JAK2 and IRAK1 in Myelofibrosis - Episode 4
Drs John Mascarenhas and Ruben Mesa review unmet needs and challenges in treating myelofibrosis.
Ruben Mesa, MD: People frequently ask me about the unmet challenges as we’re trying to treat myelofibrosis [MF]. As you and I have been very interested in working together on many different therapies, both approved and in development, that goal really becomes important. As I shared with you, it’s about ideally making the patient live longer and live better, and realizing that different patients have different features of the disease that are an issue for them, such as risk of progression, splenomegaly, symptoms, elevation in the blood cell counts, and those difficulties. But of the difficulties we have, which of those do you think at the moment have been the most difficult for us to improve?
John Mascarenhas, MD: I think with the advent and availability of JAK inhibitors, we’ve had great success in addressing symptom burden and spleen burden in the majority of patients we treat. I think one of the unmet needs that still remain challenging is anemia, particularly transfusion-dependent anemia, which becomes quite frequent in the disease course of many patients. Although we do have erythropoiesis-stimulating agents, danazol, immunomodulatory drugs, and more recently, access to an erythropoiesis maturation agent called luspatercept, I think anemia remains a challenging aspect. Many of the JAK inhibitors we both use can exacerbate that anemia. So although you can get benefits in spleen and symptoms, it may be at the cost of some degree of treatment-related anemia upon disease-related anemia. That’s why I look forward to drugs like momelotinib that are in late-stage clinical development, that are JAK2 inhibitors-plus, and may offset and improve anemia in some of the patients. That’s hopefully a need that could be met by other JAK2 inhibitors and other anemia-directed therapies. I would say the other unmet need, or the other challenge we all face in a subset of patients either up front or after ruxolitinib failure, are those patients who have extreme thrombocytopenia. This is because many of the drugs we give, again, can exacerbate the thrombocytopenia and make it very difficult to deliver effective doses. That’s particularly why pacritinib, which is also in late-phase clinical testing and has data in phase 3 studies, has the ability to deliver effective doses of JAK inhibition in patients who have platelet counts even below 50,000/µL, which marks a group of patients who do particularly poorly, as many studies have shown. I would say cytopenias are still an unmet need and a challenge in delivering adequate care.
Ruben Mesa, MD: It’s interesting that you mentioned that, and it truly is a challenge. As I visit with patients referred from physicians, it’s clear that in the broader community of people treating these patients, the cytopenias are a big driver of what’s felt to be an unmet need. I think we’ve done reasonably well in the frontline setting with spleen and symptoms. I do think without question, there are opportunities in the second-line setting, eventually there can be progression—progressive spleen and symptoms, and other difficulties. But the cytopenias are tough. They don’t present in everyone, but anemia is quite common, both at baseline or drug-emergent. Then there is the group that has thrombocytopenia, this cytopenic phase of MF. As you and I have seen, it’s an interesting group. One, it’s a bit of a Venn diagram. Almost all who have thrombocytopenia also have anemia, but not everybody who has anemia is thrombocytopenic. But the group that has both, they have perhaps additional somatic mutations. Our group has published that they likely have more symptom burden. They have been identified to have a worse prognosis, perhaps a greater risk of progression. So it’s a challenging group.
Transcript edited for clarity.