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

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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Myeloid Leukemia; Allogeneic Stem Cell Transplantation
• Intervention / Treatment: Drug: IFN-γ (interferon gamma-1b) injection

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 Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IFN-γ; 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)	Drug: IFN-γ (interferon gamma-1b) injection; Dosage form: 100 mcg (2 million International Units) per 0.5 mL solution, administered subcutaneously Dose regimen: three times weekly (Weeks 0-7), once weekly (Weeks 8-12); Other Names: ACTIMMUNE®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upregulation HLA l (HLA-ABC)	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.	Up to 6 months
Upregulation of HLA ll (HLA-DR/DQ)	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.	Up to 6 months
Upregulation of ICAM-1	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.	Up to 6 months
Adverse events related to IFN-γ	Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.	Up to 6 months
Generation of phosphorylated-STAT1	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.	Up to 6 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Sawa Ito, MD
• Collaborators: Horizon Pharma USA, Inc.
• Investigators: Principal Investigator: Sawa Ito, MD; PhD, University of Pittsburgh

Publications and helpful links

General Publications

• Ito S, Geramita E, Ventura K, Neupane B, Bhise S, Moore EM, Furlan S, Shlomchik WD. IFN-gammaand donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation . JCI Insight. 2025 Mar 25:e190655. doi: 10.1172/jci.insight.190655. Online ahead of print.

Helpful Links

• IFN-γand donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation - PubMed

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2021
• Primary Completion (Actual): October 30, 2023
• Study Completion (Actual): October 30, 2023

Study Registration Dates

• First Submitted: October 29, 2020
• First Submitted That Met QC Criteria: November 11, 2020
• First Posted (Actual): November 13, 2020

Study Record Updates

• Last Update Posted (Actual): April 29, 2025
• Last Update Submitted That Met QC Criteria: April 24, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: AML; MDS; acute myeloid leukemia; GVHD; myelodysplastic syndrome; allogeneic hematopoietic stem cell transplantation; graft versus host disease; donor lymphocyte infusion; Actimmune; IFN-g; alloSCT; interferon-gamma-1b
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Histologic Type; Disease; Hematologic Diseases; Precancerous Conditions; Bone Marrow Diseases; Syndrome; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Anti-Infective Agents; Antineoplastic Agents; Antiviral Agents; Interferons; Interferon-gamma
• Other Study ID Numbers: HCC 20-092

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No