Clinical trial NCT04628338: IFN-γ to Treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) That Has Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Myelodysplastic Syndromes
Myeloid Leukemia
Allogeneic Stem Cell Transplantation
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
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Horizon Pharma USA, Inc.
First posted: 2020-11-13
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Upregulation HLA l (HLA-ABC)
timeFrame: Up to 6 months
measure: Upregulation of HLA ll (HLA-DR/DQ)
timeFrame: Up to 6 months
measure: Upregulation of ICAM-1
timeFrame: Up to 6 months
measure: Adverse events related to IFN-γ
timeFrame: Up to 6 months
measure: Generation of phosphorylated-STAT1
timeFrame: Up to 6 months
Secondary outcomes:
measure: Malignant Blast Burden
timeFrame: Up to 6 months
measure: Incidence of GVHD
timeFrame: Up to 6 months
measure: Incidence of de novo GVHD
timeFrame: Up to 6 months
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Sawa Ito, MD; PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ito S, Geramita E, Ventura K, Neupane B, Bhise S, Moore EM, Furlan S, Shlomchik WD. IFN-gamma and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation. JCI Insight. 2025 Mar 25;10(9):e190655. doi: 10.1172/jci.insight.190655. eCollection 2025 May 8.