The purpose of this clinical trial is to learn if the study drug ropeginterferon alfa- 2b added to, standard of care, ruxolitinib is safe and effective in treating patients with Myelofibrosis.

Inclusion Criteria:

• Male or female subject aged ≥ 18 years.

• Diagnosed with PMF, post-PV MF, or post-ET MF per WHO 2016 or 2022 criteria, bearing one of these MPN phenotype defining mutations (JAK2, CALR, and MPL), and with a DIPSS score of low, intermediate-1 or intermediate-2.

• Subjects must be already on standard of care ruxolitinib per the treating physician for at least 3 months or more, and on a stable dose for at least 6 weeks prior to screening.

• Subjects must have spleen volume of > 450ml by either MRI or CT scan

• Subject must have a JAK2, CALR, or MPL allelic burden of ≥20% at screening

  --Prior treatment for PV or ET with hydroxyurea or ruxolitinib is allowed. If the patient was on pegylated interferon in the past, the progression from PV/ ET to post-PV/ET MF must not have occurred while on pegylated interferon therapy.

• ECOG Performance Status ≤ 2.

• Adequate organ function as defined as:

  • Hematologic:

    • WBC count ≥ 4 x 109/L
    • Absolute neutrophil count (ANC) ≥1500/mm3
    • Platelet count ≥ 75,000/mm3
    • Hemoglobin ≥ 8 g/dL

  • Hepatic:

    ---Total Bilirubin ≤ 1.5x institutional upper limit of normal (ULN)

    ---AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN

  • Renal:

    • Estimated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula

• Recovery to baseline or ≤ Grade 1 CTCAE v 6.0 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy per the treating investigator.

• Participants must adhere to the following sex and contraceptive/barrier requirements:

  • If participant is of childbearing potential, they must have a negative pregnancy test

  • For participants of non-childbearing potential: The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  • < 50 years of age:

    ---Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and

    ---Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

    --≥ 50 years of age:

    ---Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or

    ---Had radiation-induced menopause with last menses >1 year ago; or

    ---Had chemotherapy-induced menopause with last menses >1 year ago

    ---Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution

  • Participants of childbearing potential and participants with a sexual partner of childbearing potential must agree to use a highly effective method of contraception and lactation requirements as described in Sections 6.4.1 and 6.4.3.

• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

• PV or ET patients who progressed while on pegylated interferon or ropeginterferon therapy.

• Receiving other investigational agents.

• Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation, or suicide attempt (Patients with pre-existing depression who are well-controlled and on stable doses of antidepressants are eligible).

• Evidence of severe retinopathy or clinically significant eye disease.

• History or presence of active serious or untreated autoimmune disease.

• History of solid organ transplant.

• Liver cirrhosis Child-Pugh score B or C. -≥ 5% blasts in peripheral blood or bone marrow.

• Prior systemic anti-cancer therapy or any investigational therapy ≤ 14 days or within five half-lives prior to starting study treatment, whichever is shorter.

• Major surgery 4 weeks prior to starting study drug or who have not fully recovered from major surgery.

• The diagnosis of another malignancy which, in the investigator's opinion, is likely to significantly impact study participation.

• Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  • Cardiovascular disorders:

    • Uncontrolled hypertension, in the opinion of the investigator
    • Congestive heart failure New York Heart Association Class II or greater, unstable angina pectoris, serious cardiac arrhythmias.
    • Stroke or myocardial infarction within the past 3 months
    • Significant coronary stenosis, in the opinion of the investigator
    • QTc prolongation defined as a QTcF > 500 ms.
    • Known congenital long QT.

  • Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, [subjects may not receive the drug through a feeding tube], social/ psychological issues, etc.)

• Known HIV infection with a detectable viral load within 6 months of the anticipated start of treatment.

Note: Subjects on effective antiretroviral therapy with an undetectable viral load within 6 months of the anticipated start of treatment are eligible for this trial.

-Active infection requiring systemic therapy, including, but not limited to: tuberculosis (clinical evaluation that includes clinical history, physical examination, radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.

Note: Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

• Medical, psychiatric, cognitive, or other conditions that may compromise the subject's ability to understand the subject information, give informed consent, comply with the study protocol or complete the study.
• Known prior severe hypersensitivity to investigational product (IP) or any component in its formulations (NCI CTCAE v 6.0 Grade ≥ 3).
• Subjects taking prohibited medications as described in Section 7.8. A washout period of prohibited medications for a period of at least five half-lives or as clinically indicated should occur before the start of treatment.