Symptoms and Patient Progression


Ruben Mesa, MD, FACP: Patients with myelofibrosis will primarily experience mortality associated with the disease if they progress. It is a progressive disease. So progression as a target is a very important one. We performed a landmark study surveying both patients and physicians of unmet needs in patients with myelofibrosis, and without question the issue of progression is an important issue, in both physicians and in patients’ minds.

At the current time we have not used progression-free survival as a clinical trial end point with our therapies. Part of the difficulty for this is that we still do not know why…patients progress. Is it solely the accumulation of additional somatic mutations? Is it clonal evolution? Is it some other metric that we have yet to identify? I have little doubt that an effective therapy has some impact on delaying progression that we’ve previously discussed. Patients can progress really along 2 paths, but the biology of those 2 types of progression are likely distinct. One path is along the path of the natural history of myelofibrosis—bigger spleen, lots of symptoms, further debilitation, and usually a patient passing away from complications from that debilitation.

The other path is much more distinctly an acute leukemia path. Increasing blasts, marked cytopenias, risk of infection and hemorrhage. That path tends to have less of a link to splenomegaly. It does not necessarily correlate with an increase in fibrosis. It does not necessarily correlate with worsening symptoms. I think the biology of both of those paths are distinct. We still have a scientific unmet need of fully understanding progression for us to have both metrics of measuring progression and surrogate markers of progression, and probably being able to adequately both develop new therapies to avoid progression but best understand how our current therapies might affect progression.

John Mascarenhas, MD: So that’s the goal of treatment with any of the agents we have. But it’s not always clear that all the agents we use achieve that goal. There are a lot of debates still in the academic world about what ruxolitinib ultimately does to the disease course. We know from the COMFORT-I and COMFORT-II studies that ruxolitinib has been associated with an overall survival benefit. And that survival benefit may be more of a result in improvement—in performance status, symptom burden, reverse of pyrexia—than clear anti-clonal activity and disease burden and course modification.

Right now the drugs that we employ, whether they’re to improve anemia or to address spleen, are clearly disease-course-modifying drugs. The only therapy that has clearly been shown to have the potential to induce significant disease-course modification would be transplantation. That’s the only modality that offers the potential for use. Luspatercept, an EMA [erythroid maturation agent] that we discussed, would hopefully offer the potential to improve anemia in patients but is unlikely to change the disease course. I think pacritinib and fedratinib and ruxolitinib are excellent agents and are needed, but I think they don’t clearly, or they haven’t proven at this point to clearly modify the disease course. And we know that patients, for example, who ultimately come off ruxolitinib do very poorly, they have a short median survival.

So there’s really an unmet need to develop drugs, particularly second line after ruxolitinib failure, that will improve outcomes. And one drug that was presented at the American Society of Hematology [Annual Meeting and Exposition] this Decemberis a drug called imetelstat, which is an infusional drug that’s given every 3 weeks. And in a large multicenter randomized study at 2 dose levels, this infusional agent was shown to be associated with a survival benefit compared with the low dose, or just compared with historical controls, in patients who’d failed ruxolitinib. These are patients who were pretreated with ruxolitinib and had progressive disease or loss of response. There was a significant survival benefit compared with the 12-month expected of 30 months. So agents like these, that are hopefully directed at the malignant hematopenic stem or progenitor cell, could really modify the disease course that are exciting.

Ten percent to 20% of patients with myelofibrosis over the first decade can progress to acute myeloid leukemia. And the clinician needs to be aware of the fact that the goal would be to try to prevent that, obviously because when patients progress to acute myeloid leukemia from a background of MPN [myeloproliferative spasms], the outcome is miserable. It’s a dismal prognosis of about 3 months. It’s not really improved with standard cytoreductive chemotherapy. And bone marrow transplant is really the only potential to offer them long-term survival. But one needs to get there first, either with induction chemotherapy or a DNMT [DNA methyltransferase] inhibitor.

Ruben Mesa, MD, FACP: The Myelofibrosis Symptom Assessment Form and the broader MPN Symptom Assessment Form are patient-reported outcome forms that my colleagues and I developed really out of an unmet clinical need. When we performed the phase 1 study of ruxolitinib in patients with myelofibrosis, it was clear that there was a significant impact on the difficult disease-related symptoms. And we had already conducted some research that both identified and quantified what types of symptoms were present.

So we have developed this patient-reported outcome form that has been validated now in many languages, and it has been utilized in pretty much all the phase 3 studies conducted for the disease over the past several years. It allows us a way to be able to quantify symptoms that benefit, or symptom burden at the baseline for a patient, as well as to be able to track the impact of a therapy over time for that patient, either better or worse. We are working to evolve this from a clinical trial tool to really a tool to be able to use in clinical practice.

We are working with the electronic medical record companies, trying to be able to initiate this, so that it can be part of the standard workflow of caring for these patients, so that it can be more simple for treating clinicians to understand the symptom burden a patient faces as well as to be able to track that over time just like the hemoglobin or the white blood cell count for their patients on therapy.

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