« Patients with PV often have high JAK2 V 617F VAF (>50%) because of the emergence of a dominant clone with concurrent loss of wild-type JAK2, which in turn is associated with increased risk of vascular events and transformation to myelofibrosis. In MPN, unlike other hematologic malignancies, for example, chronic myeloid leukemia and AML, where molecular response to therapy correlates with improved outcome and directs patient management, the clinical importance of molecular response has been unclear despite the efficacy of several therapies at reducing JAK2V617F VAF. This includes recent data with pegylated interferon alpha-2b where despite showing the superiority of molecular response with this agent, correlation with clinical benefit has not yet been feasible, perhaps because of lower event rates in the frontline population, and has been explored in studies, for example, those involving MDM inhibitors. Here, we observed that ruxolitinib was associated with more frequent molecular responses, defined as 50% reduction in VAF, (P < .001) at their final FU. Importantly, JAK2V617F molecular responders at 12 months were more likely to have CR at 12 months (P = .09), and those responding at their last time point demonstrated improved PFS (). Similar to other myeloid malignancies, additional somatic mutations were associated with higher rates of events independent of age and sex, with mutated ASXL1 conferring a specific risk of major events (). Upon evaluating molecular responses at a stem/progenitor cell level, a substantial reduction in the clonal burden of JAK2V617F HSPCs in ruxolitinib-treated patients achieving a molecular response was demonstrated, consistent with ruxolitinib-induced clearance of JAK2V617F stem cells. »
CONCLUSION
The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to event-free survival (EFS), progression free survival (PFS), and OS.
