TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Primary Immunodeficiency and Inherited Metabolic Disorders in Children
Study Details
Study Description
Brief Summary
This research is being done to learn if a new type of haploidentical transplantation using TCR alpha beta and CD19 depleted stem cell graft from the donor is safe and effective to treat the patient's underlying condition. This study will use stem cells obtained via peripheral blood or bone marrow from parent or other half-matched family member donor. These will be processed through a special device called CliniMACS, which is considered investigational.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: TCR alpha beta T cell depletion The leukapheresis product will undergo TCR alpha beta negative selection following a standardized protocol |
Biological: Haploidentical Hematopoietic Cell Transplantation
TCR alpha beta T-cell and CD19 B-cell depleted haploidentical transplantation
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Outcome Measures
Primary Outcome Measures
- Incidence of successful donor engraftment [Day 100 after transplantation]
The incidence of engraftment at day 100 will be described based on donor chimerism in the whole blood and or fractions sorted for T-cell and myeloid subsets. The donor chimerism will be scored as autologous reconstitution (< 5% donor), mixed chimerism (5-49%=low mixed, 50-95%=high mixed), > 95%=full donor chimerism.
Secondary Outcome Measures
- Overall survival and Event-free survival [Up to 2 years post transplant]
Overall survival is defined as the time of enrollment to death from any cause or last follow up. Event-free survival is defined as the time of enrollment to death, primary or secondary graft failure, graft failure necessitating a second HCT procedure, DLI or stem cell boost given for treatment of falling chimerism, or disease recurrence
- Kinetics of neutrophil engraftment [Up to 42 days post transplant]
Neutrophil engraftment defined as absolute neutrophil count ≥500/μL for 3 consecutive measurements on different days
- Kinetics of platelet engraftment [Up to 42 days post transplant]
Platelet engraftment defined as sustained platelet count >20,000/μL and >50,000//μL with no platelet transfusions in the preceding seven days.
- Transplant-related mortality [Up to 100 days post transplant]
Rate of transplant-related mortality
- Acute grade II-IV GvHD [Up to 2 years post transplant]
Incidence and severity of acute graft versus host disease
- Chronic GvHD [Up to 2 years post transplant]
Incidence and severity of chronic graft versus host disease
- Primary graft failure [Up to 2 years post transplant]
Rates of primary graft failure
- Secondary graft failure [Up to 2 years post transplant]
Rates of secondary graft failure
- Transplant-related complications [Up to 2 years post transplant]
Frequency of transplant-related complications following transplantation
- Transplant-related infections [Up to 2 years post transplant]
Frequency of transplant-related infections following transplantation
- Cellular and Immunological reconstitution by laboratory evaluations [Up to 2 years post transplant]
The recovery of different lymphocyte subpopulation (CD3+; CD4+; CD8+; CD3+CD45RA+and CD45RO; TCR alpha beta; TCR gamma delta; CD19+)
Eligibility Criteria
Criteria
Inclusion Criteria:
- Patient with any form of primary immune deficiency/dysregulatory disorders characterized by aberrant immune function, abnormal hematopoiesis, systemic or organ specific autoimmunity and/or non-malignant lymphoproliferation. This includes, but not limited to:
- Disorders of phagocytes: Chronic granulomatous disease, Leukocyte adhesion deficiency, defects of IL-10 pathway, MonoMac syndrome
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Defects of cellular and humoral immunity: Severe Combined Immunodeficiency Disorder (infants with classic SCID up to 2 years of age will be excluded due to other open protocol), X-linked hyper-IgM syndrome, DOCK8 deficiency, ZAP70 deficiency, common variable immunodeficiency (CVID), Wiskott-Aldrich syndrome, NEMO deficiency.
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Disorder of immune dysregulation: Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, CTLA4 deficiency, LRBA deficiency, STAT1 GOF, STAT3 GOF, X-linked lymphoproliferative disease etc.
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Other PIDs and immune dysregulatory disorders who can be benefitted by HCT as deemed appropriate by the PI and the treating immunologist.
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Histiocytic disorders including hemophagocytic lymphohistiocytosis (familial HLH (types 1-5), secondary HLH (refractory to therapy or with recurrent episodes of hyper inflammation) and multisystem refractory Langerhans cell histiocytosis.
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Metabolic disorders that could improve or stabilize after stem cell transplantation such as mucopolysaccharidoses, neurodegenerative disorders, osteopetrosis, etc.
Inclusion Criteria:
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Patient lacks a suitable conventional donor (HLA-identical sibling or 10/10 matched unrelated donor evaluated using the genetic loci- HLA-A,-B, -C, -DRB1, -DQB1) or has rapidly progressive disease not permitting time to identify an unrelated donor.
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Patient must have a minimum genotypic identical match of 5/10.
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Patients must have adequate organ function measured by:
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Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 40% or SF ≥ 26%
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Pulmonary: asymptomatic or if symptomatic DLCO ≥ 40% of predicted (corrected for hemoglobin) or pulse oximetry ≥ 92% on room air if the patient is unable to perform pulmonary function testing.
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Renal: Creatinine clearance (CrCl) or glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2.
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Hepatic: Serum conjugated (direct) bilirubin < 2.0 x ULN for age; AST and ALT < 5.0 x ULN for age.
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Karnofsky or Lansky (age-dependent) performance score ≥ 50
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Signed written informed consent
Exclusion Criteria:
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Pregnant or breastfeeding females.
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Patient has HIV or uncontrolled fungal, bacterial or viral infections.
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Patient has received prior solid organ transplant.
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Patient has active GVHD (> grade II) or chronic extensive GVHD due to a previous allograft at the time of inclusion.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Johns Hopkins All Children's Hospital | Saint Petersburg | Florida | United States | 33701 |
Sponsors and Collaborators
- Johns Hopkins All Children's Hospital
Investigators
- Principal Investigator: Deepak Chellapandian, MD, Johns Hopkins All Children's Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- HAP-PID