Ropeginterferon for High Risk JAK2 Clonal Hematopoiesis

Inclusion Criteria:

* Adults age 18 years or older
* Evidence of JAK2 V617F clonal hematopoiesis of indeterminate potential, as defined by a JAK2 V617F mutation detected on quantitative PCR. By definition, these patients do NOT have a diagnosis of an MPN, and must have at least one additional high-risk feature.
* Have high-risk clinical/laboratory features, as defined as at least ONE of the following criteria:

  * Patients with a venous or arterial thrombotic event within 1 year prior to or any time after diagnosis of JAK2 clonal hematopoiesis
  * Patients with elevated laboratory parameters above normal limits at screening, but not meeting criteria for an MPN by WHO 2016 criteria. This would include patients with elevated laboratory parameters but an otherwise normal bone marrow biopsy.

    * White blood cell count \> 10 K/uL OR
    * Hemoglobin \> 16 g/dL in women and \> 16.5 g/dL in men; OR hematocrit \>48% for women and \>49% for men OR
    * Platelets \>400 K/uL
  * Patients with JAK2 VAF \>20%
* Willing to have a bone marrow biopsy at study entry to exclude an MPN diagnosis. Screening bone marrow biopsy must not be diagnostic of any overt hematologic malignancy by morphologic assessment and must be consistent with a diagnosis of clonal hematopoiesis as determined by multi-institutional hematopathology review. A historical bone marrow biopsy is allowed if within 3 months of C1D1 and records and pathology can be obtained. In cases where the bone marrow biopsy results are uncertain, study eligibility should be discussed with the PI. All patients will have an erythropoietin level drawn to rule out a PV diagnosis by WHO 2016 criteria.
* Must have adequate organ function as demonstrated by the following:

  * ALT (SGPT) and AST (SGOT) ≤ 2.5x upper limit of normal (ULN),
  * Direct bilirubin ≤ 1.5 x ULN
  * eGFR \>60 mL/min
  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * Platelets ≥100,000/mcL
* ECOG performance status (PS) ≤ 3
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months of C1D1 are eligible for this trial.
* For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* 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.
* The effects of ropeginterferon on the developing human fetus are unknown. For this reason, 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 and women of childbearing potential 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 ropeginterferon administration.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Meeting WHO 2016 criteria for a MPN.
* Pregnant or lactating.
* Any active malignancy in the past 2 years prior to C1D1, with the exception of non-melanoma skin cancer, or cervical carcinoma in situ or breast carcinoma in situ that has been excised or resected completely and is without evidence of local recurrence or metastasis. Any malignancy treated with curative intent and no evidence for active disease in the last 2 years are eligible.
* Evidence of severe retinopathy or clinically relevant ophthalmologic disorder.
* Participation in an investigational drug or device trial within 2 weeks prior to C1D1
* Documented autoimmune disease at screening or in the medical history which is active and serious
* History of significant and clinically relevant psychiatric illnesses, including prior suicide attempts or risk of suicide on screening
* History of thyroid dysfunction not adequately controlled
* History of major organ transplantation
* History of uncontrolled severe seizure disorder
* Participants who are receiving any other investigational agents.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ropeginterferon.