Immune Dysregulation Syndromes, Immunodeficiencies
Conditions
Keywords
Immunodeficiencies, Immune dysregulation syndromes
Brief summary
This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age.
Detailed description
This is a Phase II trial to determine the ability of a reduced intensity conditioning regimen to allow successful engraftment with alpha/beta T and CD19+ depleted peripheral stem cell grafts from unrelated or partially matched related donors. There are two conditioning regimens depending upon patient diagnosis and age. The study will include patients 0-25 years with PID, including immune dysregulation syndromes for which hematopoietic stem cell transplant is indicated. Treatment: Either conditioning regimen (listed below) followed by alpha/beta T and CD19+ depleted donor peripheral stem cells 1. Reduced intensity conditioning with busulfan x 8 doses, fludarabine 40 mg/m2 x 4, thiotepa 5 mg/kg x 2, anti-thymocyte globulin (ATG) 3 mg/kg x 3. OR 2. Myeloablative regimen with busulfan x 16 doses or Daily for four days, fludarabine 30 mg/m2 x 5, thiotepa 5 mg/kg x 2, ATG 3 mg/kg x 2. OR 3. Immunotherapy regimen on days -9, 8, 7 with anti-thymocyte globulin 3 mg/kg/day (for severe combined immunodeficiency patients only). 4. Infusion of alpha/beta T and CD19+ depleted donor peripheral stem cells. 5. Follow up, including evaluation of chimerism and immune reconstitution.
Interventions
Stem cells will be processed using the CliniMACS device for alpha/beta and CD19+ T cell depletion. Processing of cells using the CliniMACS will occur in accordance with the Investigator Brochure and Technical Manual following the laboratory standard operating procedures (SOPs) and using aseptic technique.
Sponsors
Children's Hospital of Philadelphia
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
T-depleted stem cell infusion
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
Inclusion criteria
1. Ages 0-25 years at time of enrollment 2. Diseases: * Immunodeficiencies for which allogeneic hematopoietic stem cell transplant is indicated, including severe combined immunodeficiencies, immunodeficiency polyendocrinopathy X-linked syndrome (IPEX), X-linked lymphoproliferative disease, chronic granulomatous disease, Wiskott-Aldrich syndrome (WAS), hyperIgM, and other life-threatening immunodeficiencies. * Immune dysregulation syndromes, including refractory or recurrent hemophagocytic lymphohistiocytosis, hemophagocytic lymphohistiocytosis (HLH) with genetic mutations, refractory multisystemic Langerhans cell histiocytosis, other macrophage activating syndrome (MAS) refractory to standard therapy. 3. Clinical status * Lansky or Karnofsky performance \>=60 * Organ Function: 1. Serum creatinine \<1.5 x upper limit of normal for age Hepatic: ALT \<=250; AST \<=350 2. Cardiac shortening fraction \>=27% 3. Bilirubin \<2.5x normal (unless elevation due to Gilberts disease). 4. No active untreated infection 4. Signed informed consent 5. No HLA matched related donor available. 6. Females of childbearing potential must have negative pregnancy test.
Exclusion criteria
* Uncontrolled bacterial, viral or fungal infections * HLA matched related or unrelated donor able to donate mobilized peripheral stem cells. * Pregnant Females * Matched related donor available for bone marrow donation Donors Selection Criteria: * Donor selection will comply with 21 CFR 1271 * Unrelated donor matched or up to one antigen mismatch as per National Marrow Donor Program (NMDP). * Haploidentical parent or sibling able to undergo mobilization for peripheral stem cell collection. Maternal donor preferred over paternal donor if both equally haploidentical. * Children's Hospital of Philadelphia (CHOP) Blood and Marrow Transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases. * Unrelated donor identified through the National Marrow Donor Program (NMDP) and fulfills the NMDP criteria for donation. Unrelated donor willing and able to undergo mobilization of peripheral stem cells and apheresis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event free survival | One year | Event free survival in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted |
| Stable engraftment | One year | Stable engraftment in greater than 20 percent donor cells at one year for patients with primary immunodeficiencies (PID) who receive unrelated or partially matched related donor peripheral stem cell grafts which have been alpha/beta T depleted and CD19 depleted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of graft vs. host disease (GVHD) | One and two years | Severity of acute and chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years |
| Incidence of graft vs. host disease (GVHD) | One and two years | Evaluation of incidence of chronic graft vs host disease (GVHD), incidence of mixed chimerism, primary and secondary graft rejection, and immune reconstitution at one and two years |
Countries
United States
Outcome results
None listed