Abstract Background Treatment with pegylated interferon-alpha2 (IFN) is associated with complete hematologic remissions (CHR) in a large majority of patients with essential thrombocythemia (ET) and PV. In a subset of patients, IFN can induce major molecular remissions that can be sustained for up to 4 years after discontinuation of therapy. In hypercellular myelofibrosis (MF), IFN may also induce regression of bone marrow fibrosis. To this end, long-term IFN treatment with normalization of elevated blood counts is accompanied by a reduced risk of thrombosis and hemorrhage. When initiated at the early disease stage, IFN may have the greatest chance to induce “minimal residual disease” with a low JAK2 V617F allele burden. For these reasons, IFN is foreseen to be a cornerstone in the treatment of these neoplasms. Ruxolitinib (RUX) is a JAK1-2 inhibitor that is highly efficacious in alleviating hypermetabolic symptoms and enlarged spleens in patients with MF. Although the earliest reports suggested that RUX did not significantly lower JAK2 V617F mutational load, newer findings clearly show that in a subset of patients RUX may indeed profoundly decrease JAK2 V617F allele burden; these reductions could be even larger if treatment is instituted in early stages of MF or PV. Preliminary data show RUX to be highly efficacious in PV as well. With both drugs having potent antiproliferative and anti-inflammatory effects, combination therapy with IFN and RUX may potentially promote tumor regression in MPNs, as assessed by rapid induction of CHR, reduction in spleen size, and enhanced reduction of JAK2 V617F allele burden. Case report A 55-year-old woman with PV diagnosed in the precursor stage of ET 12 years ago was referred for a second opinion due to intolerance of hydroxyurea (HU; monosymptomatic fever) and pegylated interferon-alpha2b (PEG-Intron; exanthema). The patient had suffered 2 episodes of transitory ischemic attack (TIA) since 2009, and therefore, permanent treatment with clopidogrel had been instituted. Several CT scans were normal. At the time of referral, the patient was receiving anagrelide and clopidogrel. The patient's hemoglobin was 11.9 g/dL, her leukocyte count was 21.9 x 109/L, and platelets were elevated at 526 x 109/L. CRP levels were normal. An abdominal ultrasound revealed a spleen length of 20 cm, causing intermittent pain and abdominal discomfort. Because of hypermetabolic symptoms, pronounced abdominal discomfort, and intolerance of PEG-Intron and HU, treatment with RUX was initiated at a dose of 20 mg twice daily. Within the first 3 days of RUX therapy, the patient experienced remarkable clinical improvement with resolution of severe fatigue, night sweats, abdominal pain, and pruritus, which had negatively impacted the patient's quality of life during the past 2 to 3 years. Four days after starting RUX, the patient experienced acute TIA-like symptoms with transient decrease of strength in the left arm and abnormal sensations in the left half of the tongue and neck. The symptoms were similar to those that the patient experienced during previous TIAs. The blood values disclosed a slight decrease in the leukocyte count (17.6 x 109/L) and an increase in the platelet count (573 x 109/L). A CT scan was normal. Consequently, RUX therapy was combined with PEG-IFN-alpha2a (Pegasys) at a very low dose of 45 µg every second week. After 1 month, a CHR was achieved (Figure 1), and after 2.5 months, an abdominal ultrasound showed a spleen length reduction from 20 to 13.8 cm. After 6 months, the spleen was no longer palpable. The patient had no need of phlebotomies during treatment with RUX and Pegasys. The combination therapy was exceedingly well tolerated without any side effects to either drug. Remarkably, despite an advanced PV stage, JAK2 V617F allele burden was rapidly lowered from 90% mutated alleles at referral to 59% at 6 months and 20% within 1 year (Figure 2). Conclusion This case report demonstrates for the first time that combination therapy with RUX and “low–low-dose” Pegasys is highly efficacious in rapidly reducing JAK2 V617F allele burden in concert with achieving CHR and resolution of splenomegaly. This observation warrants prospective trials of this combinatorial approach in patients with PV and hyperproliferative MF to assess whether combination therapy induces a more rapid decline in the JAK2 V617F allele burden than monotherapy with either drug. Disclosures: Hasselbalch: Novartis: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Interferon-alpha2a is used routinely in Denmark for treatment of essential thrombocythemia polycythemia vera and in some myelofrbrosis patients , as well. Ruxolitinib is being used routinely in myelofibrosis patients on strict indications including hypermetabolic symptoms and abdominaldiscomfort due to large splenomegaly ln rare cases Ruxolitinib is being used in the transitional stage of PV towards myelofibrosis when other options are not available due to intolerance to eg. interferonlor hydroryurea.