A Multi-Center Study of Conditioning With Treosulfan, Fludarabine and Escalating Doses of TBI for Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 96
- 试验地点
- 3
- 主要终点
- Non Relapse Mortality (NRM) Incidence
研究概览
简要总结
This phase II trial is studying how well giving treosulfan together with fludarabine phosphate and total-body irradiation followed by donor stem cell transplant works in treating patients with high-risk acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor bone marrow or peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and methotrexate before and after transplant may stop this from happening
详细描述
PRIMARY OBJECTIVES:
I. Decrease the incidence of relapse to < 15% at 6 month post transplant in patients with high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transplanted from related or unrelated donors, without unacceptably increasing toxicity (10% non-relapse mortality [NRM] at 6 months).
SECONDARY OBJECTIVES:
I. Evaluate the incidence of NRM at 180 days and 1 year after hematopoietic cell transplantation (HCT).
II. Evaluate overall survival (OS) and relapse-free survival (RFS). III. Incidence of grades II-IV acute graft-versus-host disease (GVHD). IV. Incidence of chronic GVHD. V. Donor chimerism on days +28 and +100.
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
- — 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute myeloid leukemia (AML):
- •All AML patients beyond 1st remission;
- •Intermediate or high risk AML patients (based on South West Oncology Group [SWOG] cytogenetic criteria) in 1st complete remission
- •Myelodysplastic syndrome (MDS)
- •Other myeloid malignancies as chronic myelogenous leukemia (CML), CML accelerated phase, CML blast crisis, chronic myelomonocytic leukemia (CMML) (to be approved by patient care conference [PCC])
- •With Karnofsky Index or Lansky Play-Performance Scale > 70% on pre-transplant evaluation
- •Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
- •Previous autologous or allogeneic HCT is allowed
- •Donors must be:
- •Human leukocyte antigen (HLA)-identical related donors or
- •Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for one HLA allele, except for HLA-C where no mismatch is allowed
- •Able to undergo peripheral blood stem cell collection or bone marrow harvest
- •In good general health, with a Karnofsky or Lansky Play Performance score > 90%
- •Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
- •Acute lymphoblastic leukemia (ALL): all ALL patients not eligible for other protocols
排除标准
- •Receiving umbilical cord blood
- •With impaired cardiac function as evidenced by ejection fraction < 35% or cardiac insufficiency requiring treatment or symptomatic coronary artery disease
- •With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and diffusing capacity of the lung for carbon monoxide (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; or receiving supplementary continuous oxygen
- •With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2x upper normal limit or dialysis-dependent
- •With hepatic dysfunction as evidenced by total bilirubin or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.0 x upper normal limit or evidence of synthetic dysfunction or severe cirrhosis
- •With active infectious disease requiring deferral of conditioning, as recommended by an Infectious Disease specialist
- •With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy
- •With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy and/or cranial radiation prior to initiating conditioning (day -6)
- •With life expectancy severely limited by diseases other than malignancy
- •Women who are pregnant or lactating because of possible risk to the fetus or infant
- •With known hypersensitivity to treosulfan and/or fludarabine
- •Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
- •Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
- •Ineligible donors will be those:
- •Deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
- •Who are HIV-positive
- •With active infectious hepatitis
- •Females with a positive pregnancy test
- •Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
研究组 & 干预措施
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: treosulfan (Drug)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: fludarabine phosphate (Drug)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: total-body irradiation (Radiation)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: tacrolimus (Drug)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: allogeneic bone marrow transplantation (Procedure)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: allogeneic hematopoietic stem cell transplantation (Procedure)
Treatment (allogeneic transplantation)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to day -2 and treosulfan IV over 2 hours on days -6 to day -4. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation or bone marrow transplantation on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously or PO BID on days -1 to 56, followed by a taper until day 180 in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, 6, and 11.
干预措施: methotrexate (Drug)
结局指标
主要结局
Non Relapse Mortality (NRM) Incidence
时间窗: At 6 months
Cumulative incidence of NRM at 6 months. NRM includes all deaths without relapse or disease progression.
Relapse Incidence
时间窗: At 6 months
次要结局
- Non Relapse Mortality Incidence(1 year after HCT)
- Overall Survival (OS)(at 2 years)
- Incidence of Chronic GVHD(at 6 months)
- Median Donor CD3 + T Lymphocyte Chimerism in Peripheral Blood(Day 28 after HCT)
- Relapse-free Survival(at 2 years)
- Incidence of Grades II-IV Acute GVHD(at 6 months)
研究者
Joachim Deeg
Investigator
Fred Hutchinson Cancer Center