IFN-γ to Treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) That Has Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation

Early Phase 1

Completed

• Conditions: Myeloid Leukemia; Allogeneic Stem Cell Transplantation; Myelodysplastic Syndromes
• Interventions: Drug: IFN-γ (interferon gamma-1b) injection

• Registration Number: NCT04628338
• Lead Sponsor: Sawa Ito, MD

Brief Summary

This study proposes a safe dosing regimen IFN-γ that is sufficient to stimulate IFN-γ receptors on malignant blasts in patients who developed relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after alloSCT with no active or history of III-IV acute graft-versus-host disease (GVHD). It is hypothesized that IFN-γ will promote graft-vs-leukemia (GVL) in patients with AML/MDS that has relapsed after alloSCT.

Detailed Description

Allogeneic hematopoietic stem cell transplantation (alloSCT) can cure patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, relapsed AML/MDS is the most significant single cause of treatment failure, and the majority of relapsed patients ultimately succumb. Alloreactive T cells in the donor graft can kill residual leukemia cells, mediating the graft-vs-leukemia (GVL) effect. Consistent with this, recipients of T cell-depleted grafts have higher rates of relapse. GVL is more potent against chronic leukemias than acute myeloblastic diseases, and the higher incidence of relapse in patients with AML/MDS reflects a failure in GVL.

The central goal of this pilot trial will be to explore whether IFN-γ in this setting is safe and whether it has the desired biological activities on malignant blasts in vivo. IFN-γ will be tested in relapsed patients as monotherapy and in conjunction with donor leukocyte infusions (DLI). The clinical and biological information from this study is essential to design a phase II trial with a therapeutic endpoint.

Treatment will be initiated at 100mcg (almost equal to the dose of 50 mcg/m2 for an adult) three times a week, with the potential to deescalate the frequency of injection for unacceptable toxicity. To explore whether this dosing regimen is sufficient to activate myeloblasts, pre- and post-treatment bone marrow specimens will be harvested to analyze for IFN-γ action (upregulation of HLA class I; HLA class II, ICAM-1 and phosphorylation of STAT1). The primary safety concern is the development of GVHD, which is routinely monitored for all alloSCT patients.

Study Timeline

• Study First Submitted: 2020-10-29
• Study First Submitted QC: 2020-11-11
• Study First Posted: 2020-11-13
• Study Start: 2021-03-08
• Primary Completion: 2023-10-30
• Study Completion: 2023-10-30
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-24
• Last Update Posted: 2025-04-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

• Recipients of allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome from a human leukocyte antigen (HLA) matched donor
• Relapsed of primary disease with 5% to 20% of blasts in the bone marrow by flow cytometry in the bone marrow with an clear leukemia-associated immunophenotype (If the patient received therapy to treat the relapse, he or she must have 5-20% residual blasts prior to enrollment on this study)
• Performance status KPS score >60% (ECOG 0-2)
• No increases in systemic immunosuppression in the prior four weeks other than to maintain therapeutic levels
• No systemic corticosteroid with a dose higher than 0.5mg/kg/day prednisone or equivalent
• No history of grade IV acute GVHD
• No new systemic immunosuppressive medications in the prior two weeks initiated due to GVHD
• Willingness to have bone marrow and peripheral blood collected as per the study protocol
• Must be able to give informed consent
• Age 18 or older

Exclusion Criteria

• Contraindication to receive IFN-γ including known hypersensitivity to interferon-gamma, E. coli derived products or any component of the product
• Subjects with a positive pregnancy test or who are breastfeeding
• For men or women of childing bearing potential (age < 50 without hysterectomy or oophorectomy or documented menopause), unwilling to use effective contraception for the duration of the study.
• Primary engraftment failure
• Active cardiac arrhythmias not controlled by medical management or current NYHA class II or higher congestive heart failure
• Active ischemic heart disease not well controlled with medications
• A seizure disorder not well controlled by medications
• Estimated GFR <30 mL/min
• AST/SGOT or ALT/SPOT > 5 x ULN
• Total bilirubin > 3 x ULN
• Chemotherapy (other than hypomethylating and/or venetoclax therapy) within the prior 4 weeks
• Body surface area at or less than 1.5 m2, or greater than 2.5 m2 so as to minimize the variation in IFN-γ exposure based on differences in BSA.
• Patients less than 18 years old.
• Pregnant or breastfeeding patients.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IFN-γ	IFN-γ (interferon gamma-1b) injection	100mcg IFN-γ subcutaneously three times per week (Weeks 0-7), once per week (Weeks 8-12) (or per protocol guidance based on tolerability, response, or DLI infusions)

Primary Outcome Measures

Name	Time	Method
Upregulation HLA l (HLA-ABC)	Up to 6 months	Upregulation of HLA l (HLA-ABC) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of HLA ll (HLA-DR/DQ)	Up to 6 months	Upregulation of HLA ll (HLA-DR/DQ) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of ICAM-1	Up to 6 months	Upregulation of ICAM-1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.
Adverse events related to IFN-γ	Up to 6 months	Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.
Generation of phosphorylated-STAT1	Up to 6 months	Generation of phosphorylated-STAT1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.

Secondary Outcome Measures

Name	Time	Method
Malignant Blast Burden	Up to 6 months	Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion.
Incidence of de novo GVHD	Up to 6 months	Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI.
Incidence of GVHD	Up to 6 months	Incidence of Graft Versus Host Disease (GVHD) progression or de novo GVHD after INF-g therapy and subsequent donor lymphocyte infusion.

Trial Locations

Locations (1)

UPMC Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States