ifn-γ to treat acute myeloid leukemia (aml) and myelodysplastic syndrome (mds) that has relapsed after allogeneic hematopoietic stem cell transplantation

Conditions: Myelodysplastic Syndromes; Myeloid Leukemia; Allogeneic Stem Cell Transplantation

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.

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.

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