Challenges in Myelofibrosis Treatment

EP: 1.Overview of Primary Myelofibrosis

EP: 2.Risk Stratification and Patient Classification for PMF

EP: 3.Treatment Strategies for Primary Myelofibrosis

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EP: 4.Challenges in Myelofibrosis Treatment

EP: 5.Impact of Cytopenias on MF Treatment

EP: 6.Monitoring Treatment Response in MF

EP: 7.Role of JAK-STAT Pathway in Myelofibrosis

EP: 8.PERSIST-1 and PERSIST-2 Trials in Myelofibrosis

Aaron Gerds, MD, MS: One of the issues that makes treating myelofibrosis so challenging is the lack of approved therapies. We often get jealous of our colleagues who treat multiple myeloma, and they seem to get a new drug every Tuesday, and they have a lot of tools in their toolbox with which to go to work with every day. Thus, I think that’s one challenge. I think the other challenge is the general age and fragility of these patients. Most patients with myelofibrosis are older. The median age at diagnosis is in the 70s. They often have other medical issues going on, heart disease, lung disease, and other organs that may make treatment more difficult to apply. I think, too, just the general illness itself can make people more frail, so consistently elevated cytokine levels leading to nutrition issues and muscle mass loss. Really, I think it makes these individuals more frail and often more difficult to treat. Luckily, we do have these drugs that are available, like ruxolitinib and fedratinib, where we can use them to restore some of the way that these people feel, restore their muscle mass, their functionality and functional status, which I think is really important for not only having people live better, but even live longer, which has been shown in some larger pooled analyses with JAK inhibitors. I think the other main challenge in treating patients with myelofibrosis is the fact that most patients are cytopenic. Roughly 40% to 50% of patients will be anemic at the time of diagnosis. Upward of another quarter to 30% will be thrombocytopenic. Also, many of the drugs that we have available to treat the myelofibrosis often cause myelosuppression, meaning that their blood cell counts will get lower with treatment. Thus, you’re stuck between a rock and a hard place. You have this myelofibrosis that you want to treat, but the available therapies can drive the counts down even further. And you’re sometimes robbing Peter to pay Paul when using these therapies.

Srdan Verstovsek, MD, PhD: Myelofibrosis is a challenging disease, as it is, for the patients, causing bone marrow failure, enlargement of the spleen and liver, with symptoms that develop through those enlargements, particularly in the abdominal area. Then, general inflammation causes body wasting, night sweating, and low-grade fevers. Thus, to have therapies that would counteract those signs and symptoms is a challenging one. We have JAK inhibitors ruxolitinib and fedratinib, approved therapies, to control symptoms and the spleen in patients, but with the limitations of not being able to be used in patients with low platelets. They are not effective in patients who have progression to acute leukemia with elevation in blasts. Overall actually, in the chronic phase, they do work on the spleen and symptoms, but there is a limitation on durability. For example, the average durability of ruxolitinib benefit is about 3 years. People fail, the spleen starts to grow, the symptoms start to come back, anemia develops. In fact, anemia is the major reason for failing ruxolitinib, as we very well know. Thus, limitations are, in a selection of patients, those with low platelets: you can’t really give them JAK inhibitors, they lower the red blood cells and platelets as an adverse effect; anemia, for the same reason; progression in the blasts, there’s no effect of the JAK inhibitors on the progression to acute myeloid leukemia. Three major areas. And to top it off, what do you do after, in a second-line setting, after fedratinib or ruxolitinib? That’s unknown at this time.

Aaron Gerds, MD, MS: Some terms are emerging in the field of myelofibrosis, and one is this thing called myeloproliferative versus myelodeplete, or myelodysplastic-like, or empty, if you will, or spent myelofibrosis. The thought is that the counts are low generally in patients with this myelodeplete myelofibrosis, where in the myeloproliferative myelofibrosis, we see very high counts, thrombocytosis. Patients are less likely to be anemic or maybe even have high white counts, where in this myelodeplete myelofibrosis, we often see lots of thrombocytopenia, and even sometimes, in addition to anemia, low neutrophil counts, or neutropenia, in these folks. What we’re starting to learn is that the mutation profiles within the myelofibrosis cells of someone who’s myelodeplete versus someone who’s myeloproliferative are very different. We’re seeing different mutations and different patterns between these 2 populations, suggesting that while we like to dump things into 1 singular bin, like myelofibrosis, we really know it’s a spectrum of disease. There are a lot of different diseases all within that 1 bin. We’re trying to start to piece some of these things out because we may benefit patients by applying different treatments in different ways going forward. Really, the thought is that this myelodeplete myelofibrosis is a distinct version of myelofibrosis and perhaps may benefit from other treatments.

There’s also this concept of primary versus secondary myelofibrosis, and I want to be clear here that that term is a little bit difficult. Secondary myelofibrosis can also refer to something that is immunologically driven. Thus, a patient with a rheumatologic disorder or a chronic infection can get myelofibrosis or scarring in the bone marrow. But that scarring is not due to a clonal process. There’s no JAK/STAT mutation. It’s just the chronic inflammation within an individual driving the scar tissue in the bone marrow. That’s a completely separate entity. A lot of times, we use the word secondary myelofibrosis to describe what’s probably more precisely called post-ET [essential thrombocythemia] or post-PV [polycythemia vera] myelofibrosis. That is, a patient had ET or PV for some period of time, and then over time, their disease progressed or morphed into myelofibrosis. Thus, I think that distinction is important. But clearly, the outcomes of patients with post-ET and post-PV myelofibrosis are a little bit different than those with primary myelofibrosis. I think the clear indicator is that we now have a model designed specifically to assess prognosis in patients with post-ET and post-PV myelofibrosis. We kind of separate those patients out using a different model, where different clinical factors are added up in order to predict prognosis in those folks. In a lot of our clinical trials, we’re also trying to parse out post-ET and post-PV myelofibrosis from primary myelofibrosis to see if there’s any differential effect on treatments as well in order to better understand how these developing therapies might be best applied to different populations.

Transcript Edited for Clarity