Background: Treatment of polycythemia vera (PV) patients with hydroxyurea (HU) normalizes elevated blood cell counts within weeks in the large majority of patients. Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte and platelets over time are scarce, and results have been reported highly heterogeneous. Purpose: Using data driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. Material and Methods: Using serial measurements of JAK2V617F and correlation analyzes of routine hematological values (Hb-concentration, leukocyte count, platelet count, lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte and platelet counts and lactic dehydrogenase in 29 PV patients who were followed in the Danish randomized trial (DALIAH) comparing the efficacy of pegylated interferon-alpha2 (IFN) versus HU in patients older than 60 years. Results: Response patterns were highly heterogeneous. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden in any patient as previously reported in patients being treated with IFN. Importantly, HU treatment was neither able to induce a sustained normalization of elevated leukocyte and platelet counts, although counts were temporarily normalized in most patients during the first months of therapy. The fluctuating leukocyte and platelet counts contrast the sustained normalization of cell counts in the large majority of patients during long term treatment with IFN. Discussion and Conclusions: Using data-driven analysis of the JAK2V617F allele burden, leukocyte and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in PV patients. Our results may explain why PV patients during treatment with HU still have a substantially increased risk of thrombosis. Based upon our previous and present findings, obtained by mathematical modelling and data driven analysis studies, a rational and cost-effective treatment might be a combination therapy of HU and IFN, both being used for decades in the treatment of PV but according to the findings in our studies now being proposed to be combined in the initial treatment period, since their combined effects might be highly efficacious and are foreseen to have the potential to minimize the risk of thrombosis and bleeding. By these studies, we have also proven mathematical modelling and data driven analysis to be highly important tools to decipher novel treatment modalities for patients suffering from MPN cancers but likely other cancers as well. Disclosures Hasselbalch: Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. OffLabel Disclosure: Interferon-alpha2 for the treatment of myeloproliferative neoplasms.