Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myeloid Leukemia (CML), Juvenile Myelomonocytic Leukemia (JMML), Lymphoma (Hodgkin's and Non-Hodgkin's), Myelodysplastic Syndrome (MDS)
Conditions
Keywords
Unrelated donor transplant, Allogenic Stem Cell Transplant, Adult Bone Marrow Transplant, Pediatric Bone Marrow Transplant, Related donor transplant, Haploidentical donor transplant, Peripheral blood stem cell transplantation, Non-malignant disease, Malignant disease, Bone marrow failure syndrome, Severe Aplastic Anemia, Severe Congenital Neutropenia, Amegakaryocytic Thrombocytopenia, Diamond-Blackfan Anemia, Schwachman Diamond Syndrome, Primary Immunodeficiency Syndrome, Acquired Immunodeficiency Syndrome, Histiocytic Syndrome, Familial Hemophagocytic Lymphocytosis, Lymphohistiocytosis, Macrophage Activation Syndrome, Langerhans Cell Histiocytosis (LCH), Hemoglobinopathies, Reduced-Intensity Conditioning, Sickle Cell Disease, Sickle Cell-beta-thalassemia
Brief summary
The purpose of this study is to learn more about the effects of (classification determinant) CD34+ stem cell selection on graft versus host disease (GVHD) in children, adolescents, and young adults. CD34+ stem cells are the cells that make all the types of blood cells in the body. GVHD is a condition that results from a reaction of transplanted donor T-lymphocytes (a kind of white blood cell) against the recipient's body and organs. Study subjects will be offered treatment involving the use of the CliniMACS® Reagent System (Miltenyi Biotec), a CD34+ selection device to remove T-cells from a peripheral blood stem cell transplant in order to decrease the risk of acute and chronic GVHD. This study involves subjects who are diagnosed with a malignant disease, that has either failed standard therapy or is unlikely to be cured with standard non-transplant therapy, who will receive a peripheral blood stem cell transplant. A malignant disease includes the following: Chronic Myeloid Leukemia (CML) in chronic phase, accelerated phase or blast crisis; Acute Myelogenous Leukemia (AML); Myelodysplastic Syndrome (MDS); Juvenile Myelomonocytic Leukemia (JMML); Acute Lymphoblastic Leukemia (ALL); or Lymphoma (Hodgkin's and Non-Hodgkin's).
Detailed description
Graft versus host disease (GVHD) is one of the serious complications following allogeneic stem cell transplantation. The incidence and severity of GVHD increase with the degree of HLA incompatibility between the host and donor. The most reliable way to prevent acute and chronic GVHD is to remove T cells from the graft. However, the incidence of graft failure increases with the efficiency of T cell depletion and low T cell numbers are predictive of graft failure. Immunomagnetic selection of HLA-mismatched CD34+ progenitor cells has demonstrated high levels of T cell depletion and successful engraftment in adult and pediatric patients with the malignant and nonmalignant disease.
Interventions
DEVICECliniMACS CD34+ Reagent System
The CliniMACS® Reagent System (Miltenyi Biotec, Germany), is a semi-automated immunomagnetic cell selection medical device that is used in vitro to select and enrich specific cell populations in a closed, sterile environment. The system is comprised of a computer controlled medical device containing a permanent magnet, a closed-system sterile tubing set containing columns coated with a ferromagnetic matrix, and a magnetic cell specific labeling reagent.
DRUGThiotepa
Standard of care: Thiotepa should be diluted in normal saline (NS) (1-5 mg/ml) and infused over 2 hrs on Days -5, -4. IV fluids should be at maintenance rate (1500 ml/m2). It is recommended that total parental nutrition not being used during Thiotepa administration as amino acid infusions may interfere with Thiotepa metabolism.
DRUGCyclophosphamide
Standard of care: Cyclophosphamide (Cytoxan) should be infused over one hour. The drug can be diluted in dextrose water solvent (D5W), NS, or other solutions (250cc) to a maximum concentration of 20 mg/mL.
