This phase 2 study aims to confirm the efficacy observed in the prior phase 1 trial in Cohort 1 and to evaluate the safety of IFN-γ in combination with DLI in Cohort 2, the haploidentical donor alloSCT recipient cohort. The study will further contribute to this effort through the collection of leukemia cells pre- and post-in vivo IFN-γ therapy. As in the previously conducted phase 1 trial, this trial will assess whether leukemia blasts are responsive to IFN-γ in vitro and in vivo. Single-cell RNA sequencing (scRNAseq) will be performed to evaluate transcriptomic changes induced by IFN-γ in leukemia cell subsets, including those with stem cell characteristics.
Age ≥ 18 years
Recipients of an alloSCT for AML or MDS from a minimally 8/8 HLA-matched donor (Cohort 1: HLA -matched alloSCT recipients) or recipients of a haploidentical donor SCT for AML or MDS from a minimally 4/8 HLA-matched donor (Cohort 2: Haplo-SCT recipients)
At least 5% or more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall 36
At least 0.1% of abnormal myeloblasts with a leukemia-associated immunophenotype (LAIP) by multiparameter flow cytometry. The abnormal cells with LAIP should not exceed 30% of nucleated cells.
Primary engraftment failure after alloSCT
Evidence of mixed phenotype leukemia with lymphoid differentiation (Cohort 1: HLA -matched alloSCT recipients)
Grade 3 or 4 aGVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) at the time of planned enrollment
History of grade 4 aGVHD per the MAGIC criteria
Single group
Interferon gamma-1b
DrugACTIMMUNE/Interferon gamma-1b is a single-chain polypeptide containing 140 amino acids that is produced by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the recombinant protein. Interferon gamma-1b is part of a drug regimen used to treat Chronic Granulomatous Disease, or CGD. CGD is a genetic disorder, usually diagnosed in childhood, that affects some cells of the immune system and the body's ability to fight infections effectively.
Donor Leukocyte Infusion (DLI)
Biological/VaccineDonor lymphocyte infusion is a procedure that transfers healthy white blood cells (lymphocytes) from a bone marrow or stem cell donor to a recipient's blood. An infusion of healthy lymphocytes helps the recipient's immune system get rid of remaining cancer cells if they have a relapse after a bone marrow or stem cell transplant for blood cancer.
Event-free survival (EFS)
Cohort 1: Occurrence of treatment failure, hematologic relapse from a CR (complete remission)/CRh/Cri), or death observed from start of IFN-γ treatment. Patients alive at 1 year after start of treatment will be censored on the date of last contact.
Incidence of steroid- and ruxolitinib- refractory GVHD within 12 weeks after the first dose of IFN-γ
Cohort 2: Lack of improvement after 7 days of methylprednisolone 2 mg/kg, AND, either of the following 1. Progression of graft-vs-host disease (GVHD) compared with baseline after 10 days of ruxolitinib, based either on an objective increase in stage/grade or new organ involvement Or 2. Lack of improvement in GVHD (PR or better) compared with baseline after at least 14 days of ruxolitinib.
Event-free survival (EFS) - Landmark 1-year
Time from start of IFN-γ treatment until event of death, date of treatment failure, or hematologic relapse from a CR/CRh/Cri. CR is defined by blasts less than 5% by morphology defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. CRi is defined by all CR criteria except for residual neutropenia less than 1,000/mL or thrombocytopenia less than 100,000/mL Treatment failure is not achieving either CR, CRh or CRi by 6 months. Patients evaluable for response without CR, CRh or CRi by 6 months and patients who die before 6 months without response assessments are considered an event at day 1 of IFN-γ treatment
Minimal residual disease (MRD)
Rate of complete remission (CR) with no measurable disease at 6 months. CR is defined as
Complete Remission (CR)
Proportion of patients who experience Complete Remission (CR). CR is defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients.
Complete remission with partial hematologic recovery (CRh)
Proportion of patients who experience Complete remission with partial hematologic recovery (CRh). CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients.
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Sawa Ito, MD
Lead sponsor
University of Pittsburgh
Sponsor institution
Evans MDS Discovery Research Grant
Collaborator
Amgen
Collaborator
FDA Office of Orphan Products Development
Collaborator
