Rationale for JAK Inhibition in PV

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Ruben Mesa, MD: JAK inhibition is a logical therapy for polycythemia vera. Prior to 2005, we did not know what the molecular underpinnings of the disease were. Since then, it has become clear that overactivation of the JAK/STAT pathway is at least in part a very important aspect of why we develop polycythemia vera. Over 90% of patients with PV have the JAK2 V617F. An additional percentage have the JAK2 exon 12 mutation. So, in particular, in polycythemia vera, the JAK2 is almost a universal mutation. Ruxolitinib is a JAK1 and JAK2 inhibitor. Now, it’s an inhibitor of the native JAK2, so it really is helpful across the spectrum of MPN mutations. But from the beginning, after the discovery of the JAK2 mutation and ruxolitinib’s role, we anticipated that it would be highly active as an inhibitor specifically for polycythemia vera in helping to decrease elevation in the counts.

Now, over time, we have found that it is very beneficial on multiple levels, and it is possible that aspects of these benefits include both the JAK1 and JAK2 inhibitory properties. The inhibition of JAK2 is particularly helpful in terms of controlling the elevation of the counts, reducing the spleen, and improving the symptoms to some degree. There may be an additional benefit to the inhibition of JAK1 that is associated with decreasing inflammation and likely a spectrum of inflammatory cytokines that may contribute to PV-related symptoms.

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