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

Ropeginterferon Alfa-2b for MDS/MPN Overlap Syndromes, Including CMML and MDS/MPN-RS-T

This phase II trial tests the safety, best dose, and effectiveness of ropeginterferon alfa-2b for the treatment of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes and chronic myelomonocytic leukemia. Ropeginterferon alfa-2b is a form of interferon. Interferons are a type of signaling protein normally produced by the body as part of the immune response. Interferons interfere with the division of cancer cells and can slow cancer cell growth. Ropeginterferon alfa-2b is a long-acting form of a type of interferon called interferon alfa-2b. In the body, ropeginterferon alfa-2b causes the production of proteins that modulate the immune system and have anticancer effects.

PRIMARY OBJECTIVE:

I. To assess the safety and efficacy (overall response, OR) of ropeginterferon alfa-2b in adult patients with myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndrome.

SECONDARY OBJECTIVES:

I. To evaluate baseline cytogenetics, mutation profile, chronic myelomonocytic leukemia (CMML)-specific prognostic scoring system - molecular (CPSS-Mol) risk.

II. To assess the percentage of patient with hematological response based on 2015 international consortium proposal (ICP) MDS/MPN criteria.

III. Based on 2015 ICP MDS/MPN criteria, to assess time to complete response, time to disease progression (TTP), progression free survival (PFS), and event free survival (EFS).

IV. To assess the change from baseline in mutant allele frequencies (MAF), with special interests in ASXL1, SRSF2, NRAS, KRAS, SETBP1, RUNX1, CBL, EZH2, SF3B1 mutations; as also in non-driver mutations.

V. To assess the percentage of splenomegaly changes on clinical exam and on computed tomography (CT).

VI. To assess changes in MPN symptom burden using the MPN Symptom Assessment Form (MPN-Symptom Assessment Form [SAF] total symptom score [TSS]).

VII. To assess changes in packed red blood cell (PRBC) transfusion burden. VIII. To assess changes in the bone marrow morphology and fibrosis (as assessed by reticulin staining).

IX. To assess the change of cytokine profile.

OUTLINE: This is a dose-escalation study followed by a dose-expansion study.

Patients receive ropeginterferon alfa-2b subcutaneously (SC) on days 1 and 15 of each cycle. Cycles repeat every 28 days for up to 24 months (26 cycles) in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy, CT, and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 28 days and then every 3 months for up to 24 months.

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