A Reduced Intensity Conditioning Regimen With CD3-Depleted Hematopoietic Stem Cells to Improve Survival for Patients With Hematologic Malignancies Undergoing Haploidentical Stem Cell Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 73
- 试验地点
- 1
- 主要终点
- Event-free Survival (EFS)
研究概览
简要总结
Blood and marrow stem cell transplant has improved the outcome for patients with high-risk hematologic malignancies. However, most patients do not have an appropriate HLA (immune type) matched sibling donor available and/or are unable to identify an acceptable unrelated HLA matched donor through the registries in a timely manner. Another option is haploidentical transplant using a partially matched family member donor.
Although haploidentical transplant has proven curative in many patients, this procedure has been hindered by significant complications, primarily regimen-related toxicity including GVHD and infection due to delayed immune reconstitution. These can, in part, be due to certain white blood cells in the graft called T cells. GVHD happens when the donor T cells recognize the body tissues of the patient (the host) are different and attack these cells. Although too many T cells increase the possibility of GVHD, too few may cause the recipient's immune system to reconstitute slowly or the graft to fail to grow, leaving the patient at high-risk for significant infection.
For these reasons, a primary focus for researchers is to engineer the graft to provide a T cell dose that will reduce the risk for GVHD, yet provide a sufficient number of cells to facilitate immune reconstitution and graft integrity. Building on prior institutional trials, this study will provide patients with a haploidentical (HAPLO) graft engineered to specific T cell target values using the CliniMACS system. A reduced intensity, preparative regimen will be used in an effort to reduce regimen-related toxicity and mortality.
The primary aim of the study is to help improve overall survival with haploidentical stem cell transplant in this high risk patient population by 1) limiting the complication of graft versus host disease (GVHD), 2) enhancing post-transplant immune reconstitution, and 3) reducing non-relapse mortality.
详细描述
This study will explore the following objectives:
- To assess if the event-free survival at one-year post-transplant for research participants with high-risk hematologic malignancies can be improved following HAPLO hematopoietic stem cell transplant (HSCT) using a graft depleted of CD3+ cells ex vivo and a reduced intensity-conditioning regimen.
Secondary objectives:
- To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment.
- To estimate the cumulative incidence of relapse for research participants who receive this study treatment.
- To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants.
- To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant.
Exploratory objectives:
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 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(transplant recipient)
- •Patients less than or equal to 21 years of age; may be greater than 21 years old if a current St. Jude patient or previously treated St. Jude patient within 3 years of completion of prior treatment.
- •Must have one of the following diagnosis:
- •ALL high risk in second remission. Examples include relapse on therapy, first remission duration of less than or equal to 30 months, or relapse within 12 months of completing therapy.
- •ALL in third or subsequent remission.
- •ALL high risk in first remission. Examples include: induction failure, minimal residual disease greater than or equal to 1% marrow blasts by morphology after induction, persistent or recurrent cytogenetic or molecular evidence of disease during therapy requiring additional therapy after induction to achieve remission.
- •High-risk AML in first remission. Examples include monosomy 7, M6, M7, t(6;9), FLT3-ITD, or patients who have greater than or equal to 25% blasts by morphology after induction or who do not achieve CR after 2 courses of therapy (includes myeloid sarcoma).
- •Relapsed or persistent AML (less than or equal to 25% blasts in marrow by morphology).
- •AML in second or subsequent morphologic remission (includes myeloid sarcoma).
- •CML in first chronic phase with detectable molecular or cytogenetic evidence of disease despite medical therapy; or CML with a history of accelerated or blast crisis, now in chronic phase; or unable to tolerate tyrosine kinase inhibitor therapy.
- •Juvenile myelomonocytic leukemia (JMML).
- •Myelodysplastic syndrome (MDS).
- •Therapy related (secondary) AML, ALL, or MDS.
- •Hodgkin lymphoma after failure of prior autologous HSCT or unsuitable for autologous HSCT.
- •Non-Hodgkin lymphoma (NHL) in second complete remission (CR2) or subsequent.
- •Has not received a prior allogeneic hematopoietic stem cell transplant.
- •Does not have a suitable HLA-matched sibling donor available for stem cell donation.
- •Does not have a suitable cord blood product or volunteer matched unrelated donor (MUD) available in the necessary time for stem cell donation.
- •Has a suitable HLA partially matched family member available for stem cell donation.
- •Cardiac shortening fraction greater than or equal to 25%.
- •Creatinine clearance or glomerular filtration rate (GFR) greater than or equal to 40 ml/min/1.73 m^
- •Forced vital capacity (FVC) greater than or equal to 40% of predicted value or a pulse oximetry value of greater than or equal to 92% on room air.
- •Direct bilirubin less than or equal to 3 mg/dl.
- •Age-dependent performance score of greater than or equal to
- •Serum glutamic pyruvic transaminase (SGPT) less than 3 times the upper limit of normal for age.
- •Karnofsky or Lansky (age-dependent) performance score of greater than or equal to
- •No known allergy to murine products or human anti-mouse antibody (HAMA) results within normal limits.
- •Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment).
- •Not breast feeding.
- •Inclusion criteria (stem cell donor):
- •Partially HLA matched family member.
- •At least 18 years of age.
- •Human immunodeficiency virus (HIV) negative.
- •Not pregnant (confirmed by negative serum or urine pregnancy test within 7 days prior to enrollment).
- •Not breast feeding.
- •Inclusion criteria (transplant recipient - stem cell boost)
- •Has experienced one of the following disorders post-transplant:
- •graft failure
- •graft rejection
- •delayed hematopoietic and/or immune reconstitution.
- •Exclusion: NA
排除标准
- 未提供
研究组 & 干预措施
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: CliniMACS (Device)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Stem cell transplantation (Procedure)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Fludarabine (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Thioplex® (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: L-phenylalanine mustard (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Mycophenolate mofetil (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Rituxan™ (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Alemtuzumab (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Cyclophosphamide (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Anti-thymocyte globulin (Rabbit) (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: G-CSF (Drug)
High-Risk Hematologic Malignancies
Participants meeting eligibility criteria undergo haploidentical stem cell transplantation along with systemic chemotherapy and antibodies, including Fludarabine, Thioplex®, L-phenylalanine mustard, mycophenolate mofetil, CellCept®, Rituxan™, Muromonab (prior to January 2010) or Alemtuzumab (after January 2010), Cyclophosphamide, Anti-thymocyte globulin (Rabbit), and G-CSF.
Grafts from suitable haploidentical donors are processed using the CliniMACS system.
干预措施: Muromonab (Drug)
结局指标
主要结局
Event-free Survival (EFS)
时间窗: one year post-transplant
To determine if one year event-free survival can be improved in pediatric patients undergoing a haploidentical transplant by using a reduced intensity conditioning regimen and a targeted dose T cell depleted donor product. EFS is defined as time from transplantation to the occurrence of relapse or death due to any cause. Patients who are alive at the time of analysis will be censored. The estimated percentage of participants with EFS at one-year post-transplantation is reported using Kaplan-Meier analysis.
次要结局
- Disease-Free Survival (DFS)(One year post-transplant)
- Incidence of Regimen-related Mortality(100 days post-transplant)
- Overall Survival (OS)(one year post-transplant)
- Incidence of Non-hematologic Regimen-related Toxicities(100 days post-transplant)
- To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.(five years post-transplant)
- To Estimate the Rate of Overall Grade III-IV Acute GVHD, and the Rate and Severity of Chronic GVHD in Research Participants.(five years post-transplant)