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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes, Myeloid Leukemia, Allogeneic Stem Cell Transplantation

Intervention / Treatment
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* Drug: IFN-γ (interferon gamma-1b) injection


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFN-γ<br>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<br>* 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)<br>* Other names: ACTIMMUNE®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, AML, allogeneic hematopoietic stem cell transplantation, acute myeloid leukemia, myelodysplastic syndrome, graft versus host disease, alloSCT, GVHD, interferon-gamma-1b, Actimmune, IFN-g, donor lymphocyte infusion