DRUGAlemtuzumab
Standard of care: Each dose of alemtuzumab is to be diluted in D5W or NS (maximum concentration: 0.3 mg/mL) for IV infusion over two hours.
DRUGTacrolimus
Standard of care: Tacrolimus dosing will be 0.03mg/kg/24 hours as continuous IV infusion or 0.12 mg/kg/day po divided Q8-12 hr
DRUGMelphalan
Standard of care: Melphalan 45mg/m2 (1.5 mg/kg IV for children \<1 year of age or \<10 kg) diluted in 0.9% NS to a concentration of 0.1- 0.45mg/ml, given IV over 30 minutes.
DRUGBusulfan
Standard of care: Busulfan will be given IV in 0.9% sodium chloride or D5W to a final solution for infusion equal to 10 times the volume of diluent to Busulfex (to a concentration \>0.5 mg/mL), through a central venous access device over 2 hours.
DRUGFludarabine
Standard of care: Fludarabine will be given IV in 50-100 ml of D5W or 0.9% sodium chloride, over 30 minutes.
DRUGMethylprednisolone
Standard of care: Methylprednisolone will be give IV slow infusion over 15-30 minutes.
Sponsors
Diane George
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 22 Years
Healthy volunteers
No
Inclusion criteria
General Eligibility (All Patients) * Must be \< 22 years of age * Diagnosed with a malignant disease * Must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects), and must sign an informed consent * For unrelated donor: A human leukocyte antigen (HLA) 8/10, 9/10 or 10/10 matched unrelated adult donor (MUD) will be required for study entry * For related donor: A 5/10, 6/10, 7/10, 8/10, 9/10 or 10/10 matched (or partially matched) family donor will be required for study entry * Adequate renal function * Adequate liver function * Adequate cardiac function * Adequate pulmonary function
Exclusion criteria
* Patients with documented uncontrolled infection at the time of study entry are not eligible * Females who are pregnant or breast feeding at the time of study entry are not eligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of acute GVHD | Up to 2 years post-transplant | Acute GVHD will be assessed and graded with standard NCI grading criteria.Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 years and yearly (366+ days post-transplant) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to immune reconstitution | Up to 2 years post-transplant | Immune reconstitution studies will be conducted (For T-cell, B-cell, natural killer (NK)-cell and immunoglobulins) 60 days post-transplant, 100 days post-transplant, 150 days post-transplant, 180 days post-transplant, 270 days post-transplant, 1-year post-transplant, and 2 years post transplant. |
| Incidence of infection complications including bacterial, viral, fungal and atypical mycobacterial and other infections | Up to 100 days post-transplant | Will be assessed weekly or more as indicated until 84 or 100 days post-transplant, then as clinically indicated. |
| Time to platelet engraftment | Up to 1 year post-transplant | Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1-year post transplant. |
| Incidence of chronic GVHD | Up to 2 years post-transplant | Chronic GVHD will be assessed and graded with standard NCI grading criteria. |
| Time to neutrophil engraftment | Up to 1 year post-transplant | Will be assessed multiple times while hospitalized, 1-60 days post transplant, 100 days post-transplant, 180 days post-transplant, and 1-year post transplant. Neutrophil engraftment is defined as the first of three days following the neutrophil nadir with an absolute neutrophil count above 500/mm3. |
| Severity of chronic GVHD | Up to 2 years post-transplant | Chronic GVHD will be assessed and graded with standard NCI grading criteria. Evaluated daily while hospitalized, then weekly (1-60 days post-transplant), as clinically indicated (60-365 days post transplant), then 1 year, 1.5 years, 2 |
| Incidence of primary graft failure | 42 (or more) days post-transplant | Primary graft rejection is defined as the presence of \< 20% donor cells |
| Incidence of secondary graft failure | 42 (or more) days post-transplant | The presence of \< 20% donor derived hematopoietic cells in peripheral blood |
| Severity of acute GVHD | Up to 2 years post-transplant | Acute GVHD will be assessed and graded with standard NCI grading criteria. |
Countries
United States
Outcome results
None listed