Severe Combined Immunodeficiency
Conditions
Keywords
SCID, Transplant, Alemtuzumab, Plerixafor
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. 1. 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. 2. 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.
Interventions
DRUGTransplant Conditioning with Mobilization Only
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
DRUGTransplant Conditioning with Mobilization and Alemtuzumab
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
Sponsors
University of California, San Francisco
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 3 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment of Donor B-cells in Blood by STR Testing | 1 Year | Number of participants in whom donor B cells were detected in the patient's blood after HSCT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Acute GVHD | 100 Days | — |
| Incidence of Chronic GVHD | 2 Years | — |
| Percentage of Patients Who Become Independent From Regular IVIG Infusion | 2 Years | 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. |
| Number of Patients With Engraftment of Donor Stem Cells in Bone Marrow by STR Testing | 1 Year | We will measure whether we are able to detect donor stem cells in the patient's bone marrow after HSCT. |
| Number of Patients Who Achieve Engraftment of Donor T-cells in Blood by STR Testing | 1 Year | We will measure whether we are able to detect donor T-cells in the patient's blood after HSCT. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| T-cell Graft Permissive SCID 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
Transplant Conditioning with Mobilization Only: 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 | 7 |
| T-cell Graft Resistant SCID Patients with SCID with NK+ phenotype with HLA-mismatched donor
Transplant Conditioning with Mobilization and Alemtuzumab: 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 | 0 |
| Total | 7 |
Baseline characteristics
| Characteristic | T-cell Graft Permissive SCID | Total |
|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 0 |
| other Total, other adverse events | 0 / 7 | 0 / 0 |
| serious Total, serious adverse events | 0 / 7 | 0 / 0 |
Outcome results
Primary
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.
Time frame: 1 Year
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T-cell Graft Permissive SCID | Engraftment of Donor B-cells in Blood by STR Testing | 0 participants |
Secondary
Incidence of Acute GVHD
Time frame: 100 Days
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| T-cell Graft Permissive SCID | Incidence of Acute GVHD | 1 participants |
Secondary
Incidence of Chronic GVHD
Time frame: 2 Years
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-cell Graft Permissive SCID | Incidence of Chronic GVHD | 1 Participants |
Secondary
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.
Time frame: 1 Year
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-cell Graft Permissive SCID | Number of Patients Who Achieve Engraftment of Donor T-cells in Blood by STR Testing | 7 Participants |
Secondary
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.
Time frame: 1 Year
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-cell Graft Permissive SCID | Number of Patients With Engraftment of Donor Stem Cells in Bone Marrow by STR Testing | 0 Participants |
Secondary
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.
Time frame: 2 Years
Population: No patients with T-cell Graft Resistant SCID were enrolled during the time the trial was open.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| T-cell Graft Permissive SCID | Percentage of Patients Who Become Independent From Regular IVIG Infusion | 0 Participants |