The use of Pegasys in combination with other targeted agents for the treatment of PV/ET would allow for the administration of lower doses of Pegasys, thereby reducing dose dependent toxicities. Preclinical studies by Lu et al. have demonstrated preferential inhibition of PV CD34+ cell proliferation and colony formation at subtherapeutic doses of Pegasys in combination with Nutlin-3 [33]. Pegasys increases p53 expression through enhanced transcriptional activity via the p38 Map kinase pathway and Nutlin-3 prevents p53 degradation via interruption of the MDM2-p53 interaction [34]. Due to the common downstream target effect of increased tumor suppressor p53 expression with combination Pegasys and Nutlin-3, lower doses of each agent can be used together in PV patients. Thus, the use of RG7388 alone or in combination with Pegasys would be anticipated to enhance p53 expression by different mechanisms and presents a novel approach to the treatment of PV/ET.