• Willing and able to provide informed consent

• Age ≥18 years

• Diagnosis of Overt Myelofibrosis (primary, post-ET, or post-PV) per World Health Organization (WHO) 2022 diagnostic criteria

• Intermediate-1, Intermediate-2, or high-risk disease by Dynamic International Prognostic Scoring System (DIPSS)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Platelet count ≥75 x 109/L prior to dosing on Cycle 1 Day 1

• Absolute neutrophil count ≥0.5 x 109/L prior to dosing on Cycle 1 Day 1

• Peripheral blast count ≤10% prior to dosing on Cycle 1 Day 1

• Women of childbearing potential and fertile men must agree to use an approved method of contraception from screening until 30 days after the last dose of ropeginterferon and ruxolitinib.

• Patients with suboptimal response to ruxolitinib as per one of the below:

• i. Relapsed: Ruxolitinib treatment for ≥3 months with spleen regrowth, defined as \<10% SVR or \<30% decrease in spleen size from baseline, following an initial response\* ii. Refractory: Ruxolitinib treatment for ≥3 months with \<10% SVR or \<30% decrease in spleen size from baseline.

• \* Response to ruxolitinib is defined as a ≥35% reduction in spleen volume from baseline, or a ≥50% reduction in spleen size for baseline spleen sizes \>10 cm below left costal margin (LCM); a non-palpable spleen for baseline spleen sizes between 5-10 cm below LCM; or not eligible for spleen response for baseline spleen \<5 cm below LCM.