Interferon-γ (IFN-γ) With Donor Leukocyte Infusion to Treat Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes Post Allogeneic Hematopoietic Stem Cell Transplantation

This novel regimen has the potential to fill a large unmet need for this high-risk population of patients who have few, if any, effective therapeutic options. If this trial confirms the clinical efficacy of IFN-γ/DLI, it will establish a new standard of care for post-transplant AML/MDS relapse. It would also provide a rationale to explore other indications for IFN-γ in the context of an alloSCT, including 1) IFN-γ/DLI for relapsed disease after haploidentical alloSCT; 2) pre-emptive post-alloSCT treatment of patients transplanted with measurable residual disease (MRD) or with poor-risk AML/MDS such as with TP53 mutations; and 3) prevention of relapse in patients who can only tolerate reduced-intensity conditioning regimens which in most studies results in higher rates of post-alloSCT AML/MDS relapse than when intensive conditioning regimens are employed. Together, this work would allow more patients with AML/MDS to be referred for and ultimately benefit from an alloSCT.

Inclusion criteria

• 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)
• AML/MDS relapsed post-alloSCT with measurable residual disease defined by either of the following criteria:

• 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.
• Recurrent or persistent cytogenetic abnormalities detectable by FISH or karyotype analysis.
• For patients with mutant NPM1, at least 1,000 mutant transcript copies per 106 ABL or equivalent housekeeping transcripts in bone marrow by qPCR or dPCR
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
• A DLI is available, or the donor is available and agrees to undergo apheresis to collect lymphocytes for infusion
• If salvage therapy for post-alloSCT relapse was received, the therapy is limited to 1 line of the following:

• For hypomethylating agents, venetoclax, and targeted therapies (e.g., tyrosine kinase inhibitors, IDH1/IDH2 inhibitors, or FLT3 inhibitors), the last dose must be > 2 week prior to the initiation of IFN-γ
• For cytotoxic chemotherapy agents, the last dose must be >2 weeks prior to start of treatment for the present study
• For investigational agents, the last dose must be ≥ 4 weeks or 5 half-lives (whichever is longer) prior to the start of treatment for the present study
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• For female subject, who is < 55 years old without hysterectomy, oophorectomy or documented menopause, willingness to use two forms of contraception including one form of highly effective contraception (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
• For male subject, willingness to use highly effective contraception methods including male condoms by male subject and one form of highly effective contraception by his female partner (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study

Exclusion criteria

• 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
• Moderate or severe cGVHD per NIH Consensus Criteria at time of planned enrollment
• Any systemic immunosuppressive medications taken within 2 weeks before the enrollment
• Grade 3 or higher non-hematologic toxicity related to any prior therapy at the time of enrollment
• A contraindication to receive IFN-γ including a known hypersensitivity to IFN-γ, E. coli derived products or any other component of the product
• Positive pregnancy test or currently breastfeeding on Day 1 of study treatment 37
• Active cardiac arrhythmia not controlled by medical management or current NYHA class II or higher congestive heart failure within 2 months of enrollment unless it was due to a tachyarrhythmia which is under control at the time of enrollment
• Active ischemic heart disease not controlled with medications within 2 months of enrollment
• Acute or chronic pulmonary disease requiring continuous oxygen treatment
• Seizure disorder not controlled by medications within 2 months of enrollment
• AST or ALT > 5x ULN or total bilirubin >3x ULN at time of enrollment
• Renal function CrCl <30 mL/min at time of enrollment using modified Cockcroft-Gault formula
• Detection of HLA loss of heterozygosity (LOH) in relapsed malignant cells. Specifically, there has been a loss of the mismatched set of HLA alleles encoded on chromosome 6 (ie uniparental disomy of chromosome 6), within 30 days prior to enrollment (Cohort 2: Haplo-SCT recipients)