Future Directions for Polycythemia Vera Treatment


Harry Erba, MD, PhD:It’s not clear that ruxolitinib changes the overall natural history of the disease. And, we really don’t have enough data looking at the risk of progression to myelofibrosis and acute leukemia and the effects on survival with ruxolitinib. We do not have much data on the biologic effect. In other words, we know in the COMFORT-1 Study, for example, in myelofibrosis, when you look at the allelic burden of the JAK2 mutation over time, it doesn’t change very much. It’s not like treatment with a BCR-ABL tyrosine kinase inhibitor in CML where you can expect a thousand-fold reduction in a year. You see much less reduction in the burden of disease. Now, some early follow-up from the RESPONSE Trial does suggest that the JAK2 allelic burden does go down with time, but we need longer-term follow-up to see how the JAK2 inhibitors are going to actually affect the natural history of the disease. So, ultimately though, I don’t think JAK2 inhibition is going to be sufficient for completely controlling the disease or curing the disease. There are other factors in polycythemia vera that appear to drive the disease.

There are a number of other JAK inhibitors in production, but interferon continues to be a drug that people are evaluating, especially the pegylated forms that have less toxicity, clearly appears to have activity in polycythemia vera. One of the more exciting new drugs in PV is imetelstat. Imetelstat is an antisense oligonucleotide given as a 2-hour intravenous infusion. It binds to a component of the telomerase enzyme that is important in adding telomeres to the ends of chromosomes to prevent chromosomes from shrinking over time, and senescence of cells. In a small study that’s been now published in the New England Journal of Medicine, it’s clear that from that study, imetelstat did lead to hematologic responses in patients with myelofibrosis, and is being tested in other myeloproliferative neoplasms as well.

I think, as we become more comfortable with using ruxolitinib, clinicians will start recognizing that our management of PV has been suboptimal. It’s been what it’s been for the last several decades with hydroxyurea and aspirin. But, it doesn’t mean that we have effectively improved the quality of life of all of these patients with just those two drugs. And, I think over time, there’s going to be a shift more toward a targeted approach with a drug like ruxolitinib, or other JAK inhibitors, to really control the disease so that symptom burden is decreased, and we can get away from some of these more archaic medical treatments, such as phlebotomy, unless we all want to become barbers again and start phlebotomizing our patients more and more.

A Patient with Disease Progression on Hydroxyurea

Case 1:

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