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.
This study will explore the following objectives: 1. 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: 1. To estimate the one-year overall survival (OS) and disease-free survival (DFS) for research participants who receive this study treatment. 2. To estimate the cumulative incidence of relapse for research participants who receive this study treatment. 3. To estimate the rate of overall grade III-IV acute GVHD, and the rate and severity of chronic GVHD in research participants. 4. To estimate the incidence of non-hematologic regimen-related toxicity and regimen-related mortality in the first 100 days post-transplant. Exploratory objectives: 1. To explore the biologic significance of soluble interleukin-2 receptor and immunologic state \[quantitative lymphocyte studies, V beta spectratyping, T-cell receptor excision circles (TREC) assay\] to predict the development of acute and chronic GVHD in these research participants. 2. To measure the pharmacokinetics of Campath-1H in pediatric HAPLO HSCT recipients NOTE: This protocol originally used muromonab (OKT3) in the conditioning regimen to prepare participants for haploidentical HCT. After muromonab became unavailable from the manufacturer in 2010, muromonab was replaced by alemtuzumab (Campath-1H) for use in subsequent participants.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
73
Miltenyi Biotec CliniMACS stem cell selection device
An infusion of HLA mismatched family member donor stem cells processed through the use of the investigational Miltenyi Biotec CliniMACS device.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
After January 2010, due to the unavailability of muromonab, transplant recipients received a conditioning regimen consisting of systemic chemotherapy and antibodies, including alemtuzumab.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Transplant recipients will receive a conditioning regimen consisting of systemic chemotherapy and antibodies.
Prior to January 2010, transplant participants received a conditioning regimen consisting of systemic chemotherapy and antibodies, including muromonab. Muromonab became unavailable from the manufacturer at that time and was replaced by alemtuzumab.
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Event-free Survival (EFS)
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.
Time frame: one year post-transplant
Overall Survival (OS)
Estimate the one-year overall survival (OS) for research participants who receive this study treatment. OS is defined as time from transplantation to death due to any cause. Patient who are alive at the time of analysis will be censored. The estimated percentage of participants with OS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Time frame: one year post-transplant
Disease-Free Survival (DFS)
Estimate the one-year disease-free survival (DFS) for research participants who receive this study treatment. DFS is defined as time from transplantation to the occurrence of relapse or death due to relapse. Patients who are alive at the time of analysis or die due to other causes will be censored at the time of their events. The estimated percentage of participants with DFS at one-year post-transplantation is reported using Kaplan-Meier analysis.
Time frame: One year post-transplant
Incidence of Non-hematologic Regimen-related Toxicities
Estimate of the incidence of non-hematologic regimen-related toxicity and regimen-related toxicity in the first 100 days post-transplant. The percentage of participants are reported by maximum grade seen using binomial distribution. Participants were graded for toxicity using Common Terminology Criteria for Adverse Events version 3.0. In general, Grade 1 is mild, 2 is moderate toxicity but generally does not require treatment, 3 is severe enough to require treatment, 4 is life-threatening, and 5 means it was associated with death.
Time frame: 100 days post-transplant
Incidence of Regimen-related Mortality
The incidence of regimen-related mortality in the first 100 days post-transplant is estimated based on binomial distribution.
Time frame: 100 days post-transplant
To Estimate the Cumulative Incidence of Relapse for Research Participants Who Receive This Study Treatment.
The Cumulative Incidence of Relapse will be reported as the proportion of number of relapses since transplant to the total number of patients at risk at five years post-transplant.
Time frame: 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.
The rate of Overall Grade III-IV Acute AVHD will be report as the proportion of patients who have Grade III-IV Acute GVHD to the total patients with transplant. The rate of Chronic GVHD will be report as the proportion of patients who have Chronic GVHD to the total patients with transplant. The Severity of Chronic GVHD will be reported using CTCAE grading system, as a number.
Time frame: five years post-transplant
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