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
试验速览
- 阶段
- 早期 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Upregulation HLA l (HLA-ABC)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
IFN-γ
100mcg IFN-γ subcutaneously three times per week (Weeks 0-7), once per week (Weeks 8-12) (or per protocol guidance based on tolerability, response, or DLI infusions)
干预措施: IFN-γ (interferon gamma-1b) injection (Drug)
结局指标
主要结局
Upregulation HLA l (HLA-ABC)
时间窗: Up to 6 months
Upregulation of HLA l (HLA-ABC) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of HLA ll (HLA-DR/DQ)
时间窗: Up to 6 months
Upregulation of HLA ll (HLA-DR/DQ) in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry.
Upregulation of ICAM-1
时间窗: Up to 6 months
Upregulation of ICAM-1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.
Adverse events related to IFN-γ
时间窗: Up to 6 months
Adverse events of IFN-γ in relapsed patients after alloSCT per CTCAE v5.0.
Generation of phosphorylated-STAT1
时间窗: Up to 6 months
Generation of phosphorylated-STAT1 in bone marrow malignant blasts post-IFN-γ treatment, measured by the change in mean florescent intensity by flow cytometry as a percentage of positive cells.
次要结局
- Malignant Blast Burden(Up to 6 months)
- Incidence of de novo GVHD(Up to 6 months)
- Incidence of GVHD(Up to 6 months)
研究者
Sawa Ito, MD
Assistant Professor
University of Pittsburgh