Hematopoietic Stem Cell Transplantation (HSCT) for Children With SCID Utilizing Alemtuzumab, Plerixafor & Filgrastim

Study Overview
=================
Brief Summary
-----------------
The goal of this study is to develop a novel approach to hematopoietic stem cell transplantation for children with Severe Combined Immunodeficiency Disease (SCID) that eliminates the use of toxic chemotherapy conditioning and maximizes the likelihood of T and B cell immune reconstitution. Rather than classic chemotherapeutic agents, the investigators will utilize a targeted stem cell mobilizer, plerixafor, in combination with alemtuzumab, a monoclonal antibody. Correlative scientific questions will include: 1) efficacy and characteristics of host stem cell mobilization; and 2) alemtuzumab pharmacokinetics in very young children.

Detailed Description
-----------------
The goal of this study is to develop an approach to hematopoietic stem cell transplantation for children with Severe Combined Immunodeficiency Disease (SCID) that eliminates the use of toxic chemotherapy conditioning and maximizes the likelihood of T and B cell immune reconstitution. SCID is a rare primary immunodeficiency disease in which there are multiple genotypes and phenotypes, and depending on various factors including the presence of B cell and NK cells, and the presence of maternal cells in the patient's circulation, there are numerous ways to approach a transplant. The major issues that must be addressed in any approach to transplantation for SCID are graft rejection and T and B cell immune reconstitution. Depending on the specific SCID diagnosis, the phenotype, and the presence of maternal engraftment at diagnosis, we will evaluate two transplant approaches that will attempt to optimize the engraftment of donor HSC and the likelihood of T and B cell reconstitution while eliminating the use of toxic chemotherapy conditioning. Primary Objective: To determine if the administration of plerixafor & filgrastim (G-CSF) prior to stem cell infusion results in increased donor stem cell occupancy of available bone marrow niches and B-cell engraftment in patients with SCID. Secondary Objectives: i. To determine if NK cell depletion with Alemtuzumab will overcome NK-mediated graft resistance in haplocompatible transplants for NK+ SCID. ii. To determine the optimal dosing of Alemtuzumab in very young children. iii. To determine the immunophenotypic characteristics of CD34+ cells mobilized and engrafted in patients receiving plerixafor & filgrastim prior to HCT. iv. To determine the thymic output, as measured by T-cell receptor excision circles, in patients receiving haplocompatible transplants & boosts.

Official Title
-----------------
Hematopoietic Stem Cell Transplantation for Children With Severe Combined Immunodeficiency Disease Utilizing Alemtuzumab and Mobilization With Plerixafor & Filgrastim

Conditions
-----------------
Severe Combined Immunodeficiency

Intervention / Treatment
-----------------
* Drug: Transplant Conditioning with Mobilization Only
* Drug: Transplant Conditioning with Mobilization and Alemtuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with classic SCID phenotype (<400 CD3/ul or maternally engrafted and <10% of normal PHA lymphoproliferative response). Genotypic identification is preferable, but not required. Patients must have an acceptable stem cell donor (HLA matched relative, 9 or 10/10 HLA-matched unrelated, or haplocompatible relative). Exclusion Criteria: Patients with leaky SCID syndromes, Omenn's Syndrome, reticular dysgenesis, ADA deficiency Lansky score <60% Patient with expected survival <4 weeks (including disseminated CMV infection involving lungs and/or CNS)

Ages Eligible for Study
-----------------
Maximum Age: 3 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-cell Graft Permissive SCID<br>Patients with SCID with: i. NK- phenotype; ii. NK+ phenotype with 10/10 HLA-matched relative or unrelated donor; or iii. NK+ phenotype with maternal engraftment by STR analysis and undergoing haplocompatible HSCT from maternal donor Intervention: Transplant Conditioning with Mobilization Only | Drug: Transplant Conditioning with Mobilization Only<br>* Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0 Transplant<br>* Other names: Conditioning with Filgrastim and Plerixafor;|
| Experimental: T-cell Graft Resistant SCID<br>Patients with SCID with NK+ phenotype with HLA-mismatched donor Intervention: Transplant Conditioning with Mobilization and Alemtuzumab | Drug: Transplant Conditioning with Mobilization and Alemtuzumab<br>* Day -7: Alemtuzumab 0.3 mg test dose then 0.3 mg/kg IV; Day -6: Alemtuzumab 0.3 mg/kg IV; Day -5: Alemtuzumab 0.3 mg/kg IV; Day -4: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -3: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -2: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day -1: Filgrastim (G-CSF) 5 mcg/kg IV q12 hours; Day 0: Plerixafor 240 mcg/kg subcutaneous 9-12 hours prior to transplant; Day 0: Transplant<br>* Other names: Conditioning with Filgrastim, Plerixafor, and Alemtuzumab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment of Donor B-cells in Blood by STR Testing | Number of participants in whom donor B cells were detected in the patient's blood after HSCT. | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Acute GVHD |  | 100 Days | 
| Incidence of Chronic GVHD |  | 2 Years | 
| Percentage of Patients Who Become Independent From Regular IVIG Infusion | Based on B-cell function assays from the patient's blood, we will be able to determine if patients are able to successfully discontinue IVIG infusions. | 2 Years | 
| Number of Patients With Engraftment of Donor Stem Cells in Bone Marrow by STR Testing | We will measure whether we are able to detect donor stem cells in the patient's bone marrow after HSCT. | 1 Year | 
| Number of Patients Who Achieve Engraftment of Donor T-cells in Blood by STR Testing | We will measure whether we are able to detect donor T-cells in the patient's blood after HSCT. | 1 Year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SCID, Transplant, Alemtuzumab, Plerixafor