we have intermediate-1 risk patients, who would not be usual candidates for the transplant, and we have intermediate-2 or high-risk patients, who have a life expectancy of less than 5 years. They are transplant candidates.

Of course, prognostic factors are evolving, not fixed forever. We have, over the last 2 years, about 10 new prognostic scoring systems. With 1 prognostic scoring system, patients may have earlier-stage disease. But if you include, for example, abnormalities in chromosomes or genetic complexity that may be discovered through extra genetic testing, then patients may move up with a different prognostic scoring system to intermediate-2 or high risk.

For earlier stage, like intermediate-1, NCCN [National Comprehensive Cancer Network] Guidelinessuggest therapies that are related to controlling the blood cell count if it’s too high, with hydroxyurea or pegylated interferon or ruxolitinib in patients who are symptomatic with either symptomatic splenomegaly or general systemic symptoms.

When we move to intermediate-2 and high risk, the first question is about the transplant, right? If they are not transplant candidates, you would treat them similarly, with anemia drugs for anemia, with JAKinhibitors for symptomatic splenomegaly or general systemic symptoms. Many times in my clinic, we combine them together, an anemia drug with a JAKinhibitor.

If that 1JAK inhibitor does not work, we may go to the next 1. In the United States, we have 2 approved: 1 in 2011, ruxolitinib, and fedratinib in 2019. Fedratinib has been published as a possibility in patients who have not done well with ruxolitinib. The second-line setting is where fedratinib can be used to control the symptoms and signs of the disease, symptomatic splenomegaly, and general systemic symptoms.

We must be careful in switching from 1 to the other because there might be a rebound in inflammation that is controlled withJAK inhibitors. Tapering 1 and starting the other, or utilizing prednisone as an anti-inflammatory agent, with steroids in the transition period, is wise so you don’t a rebound that is known to happen in some patients when you switch from 1 drug to another.

Transcript edited for clarity.

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