A Phase II Study to Evaluate the Efficacy of Posttransplant Cyclophosphamide for Prevention of Chronic Graft-versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 1
- 主要终点
- Chronic GVHD Requiring Systemic Immunosuppressive Treatment
研究概览
简要总结
This phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Giving chemotherapy and total-body irradiation before transplantation helps stop the growth of cancer cells and prevents the patient's immune system from rejecting the donor's stem cells. Healthy stem cells from a donor that are infused into the patient help the patient's bone marrow make blood cells; red blood cells, white blood cells, and platelets. Sometimes, however, the transplanted donor cells can cause an immune response against the body's normal cells, which is called graft-versus-host disease (GVHD). Giving cyclophosphamide after transplant may prevent this from happening or may make chronic GVHD less severe.
详细描述
PRIMARY OBJECTIVES:
I. The primary objective of this study is to assess outcomes when high-dose cyclophosphamide (CY) is administered on days 3 and 4 followed by cyclosporine (CSP) after human leukocyte antigen (HLA)-matched related or unrelated mobilized blood cell transplantation with total-body irradiation (TBI) or busulfan (BU)-based conditioning.
SECONDARY OBJECTIVES:
I. The secondary objective of this study is to assess hematopoietic cell transplantation (HCT) outcomes when withdrawal of CSP is accelerated in patients without acute graft-versus-host disease (GVHD).
OUTLINE: Patients' conditioning regimens are determined by the Clinical Coordinator after consultation with the attending physician. Based on disease, patients receive either TBI or fludarabine and busulfan.
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 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Acute lymphocytic leukemia (ALL) in morphologic first complete remission (CR1) with high risk features defined as, but not limited to: evidence of adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or mixed-lineage leukemia (MLL) rearrangements; presence of minimal residual disease; progenitor B-cell immunophenotype; high white blood cells (WBC) at diagnosis (> 30,000/ul in B-ALL; > 100,000/ul in T-ALL); or delayed attainment of CR (> 4 weeks) after induction therapy; additional clinical characteristics deemed to confer a high relapse risk may be discussed with and approved by the Principal Investigator (PI)
- •Acute myeloid leukemia (AML) in CR1 EXCEPT patients with low-risk features defined as:
- •Inv 16 or t(8;21) in the absence of c-kit mutations
- •Normal karyotype who are FLT3-ITD-negative and NPM1-positive in the absence of c-kit mutations
- •Patients with respective "low-risk" features are eligible, however, if (i) more than 1 cycle of induction therapy was required to achieve CR1 (ii) the patient had a preceding myelodysplastic syndrome (MDS) other than myelofibrosis, or (iii) secondary AML
- •Acute leukemia in 2nd or greater CR (CR >= 2)
- •Refractory or relapsed AML with =< 10% bone marrow blasts and no circulating blasts or proven extramedullary disease
- •AML transformed from myelodysplastic syndrome (MDS) with < 10% bone marrow blasts
- •MDS with following high risk features:
- •High risk cytogenetics (including, but not limited to: 7q--, inv[3], t[3q], del[3q] or complex karyotype)
- •International Prognostic Scoring System (IPSS) intermediate (INT)-2 or greater
- •Treatment-related MDS
- •Any phase of MDS if patient is < 21 years of age
- •Chronic myelogenous leukemia (CML) beyond 1st chronic phase or resistant or intolerant to tyrosine kinase inhibitors (adults) or any phase (pediatric < 21 years)
- •Chronic myelomonocytic leukemia
- •Philadelphia-negative myeloproliferative disorder
- •Lymphoma: relapsed chemotherapy-sensitive (complete or partial response) Hodgkin or non-Hodgkin lymphoma
- •Multiple myeloma-stage III
- •The patient or legal representative must be able to understand and give written informed consent
- •DONORS: The donor must be a genotypically HLA-identical sibling, a phenotypically HLA-matched first-degree relative, or an unrelated donor who is molecularly matched with the patient at HLA-A, B, C, DRB1
