interferon-γ (ifn-γ) with donor leukocyte infusion to treat relapsed acute myeloid leukemia and myelodysplastic syndromes post allogeneic hematopoietic stem cell transplantation

Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes

Summary: this phase 2 study aims to confirm the efficacy seen in the prior phase 1 trial, and 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 test whether leukemia blasts were responsive to ifn-γ in vitro and in vivo, with single-cell rna sequencing (scrnaseq) conducted to understand the transcriptomic changes induced by ifn-γ in leukemia cell subsets, including those with stem cell characteristics.

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.

Eligibility criteria:
inclusion criteria: * recipients of an allosct for aml or mds from an hla-matched donor * aml/mds relapsed post-allosct with measurable residual disease defined by at least 5% of more myeloblasts based on bone marrow biopsy morphology by pathologist review. abnormal myeloblasts cannot not exceed 30% overall * 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 cycle of the following: 1. 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 2. for cytotoxic chemotherapy agents, the last dose must be \>2 weeks prior to start of treatment for the present study 3. 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 * 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 * 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 egfr \<30 ml/min at time of enrollment using modified cockcroft-gault formula * body surface area ≤ 1.5 m2 or ≥ 2.5 m2 so as to minimize variation in ifn-γ exposure based on differences in body surface area

Keywords: interferon-γ (ifn-γ) donor leukocyte infusion (dli) allogeneic hematopoietic stem cell transplantation (allosct)