Nonmyeloablative Hematopoietic Cell Transplantation (HCT) for Patients With Hematologic Malignancies Using Related, HLA-Haploidentical Donors: A Pilot Trial of Peripheral Blood Stem Cells (PBSC) as the Donor Source
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Acute GvHD
研究概览
简要总结
The purpose of this study is to determine whether stem cells collected from a donor's blood stream will be as safe and effective as using bone marrow collected from a donor's pelvic bone.
详细描述
This is a pilot study to assess the safety and potential efficacy of haploidentical peripheral blood stem cell transplantation using a nonmyeloablative preparative regimen and post-transplant cyclophosphamide. The overall objective of this study is to collect the efficacy and safety data to provide the basis to decide whether a larger study of clinical efficacy is warranted in this setting.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Molecular based HLA typing will be performed for the HLA-A, -B, -Cw, DRB1 and -DQB1 loci to the resolution adequate to establish haplo identity. A minimum match of 5/10 is required. An unrelated donor search is not required for a patient to be eligible for this protocol if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral or low-likelihood of finding a matched, unrelated donor.
- •Subjects must meet one of the disease classifications listed below:
- •Acute leukemias (includes T lymphoblastic lymphoma). Remission is defined as < 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with > 20% cellularity, peripheral blood counts showing ANC >1000/ul, including patients in CRp.
- •Acute Lymphoblastic Leukemia in high risk CR1 as defined by at least one of the following:
- •Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), MLL rearrangements White blood cell counts >30,000/mcL Patients over 30 years of age Time to complete remission >4 weeks Presence of extramedullary disease
- •Acute Myelogeneous Leukemia in high risk CR1 as defined by at least one of the following:
- •Greater than 1 cycle of induction therapy required to achieve remission Preceding myelodysplastic syndrome (MDS) Presence of Flt3 abnormalities FAB M6 or M7 leukemia or
- •Adverse cytogenetics for overall survival such as:
- •those associated with MDS Complex karyotype (≥ 3 abnormalities) Any of the following: inv(3) or t(3;3), t(6;9), t(6;11), + 8 [alone or with other abnormalities except for t(8;21), t(9;11), inv(16) or t(16;16)], t(11;19)(q23;p13.1)
- •Acute Leukemias in 2nd or subsequent remission
- •Biphenotypic/Undifferentiated Leukemias in 1st or subsequent CR.
- •High-risk MDS status-post cytotoxic chemotherapy
- •Myelofibrosis
- •Burkitt's lymphoma: second or subsequent CR.
- •Chemotherapy-sensitive (complete or partial response; see response criteria Appendix C) large cell, Mantle Cell or Hodgkin's lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant.
- •Marginal zone B-cell lymphoma or follicular lymphoma that has progressed after at least two prior therapies (excluding single agent Rituxan) and are ineligible for an autologous transplant or relapsed/progressed after autologous stem cell transplant..
- •Patients with adequate physical function as measured by:
- •Cardiac: left ventricular ejection fraction at rest must be ≥ 35%.
- •Hepatic: bilirubin ≤ 2.5 mg/dL; and ALT, AST, and Alkaline Phosphatase < 5 x ULN.
- •Renal: serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function(creatinine clearance or GFR) > 40 mL/min/1.73m
- •Pulmonary: FEV1, FVC, DLCO (diffusion capacity) ≥ 40% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air.
- •Performance status: Karnofsky/Lansky score ≥ 60%.
- •Patients who have received a prior allogeneic HSCT and who have either rejected their grafts or who have become tolerant of their grafts with no active GVHD requiring immunosuppressive therapy.
- •Donors must be HLA-haploidentical first-degree or second degree relatives of the patient.
- •Age ≥ 18 years
- •Weight ≥ 40 kg
排除标准
- •HLA-matched donor able to donate.
- •Pregnancy or breast-feeding.
- •Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
- •Positive anti-donor HLA antibody.
研究组 & 干预措施
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Mesna (Drug)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Total Body Irradiation (Radiation)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Hematopoietic stem cell infusion (Other)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Fludarabine (Drug)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Cyclophosphamide (Drug)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Tacrolimus (Drug)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: Mycophenolate (Drug)
Treatment
Day -6, -5 Fludarabine 30 mg/M2 IV over 30-60 minutes Cyclophosphamide 14.5 mg/kg IV over 1-2 hours*, Mesna 14.5 mg/kg IV in 4 divided doses
Day -4 through -2 Fludarabine 30 mg/M2 IV over 30-60 minutes
Day -1 Total Body Irradiation 200 cGy, donor apheresis
Day 0 T cell replete PBSC
Days 3, 4 Cyclophosphamide 50 mg/kg IV Mesna 50 mg/kg IV in 4 divided doses
Day 5 Begin tacrolimus ,mycophenolate, and G-CSF
干预措施: G-CSF (Drug)
结局指标
主要结局
Acute GvHD
时间窗: Day +84
The cumulative incidence of grades III/IV acute GvHD at day +84 will be assessed. The first day of acute GvHD onset will be used to calculate a cumulative incidence curve by certain grade. An overall cumulative incidence curve will be computed along with a 90% CI with graft failure, relapse/progression, and death as competing risks.
Chronic Graft-versus-Host Disease
时间窗: 1 year
The cumulative incidence of chronic GvHD at one year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with graft failure, relapse/progression, and death as competing risks.
Nonrelapse Mortality (NRM)
时间窗: 1 year
The cumulative incidence of NRM at 1 year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with relapse/progression as competing risk.
Relapse of Malignancy
时间窗: 1 year
The cumulative incidence of relapse at 1 year will be assessed. An overall cumulative incidence curve will be computed along with a 90% CI with NRM as competing risk.
次要结局
- Primary graft failure(Day +84)
- Secondary graft failure(Up to 1 year)
- Neutrophil Recovery(Up to day +84)
- Platelet recovery(Up to day +84)
- Donor Cell Engraftment(Day +28, Day >= +84)
- Progression-free Survival(Up to 1 year)
- Infections(Date of onset)
研究者
Rafic Farah, MD
Assistant Professor of Medicine
University of Pittsburgh