Pre-Transplant Immunosuppression and Related Haploidentical Hematopoietic Cell Transplantation for Patients With Severe Hemoglobinopathies
试验速览
- 阶段
- 早期 1 期
- 状态
- 撤回
- 主要终点
- Event-free survival (EFS)
研究概览
简要总结
This clinical trial studies the effect of pre-transplant immunosuppression (PTIS) and donor stem cell transplant in treating patients with severe blood diseases (hemoglobinopathies). PTIS helps prepare the body for the transplant and lowers the risk of developing graft versus host disease (GVHD). Hematopoietic cells are found in the bone marrow and produce blood cells. Hematopoietic cell transplantation (HCT) injects healthy hematopoietic cells into the body to support blood cell production. PTIS and HCT may help to control severe hemoglobinopathies.
详细描述
PRIMARY OBJECTIVE:
I. To estimate event-free survival (EFS) at 2-years post HCT.
SECONDARY OBJECTIVES:
I. Assess event-free survival (EFS) at 100 days and 1 year post HCT. II. Assess overall survival (OS) at 100 days and 1 year post HCT. III. 30-day transplant-related mortality (TRM). IV. Time to platelet and neutrophil engraftment. V. Rate of graft failure (primary and secondary) through day 100. VI. Incidence of acute graft-versus-host disease (aGVHD) by day 100. VII. Incidence of chronic graft-versus-host disease (cGVHD) by 1 year and 2 years.
VIII. Rate of grade II or greater organ toxicity through day 100. IX. Incidence of hepatic sinusoidal obstruction syndrome (SOS) by day 100. X. Incidence of central nervous system (CNS) toxicities including posterior reversible encephalopathy syndrome (PRES) by day 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
- 2 Years 至 30 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients 2-30 years-of-age with confirmed sickle cell disease (SCD) (SS & sickle beta [SB]-thalassemia, both sickle beta 0 [SB0] and sickle beta plus [SB+]) or severe B-thalassemia major are potentially eligible
- •Patients with SCD should also meet the following eligibility criteria as outlined by the Center for Medicaid and Medicare Services: sickle cell disease and at least one of the following:
- •Stroke or neurological deficit lasting > 24 hours
- •Recurrent acute chest syndrome (ACS): 2 or more episodes of ACS in 2-year period preceding enrollment
- •Recurrent vaso-occlusive pain crises: 3 or more episodes per year in 2-year period preceding enrollment or recurrent priapism (3 or more episodes in the 2 years preceding enrollment)
- •Chronic transfusion program defined as 8 or more packed red blood cells (PRBC) transfusions per year to prevent central nervous system and/or vaso-occlusive complications in 1-year period preceding enrollment
- •Impaired neuropsychological function and abnormal cerebral magnetic resonance imaging (MRI) scan (silent strokes)
- •Stage I or II sickle lung disease
- •Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of predicted normal value)
- •Bilateral proliferative retinopathy and major visual impairment in at least one eye
- •Osteonecrosis of multiple joints
- •Echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) >= 2.7 m/sec
- •Patients with B-thalassemia are considered as severe if they are/have any of the following:
- •Transfusion-dependent
- •Evidence of extra-medullary hematopoiesis
- •Pesaro Class III
- •Patients shall not proceed to HCT without confirmation of primary diagnosis by review of available newborn screening results or hemoglobin electrophoresis and/or genetic testing
- •DONOR: High resolution HLA typing will be performed on all willing and available biologic parents and siblings without clinically significant hemoglobinopathy. Preference will be given to donors with the lowest number of HLA-allele mismatches
- •DONOR: Donor-specific anti-HLA antibodies will be obtained and analyzed from all patients. Preference will be given to donors with absent or low titer anti HLA-donor specific antibody levels when possible
排除标准
- •Uncontrolled infection
- •Females who are pregnant and/or unwilling to cease breastfeeding
- •Seropositivity for human immunodeficiency virus (HIV)
- •Lansky or Karnofsky performance status < 70%
- •Life expectancy severely limited by concomitant illness
- •Uncontrolled arrhythmias or symptomatic cardiac disease
- •Uncontrolled symptomatic pulmonary disease
- •Evidence of chronic active hepatitis or cirrhosis
- •Serum conjugated (direct) bilirubin > 2 x upper limit of normal for age. Participants are not excluded if the serum conjugated (direct) bilirubin is > 2 x the upper limit of normal for age as per local laboratory and:
- •There is evidence of a hyperhemolytic reaction after a recent red blood cell (RBC) transfusion, OR
- •There is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times upper limit of normal (ULN) and not caused by underlying hepatic disease
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5 x upper limit of normal for age
- •Serum creatinine > 1.5 x upper limit of normal for age AND estimated or measure creatinine clearance < 70 mL/min/1.72 m^2
- •Patient, parent or guardian unable/unwilling to provide consent and when indicated, assent
- •Patients with available HLA-matched related donor
- •Prior receipt of gene therapy
- •DONOR: All potential donors shall be tested by hemoglobin electrophoresis. Any potential donor with a clinically significant hemoglobinopathy will be deemed ineligible. Donors with sickle cell trait and beta thalassemia trait are eligible to donate
研究组 & 干预措施
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Mycophenolate Mofetil (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Bortezomib (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Busulfan (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Cyclophosphamide (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Dexamethasone (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Fludarabine Phosphate (Drug)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Hematopoietic Cell Transplantation (Procedure)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Lapine T-Lymphocyte Immune Globulin (Biological)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Plasmapheresis (Procedure)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Rituximab (Biological)
Treatment (PTIS, HCT)
See Detailed Description.
干预措施: Tacrolimus (Drug)
结局指标
主要结局
Event-free survival (EFS)
时间窗: At 2 years post-hematopoietic cell transplantation (HCT)
EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
次要结局
- Overall survival(Up to 1 year post-HCT)
- Incidence of chronic graft-versus-host disease(Up to 2 years post-HCT)
- Event-free survival(Up to 1 year post-HCT)
- Incidence of acute graft-versus-host disease(Up to 100 days post-HCT)
- Incidence of graft failure (primary and secondary)(Up to 100 days post-HCT)
- Incidence of grade II or greater organ toxicity(Up to 100 days post-HCT)
- Time to platelet and neutrophil engraftment(Up to 2 years post-HCT)
- Incidence of infectious complications(Up to 100 days post-HCT)
- Transplant-related mortality(Up to 30 days post-HCT)
- Incidence of hepatic sinusoidal obstruction syndrome(Up to 100 days post-HCT)
- Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome(Up to 100 days post-HCT)