Ropeginterferon Alfa-2b for the Treatment of Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes and Chronic Myelomonocytic Leukemia

Inclusion Criteria:

* Male or female ≥ 18 years of age at time of consent
* Documentation of a diagnosis of MDS/MPN overlap syndrome based on World Health Organization (WHO) 2022 classification, including CMML, MDS/MPN with neutrophilia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), or MDS/MPN, not otherwise specified, by local pathology review, and deemed to potentially benefit from study participation by the investigator
* Written informed consent obtained from participant or participant's legal representative and ability for participant to comply with the requirements of the study
* Blast =\< 10% by marrow immunohistochemistry stain
* Platelet count of \> 50,000/uL
* Absolute neutrophils count (ANC) of \> 1000/uL
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) =\< 2
* Serum creatinine =\< 2.5 mg/dL
* Serum direct bilirubin \< 2.0 mg/dL
* Serum transaminase \< 2.5 times the upper limit of the normal range (ULN) or \< 5 times ULN if the transaminase elevation was deemed related to the MDS/MPN

Exclusion Criteria:

* Prior therapy with interferon or pegylated interferon product, or azacitidine
* Spleen overtly enlarged by physical exam (eg. greater than 5 fingerbreadth below costal margin)
* Other standard (including erythropoietin-stimulating agents \[ESA\] or luspatercept) or experimental therapy for MDS/MPN within 28 days of starting study therapy with the exception of hydroxyurea, which is allowed to continue up to 28 days after cycle 1 day 1 (C1D1) while on protocol
* Clinically significant autoimmune disease by investigator assessment, regardless if the autoimmune phenomena is related to MDS/MPN overlap syndrome
* History of or current clinically relevant depression or anxiety per investigator's judgement. Previous suicidal ideation or attempts are not allowed to participate in interferon (IFN) therapy
* Evidence of severe retinopathy or clinically relevant ophthalmological disorder
* History of organ transplant
* Pregnant or breastfeeding women
* Active uncontrolled infection with clinical symptoms, e.g., presence of bacteria, fungal, human immunodeficiency virus (HIV), hepatitis B or C
* Active uncontrolled thromboembolic complications or hemorrhage
* History of any malignancy within 5 years (except adequately treated non-melanoma skin cancer, prostate cancer status post resection with an undetectable prostate-specific antigen \[PSA\], curative treated in-situ cancer of the cervix, ductal carcinoma in situ \[DCIS\] of the breast, stage 1 grade 1 endometrial carcinoma, or other solid tumors including lymphomas curatively treated with no evidence of disease for ≥ 1 year prior to study)
* Uncontrolled active clinically significant illness that, in the investigator's opinion, may affect the patient's participation in this study
* Active abuse of alcohol and/or illicit drugs