Inclusion Criteria:

• - Patients with a diagnosis essential thrombocythemia (Cohort 1) or polycythemia vera (Cohort 2) by World Health Organization 2016 diagnostic criteria.

• - Patients with essential thrombocythemia must be very low (no history of thrombosis, age ≤ 60, and no JAK2 mutation), low (no history of thrombosis, age ≤ 60, presence of JAK2 mutation), or intermediate risk (no history of thrombosis, age >60, no JAK2 mutation) by IPSET criteria.

1 Patients with polycythemia vera must be low risk (no history of thrombosis and age <60) by NCCN guidelines.

• - Patients with an MPN-SAF TSS score ≥ 10 AND at least one individual feature ≥ 5 documented on a separate visit within 3 months prior to study registration, as documented in the clinical record or obtained by clinician.

If not previously documented in the electronic medical record, participants must be blinded to purpose of MPN SAF TSS scoring for eligibility determination. Average daily MPN-SAF TSS score must remain ≥10 with any individual feature ≥ 5 for the week-long baseline assessment prior to ruxolitinib initiation .

• - Patients who have previously received or are receiving cytoreductive therapy (i.e. hydroxyurea, anagrelide, interferon) are eligible for the study if therapy was used for the indication of symptom control, in which case there will be a wash-out period of one week from prior therapy discontinuation to ruxolitinib initiation.

Patients who temporarily required cytoreductive therapy for pre-operative control of blood counts prior to surgery are also eligible.

• - Age ≥18 years.

• - ECOG performance status ≤2 (Karnofsky ≥60% - Participants must have adequate organ and marrow function as defined below: - leukocytes ≥3,000/mcL.

• - absolute neutrophil count ≥1,500/mcL.

• - platelets ≥100,000/mcL.

• - total bilirubin ≤ institutional upper limit of normal (ULN) - AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN.

• - creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.

• - Participants with a prior or concurrent malignancy not receiving treatment for concurrent cancer diagnosis and/or prior concurrent malignancy within 5 years except for basal cell carcinoma or squamous cell carcinoma of the skin.

• - For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

• - For participants with evidence of chronic human immunodeficiency virus (HIV) infection, they must be negative for HBV DNA, HCV RNA, or hepatitis B surface antigen (BsAg) on suppressive therapy, if indicated.

• - Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.

To be eligible for this trial, participants should be class 2B or better.

• - Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• - Essential thrombocythemia patients who are high risk by IPSET-R criteria (age > 60 with JAK2 V617F mutation and/or history of thrombosis).

1 Polycythemia vera patients who are high risk by NCCN guidelines (age > 60 and/or history of thrombosis).

• - Patients with >5% blasts on baseline marrow exam or at any other time in peripheral blood.

• - Participants who are receiving any other investigational agents.

• - History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib or excipients of ruxolitinib.

• - Participants requiring any medications or substances that are inhibitors or inducers of 3A4 isozyme are ineligible.

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.

• - Participants with uncontrolled intercurrent illness.

• - Participants with inadequate liver or renal function at screening as evidenced by lab values not meeting criteria.

• - Participants with psychiatric illness/social situations that would limit compliance with study requirements.

• - Pregnant women are excluded from this study because ruxolitinib is a Class C agent with the potential for teratogenic or abortifacient effects.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib.

• - The effects of ruxolitinib on the developing human fetus are unknown.

Pregnant women and subjects of childbearing potential who are unwilling to take appropriate precautions to avoid becoming pregnant or fathering a child are ineligible. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ruxolitinib administration.

This is a multi-center, non-randomized, two-stage phase II clinical trial evaluating ruxolitinib in low-risk but symptomatic essential thrombocythemia (ET) and polycythemia vera (PV) patients. This research is being done to see if Ruxolitinib is effective in reducing the symptoms people with essential thrombocythemia (ET) and polycythemia vera (PV) are experiencing. Ruxolitinib is a type of drug that blocks the specific proteins that may be causing the symptoms people with essential thrombocythemia (ET) and polycythemia vera (PV are experiencing. The research study procedures include screening for eligibility and study treatment, including evaluations and follow up visits.

• - Participants will receive Ruxolitinib for approximately 6 months and if benefitting from it may continue to receive Ruxolitinib for as long as there is no unacceptable side effects or disease progression.

It is expected that about 60 people will take part in this research study. The U.S. Food and Drug Administration (FDA) has approved Ruxolitinib for polycythemia vera (PV) but not for people with essential thrombocythemia (ET) and polycythemia vera (PV). Incyte, a biopharmaceutical company, is supporting this research study by providing funding for the study, including the study drug.

Arms

Experimental: Ruxolitinib Stage 1

In stage 1, participants will be divided into two cohorts: Very low, Low, and Intermediate-risk ETpatients with significant symptom burden and Low-risk PV patients with significant symptom burden Study cycles are 28 days long, participants in both cohorts will receive: Ruxolitinib 2x daily for 6 study cycles.

Experimental: Ruxolitinib Stage 2

Stage 2 will commence based on 3 or more participants in Stage 1 showing a predetermined positive response to Ruxolitinib. In stage 2, participants will be divided into two cohorts: Very low, Low, and Intermediate-risk ET patients with significant symptom burden and Low-risk PV patients with significant symptom burden Study cycles are 28 days long, participants in both cohorts will receive: Ruxolitinib 2x daily for 6 study cycles.

Interventions

Drug: - Ruxolitinib

Pill taken by mouth.