Aaron Gerds, MD, MS; and Srdan Verstovsek, MD, PhD, share insights on the importance of allele burden in myelofibrosis (MF) and how cytopenias can limit treatment options for patients with myelofibrosis.
Aaron Gerds, MD, MS: Allele burden is a concept in myelofibrosis. In general, MPNs [myeloproliferative neoplasms], where we look at the ratio of mutated reads in, say, a PCR [polymerase chain reaction] test vs nonmutated reads—it’s almost a rough approximation for disease burden. You get out a percentage, so 7% of the transcripts that were looked at were mutated vs wild type, or 80% of the transcripts were mutated vs wild type. That’s a way of quantifying how much mutation you’re seeing. There are clearly some associations with disease course, and low-variant allele frequencies often associate with essential thrombocythemia in MPNs. High-variant allele frequencies of the driver mutation, or the JAK/STAT [Janus kinase/signal transducer and activator of transcription]-activating mutation, will often correlate with, say, PV [polycythemia vera] or myelofibrosis, so there is some difference there. Over time—we particularly see this in patients with PV—the mutant allele burden can increase in patients. In some treatments, we see the mutant allele burden decrease. Again, the prime example is patients with ET [essential thrombocythemia] and PV who get treatment with interferons. Over time, we often see the mutant allele burden decreasing and even patients going into molecular remissions.
In myelofibrosis, allele burden is a little trickier to think about. Sometimes, in these myelodepleted myelofibroses, we often see lower allele burdens of the JAK/STAT-driving mutation, and we see a lot of additional mutations that may be present that are outside of that JAK/STAT-activating mutation. In the proliferative version of myelofibrosis, we sometimes see that’s the dominant mutation with the highest allele burden. I don’t think prognosis is tightly connected to variant allele frequency or allele burden, as best as our knowledge is yet. It’s something we’re still exploring. When we get together at fancy academic meetings, say, the American Society of Hematology Annual Meeting, or the EHA [European Hematology Association] Meeting, we’ll talk about, “Well, is allele burden going up and down?” Not because we think it’s the end-all be-all of measuring disease or treatment efficacy, but it’s something we can measure easily and something we know about, so we’re trying to make that link there. Does a treatment truly affect the disease? Is it disease-modifying? Can we measure that by seeing what the changes are in the allele burden? A lot of us suspect there’s more to the story than just allele burden of the JAK/STAT mutation, or that driver mutation, if you will. It also probably has more to do with the other mutations and other things going on in the bone marrow when we’re looking at responses.
Srdan Verstovsek, MD, PhD:Cytopenias are often present in patients with myelofibrosis. Primary myelofibrosis patients are about two-thirds of the patients. One-third are secondary myelofibrosis from ET or PV patients that transform or progress from essential thrombocythemia. Polycythemia tumor fibrosis is a secondary one. In foraminal fibrosis, cytopenias are particularly present. These are patients that come out of the blue, for example, with the fibrosis in the bone marrow with all these signs and symptoms of bone marrow failure, spleen enlargement, symptomatic splenomegaly, and bad quality of life. In this case, there is a high percentage of the patients present with anemia already. One-third is anemic at diagnosis. Two-thirds are already significantly anemic after living with the disease for 1 year.
Concerning thrombocytopenia, about the same percentages are present in these foraminal fibrosis patients from the beginning. If we cut the number at, let’s say 100,000 or less—which is a significant grade 2, 3, and 4 thrombocytopenia—higher percentage of the patients develop these problems throughout their life with myelofibrosis, starting from about 20% at the beginning to 40% after a couple of years living with the disease. Up to 60% of the patients having low platelets, below 100,000, in a second-line setting. Perhaps cytopenias are present in minority at the beginning, but after 2 or 3 years of living with myelofibrosis, it can become a predominant problem. The problem here is not just that they’re there, but that we cannot counteract them, and they affect what we do with the JAK inhibitors, for example.
How do different cytopenias limit treatment options? They limit treatment options a lot. First, the ruxolitinib, which is used for control of spleen and symptoms, must be given in a limited way with a lower dose, if the platelets are low. Presence of anemia would also affect the delivery of ruxolitinib and will affect the delivery of fedratinib and other approved JAK inhibitors. Because they use the inhibition of JAK/STAT pathway as their primary mode of action, that will decrease the proliferation of malignant cells, but they also lower the production of normal cells. Thrombocytopenia and anemia affect the delivery and management of the patients with currently approved JAK inhibitors, ruxolitinib and fedratinib. Therefore, the presence of cytopenias provide a reason for us to say that suboptimal responses are evident in patients with cytopenias, because of us not being able to deliver the JAK inhibitors in an optimal way. The cytopenias prevent us from giving a patient’s optimal dose of currently approved JAK inhibitors.
Transcript Edited for Clarity