Overview of Myelofibrosis


John Mascarenhas, MD, and Ruben Mesa, MD, provide insight on the diagnosis and prognosis of myelofibrosis.

John Mascarenhas, MD: Hello, and thank you for joining this Targeted OncologyTM presentation titled “JAK2 and IRAK1 in Myelofibrosis.” The treatment of myelofibrosis [MF] has undergone a transformation over the last several years, driven by the approval of several targeted therapies. The availability of these therapies has allowed hematologists and oncologists treating MF to use a precision medicine approach that was previously out of reach. Our discussion today will focus on JAK2-directed therapies, their roles in treatment, and the key clinical trials guiding their use. We will also discuss some relevant data recently presented at the 2021 ASCO [American Society of Clinical Oncology annual meeting]. I am Dr John Mascarenhas, associate professor of medicine at the Icahn School of Medicine at Mount Sinai and a member of the Tisch Cancer Institute in New York, New York. I’m joined by my close friend and colleague Dr Ruben Mesa. He is the executive director of the Mays Cancer Center at UT Health San Antonio at MD Anderson Cancer Center in Texas. I welcome you joining us today. Ruben, thanks for joining us.

Ruben Mesa, MD: John, I’m excited to be here. There are a lot of exciting things evolving in myelofibrosis, as well as evolving targets. I’m interested for us to get a chance to dig into it and talk about some of the new drugs, the new targets, including JAK2 and IRAK1.

John Mascarenhas, MD: This will be a good conversation between the two of us, and I’ll help roll it along. Feel free to jump in and correct or add to what I’m saying. But I thought we’d start off describing the incidence and prevalence of myelofibrosis, which is a clonal hematologic malignancy. It’s estimated to be about 1 person per 100,000. It’s usually diagnosed by a hematologist and involves a bone marrow biopsy. There are also specific WHO [World Health Organization] diagnostic criteria. You need a good hematopathologist to be able to grade the bone marrow fibrosis and be able to describe the megakaryocyte atypia and other features. But it’s in the context typically of anemia, elevated LDH [lactate dehydrogenase], an increased spleen on examination, and symptom burden. There is also a clonal marker of disease, such as JAK2 V617F in approximately 50% of patients, or CALR exon 9 mutation in approximately 25% of patients. A small percentage, perhaps 5%, harbor MPL, which is a thrombopoietin receptor mutation. Then there’s this triple-negative 10% of the population that lacks the classic driver mutations. Ruben, when you see these patients and you’ve made the diagnosis of myelofibrosis, how do you approach risk stratification and prognostication?

Ruben Mesa, MD: It’s a good question. First, I’d emphasize for folks that when we speak of myelofibrosis, we’re really talking about more than 1 group. There are those who have had a longstanding earlier MPN [myeloproliferative neoplasm]—ET [essential thrombocythemia] or PV [polycythemia vera]—that has evolved into a secondary form of myelofibrosis that we call post-ET or post-PV myelofibrosis. I do think there’s sometimes a delay in those individuals being identified and being diagnosed. It is a continuum, as I try to share with patients. It’s not similar to a pregnancy test. It’s not a yes or no; it’s continuous and people are evolving. The second group are individuals with primary myelofibrosis. That’s the first disease they are diagnosed with. I’ve already done 2 new patient consults today. One was someone who had evolved from earlier PV for 14 years. The second was an older gentleman, who was found to have leukocytosis and evolved to be studied and found to have primary myelofibrosis.

Now with MF, I like to think about both prognosis as well as disease burden. Prognosis meaning on average, what is the number of days, months, or years a patient is going to live potentially with the disease? We realize these are averages and they are estimates, but it’s at least a guidance. Then, we think about the disease burden. The disease burden being potentially splenomegaly, sometimes significant. There are difficult symptoms, which we’ll get into in greater detail, but they can be diseased-associated, cytopenias, as well as the burden of the risk of progression. With these, there have been a litany of prognostic scores that have been developed. There are so many that few people could name them all, and almost nobody could memorize them. I think they fall into a couple of different categories. The most broadly used globally are the IPSS [International Prognostic Scoring System], DIPSS [Dynamic International Prognostic Scoring System], and DIPSS-plus. These are ones that primarily look at clinical features that most people have access to—anemia, white blood cell count, symptoms, age, and so forth. There are many new molecular-based or hybrid-type scores, which I think the MIPSS70 [Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis], is about as helpful as any of them. There are so many of these scores, and they do have a website. I think that’s by far the most helpful piece.

With that, we are able to see the potential prognostic significance of additional molecular mutations. One, there is either the absence CALR type 1, which is a more favorable prognostic marker, as well as being triple negative. Or second, there is the presence of 1 or more of let’s say the problematic mutations—ASXL1, EZH2, things of this nature. You can factor all of these things and you can get a score. It can give you a fair sense of prognosis from really indolent disease, where the median survival is an excess of 10 years, or a more problematic disease with survivals that are much shorter. There is an additional score for those individuals who have evolved from ET or PV, called the MYSEC-PM [Myelofibrosis Secondary to PV and ET Prognostic Model]. Why that’s helpful is that some of the cytopenias that are more prevalent in primary MF are somewhat later, or don’t manifest themselves in post-ET or post-PV MF. So, it’s a little different score for those. That is the prognostic part, but John, let me fire it back at you. I’ve done my prognostication. How do you, as an expert myelofibrosis physician, use those data?

John Mascarenhas, MD: We talk about it a lot. You and I have joked previously that there are an abundance of prognostic scoring systems available. But the real question is, how do you utilize them in the individual care of a patient? For the most part, the scoring systems achieve a broad stroke of being able to determine whether patients are considered sick enough or risky enough in terms of their outcome to warrant certain types of therapies. For example, patients who have higher risk disease, those who have usually intermediate-2 or high-risk disease, those are patients we would typically consider for transplant as a potential curative option if they are so inclined, if they don’t have significant competing comorbidities, or advanced age. The first way in which risk stratification helps us is to quickly decide whether a patient is appropriate for transplant; it is potentially curative, but also a risky therapeutic option. I think they are most helpful for clinical trial determination, at least in my practices, making sure the patient meets the WHO criteria for the diagnosis, but also the risk score that’s at least intermediate-2, if not intermediate-1, or high risk.

Then we share patients who are low risk, by any of the risk scoring systems. They lack symptoms, they’re not anemic and needing transfusions. They don’t have circulating blasts. They have a type 1 CALR mutation. They lack any high molecular risk mutations and their platelet count is sufficient. Some of these patients are asymptomatic, and they may have been diagnosed by routine blood work. Those patients may be appropriate for a watch-and-wait approach. So, I think the risk stratification helps. It’s really a risk-adapted therapeutic approach in myelofibrosis. That generally helps formulate an approach. But the reality is that for many patients, the risk score doesn’t specifically tell you the best therapy. That’s really the next discussion, which is regarding our goals of therapy. That is intimately intertwined with risk scoring as well. You set the stage many years ago for the fact that symptom burden is a very significant component of the disease. For many patients, it’s addressing symptoms. For other patients it may be addressing anemia as the most leading issue associated with the disease. For some patients, it’s survival. It’s trying to go for a cure and improve survival, and that’s where transplantation comes into play.

Transcript edited for clarity.

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