- •DONORS: Donors must meet the selection criteria for administration of G-CSF (filgrastim) and apheresis defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened per the American Association of Blood Banks (AABB)
- •DONORS: Donors must be capable of giving informed consent
排除标准
- •Prior autologous or allogeneic stem cell transplant
- •Performance status > 2 (Eastern Cooperative Oncology Group [ECOG]) or < 50 (Lansky; for patients < 16 years old)
- •Uncontrolled infection; the protocol principal investigator (PI) will be final arbiter if there is uncertainty regarding whether a previous infection is under adequate control to allow enrollment in the study
- •Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T cell lymphotropic virus (HTLV)-1, 2
- •Left ventricular ejection fraction < 45% or shortening fraction < 25%; no uncontrolled arrhythmias or symptomatic cardiac disease
- •Symptomatic pulmonary disease; forced expiratory volume in one second (FEV1), forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =< 50% of predicted (corrected for hemoglobin); if pulmonary function tests cannot be performed, an oxygen saturation < 92% on room air
- •Calculated (Cockcroft-Gault or appropriate calculation for pediatric patients) serum creatinine clearance =< 60 mL/min; if the calculated CrCl is 50-60 mL/min, but a measured CrCl by 24 hour urine collection is > 60 mL/min, this measurement is acceptable
- •Total serum bilirubin more than twice upper normal limit
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold higher than laboratory upper normal limits
- •Female patient must have negative serum pregnancy test (all women of child bearing-potential must have test performed)
- •DONORS: Potential donors who for psychological, physiological, or medical reasons cannot tolerate administration of G-CSF or apheresis
- •DONORS: Donors who are allergic to filgrastim or Escherichia (E.) coli-derived proteins
- •DONORS: Donor-related risks to recipients
- •DONORS: Positive anti-donor lymphocytotoxic crossmatch
- •DONORS: Donors who are positive for HIV
研究组 & 干预措施
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: allogeneic hematopoietic stem cell transplantation (Procedure)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: cyclophosphamide (Drug)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: cyclosporine (Drug)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: peripheral blood stem cell transplantation (Procedure)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: total-body irradiation (Radiation)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: fludarabine phosphate (Drug)
Treatment (TBI, PBSCT, and cyclophosphamide GVHD prophylaxis)
PREPARATIVE REGIMEN: Patients receive TBI BID on days -4 or -3 to -1. Some patients also receive fludarabine IV daily on days -5 to -2 and busulfan IV over 3 hours QD or over 2 hours every 6 hours on days -5 to -2. Patients may also undergo CNS prophylaxis, testicular irradiation, and/or involved field irradiation as per standard practice.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0 per standard practice.
GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper on days 56-126.
干预措施: busulfan (Drug)
结局指标
主要结局
Chronic GVHD Requiring Systemic Immunosuppressive Treatment
时间窗: At 1 year after transplantation
Chronic GVHD will be defined by National Institutes of Health (NIH) criteria and requiring systemic treatment. A reduction in the cumulative incidence of GVHD from \~35% to \~15% at 1 year would represent a reasonable goal. A sample size of 42 patients provides 90% power to observe such a difference with one-side 5% type-1 error.
次要结局
- Donor Engraftment(At day 28)
- Grades II-IV and III-IV Acute GVHD(Through day +100 post-transplant)
- Duration of Systemic Immunosuppressive Treatment(Up to 5 years)
- Persistent or Recurrent Malignancy After HCT(At 2 years)
- Non-relapse Mortality(At 2 years)
- Overall Survival(At 1 year post-transplant)
- Disease-free Survival(At 1 year post-transplant)
- Hematologic Recovery(Up to day +100)
- Graft Failure(By greater than or equal to 28 days post-transplant)
研究者
Marco Mielcarek
Principal Investigator
Fred Hutchinson Cancer Center