Allogeneic Stem Cell Transplantation, Myelodysplastic Syndromes, Myeloid Leukemia
Conditions
Keywords
allogeneic hematopoietic stem cell transplantation, acute myeloid leukemia, myelodysplastic syndrome, graft versus host disease, AML, MDS, alloSCT, GVHD, interferon-gamma-1b, Actimmune, IFN-g, donor lymphocyte infusion
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.
Interventions
DRUGIFN-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)
Sponsors
Horizon Pharma USA, Inc.
Sawa Ito, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Incidence of de novo GVHD | Up to 6 months | Incidence of graft-versus-host disease (GVHD) progression after IFN-γ therapy and subsequent DLI. |
| Malignant Blast Burden | Up to 6 months | Change in malignant blasts number after IFN-γ therapy and subsequent donor lymphocyte infusion. |
Countries
United States
Outcome results
None listed