Severe Combined Immunodeficiency
Conditions
Keywords
Severe Combined Immune Deficiency, SCID, HLA-matched unrelated donor, unrelated, MUD, bone marrow, cord blood, haplo-identical, peripheral blood, CD34+ selection, T cell depletion, HSCT, BMT, CliniMACS
Brief summary
This is a pilot clinical trial of hematopoietic stem cell transplantation for patients with a diagnosis of Severe Combined Immune Deficiency (SCID) who do not have an HLA-matched sibling donor. The stem cells will be derived from a 1) matched unrelated donor (MUD), 2) unrelated cord blood donor, or 3) a haplo-identical (parental) donor (in descending order of preference).Patients will receive a novel conditioning regimen with Busulfan, Fludarabine and Anti-thymocyte globulin (ATG) followed by an unrelated donor hematopoietic stem cell transplant (HSCT) with T-cell depletion using the CliniMACS device.
Detailed description
The study is being conducted to assess the following: * overall survival * event-free survival (events are defined as: death,non-engraftment/2nd transplant, immune reconstitution failure) * acute toxicity of the conditioning regimen * engraftment frequency immune reconstitution frequency and tempo acute and chronic graft-versus-host disease (GVHD), frequency and severity. The outcome from this protocol will be compared to the retrospective cohort consisting of all patients who have undergone haplo-identical HSCT for SCID at CHLA from 1984-2006 based on the assessment of the above-listed endpoints. The CliniMACS device will be used for CD34+ selection in place of the Isolex 300i. The CliniMACS CD34 Reagent System is an investigational medical device that has not yet been approved by the FDA. This device is used in vitro to select and enrich specific cell populations. When using the CliniMACS CD34 Reagent, the system selects CD34+ cells from heterogenous hematological cell populations for transplantation in cases where this is clinically indicated.
Interventions
BIOLOGICALunrelated BM with T cell depletion
Remaining unmanipulated bone marrow will be processed to isolate CD34+ cells (T cell depleted).
BIOLOGICALunrelated cord blood
Cord blood will be thawed (and processed if ABO incompatibility) per institutional SOP.
BIOLOGICALhaplo BM with T cell depletion
haplo-identical (parental) bone marrow will be processed for CD34+ cell isolation.
DEVICEunrelated PBSC with T cell depletion
peripheral blood stem cell will be processed for CD34+ cell isolation.
Sponsors
Neena Kapoor, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* All patients with SCID who lack a histocompatible sibling or HLA-matched related donor will be considered as candidates for this study protocol. * Eligible patients must have adequate physical function to tolerate the chemotherapy conditioning regimen and the HSCT, as measure by: 1. Renal: creatinine clearance or GFR ≥50 ml/min/1.73m2, and not requiring dialysis 2. Pulmonary: Because patients with SCID frequently present with infectious pneumonia causing ventilatory failure, patients will be considered for enrollment in the study even if respiratory failure requiring mechanical ventilatory support is present. In patients recently diagnosed with pneumonia, efforts to stabilize the respiratory status will be made prior to enrollment in the study. 3. Infectious disease status. The presence of infection per se will not be a reason for exclusion from the study. Patients with SCID are frequently infected with both routine pathogens as well as opportunistic infections. Antibiotic, antifungal and antiviral prophylaxis and therapy will be instituted as clinically indicated. Despite the use of antimicrobial therapy, the ability to control infections will not be achieved unless HSCT is performed. Therefore, subjects may be enrolled in the study, even though infection is present, because control of infection may depend on engraftment of a donor immune system. 4. Patients will be 0-21 years of age.
Exclusion criteria
* Patient with histocompatible sibling or other related donor * End-organ failure that precludes the ability to tolerate the transplant procedure, including conditioning. * Renal failure requiring dialysis * Congenital heart disease resulting in congestive heart failure * Severe CNS disease, e.g., coma or intractable seizures * Ventilatory failure due to non-infectious etiology * Major congenital anomalies that adversely affect survival, eg CNS malformations * Metabolic diseases that would affect transplant survival, eg urea cycle disorders * HIV infection Since the only chance of survival for patients with SCID is successful transplantation, all patients with SCID will be considered to be potential subjects for the study, regardless of end-organ dysfunction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Engraftment | 100 day | Engraftment is defined as recovery of blood counts (neutrophil and platelet engraftment) with cells of donor origin, documented by either bone marrow or peripheral blood chimerism assays after hematopoietic stem cell transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3 | 1 year | Absolute number of donor-derived CD3+ T lymphocytes \>/= 100/mm3 in participating subjects. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe | 100 days | Evaluation of veno-occlusive disease determined by the presence of the following features; fluid retention, weight gain, leaky capillary syndrome, painful liver enlargement, refractoriness to platelet tranfusion and hyperbilirubinemia |
| Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV | 1 year | GVHD disease surveillance done by clinical evaluation, to include history, physical examination, specifically for rash, jaundice, liver dysfunction, nausea and vomiting, diarrhea and failure to thrive. |
| Overall Survival | 1 year | Overalls survival of patient at 1 year post transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Unrelated BM With T Cell Depletion Acceptable matching for matched unrelated donor (MUD) bone marrow will be genotypic matches at 10 of 10 HLA alleles (HLA-A, B, C, DR and DQ) or 9 of 10 HLA alleles.
unrelated BM with T cell depletion: Remaining unmanipulated bone marrow will be processed to isolate CD34+ cells (T cell depleted). | 7 |
| Unrelated Cord Blood Acceptable matching for unrelated cord blood will be a genotypic match at 6 of 6 alleles (HLA A, B and DR) or 5 of 6 alleles, but not with mismatches at both alleles of a single locus (e.g. not mismatched for both HLA A alleles).
unrelated cord blood: Cord blood will be thawed (and processed if ABO incompatibility) per institutional SOP. | 2 |
| Haplo BM With T Cell Depletion If there is no unrelated donor available meeting the matching criteria for unrelated bone marrow or unrelated cord blood donors.
haplo BM with T cell depletion: haplo-identical (parental) bone marrow will be processed for CD34+ cell isolation. | 0 |
| Unrelated PBSC With T Cell Depletion The preferred source will be bone marrow, however, if a donor is unable or unwilling to donate bone marrow, peripheral blood stem cells (PBSC) will be allowed.
unrelated PBSC with T cell depletion: peripheral blood stem cell will be processed for CD34+ cell isolation. | 0 |
| Total | 9 |
Baseline characteristics
| Characteristic | Unrelated BM With T Cell Depletion | Unrelated Cord Blood | Haplo BM With T Cell Depletion | Unrelated PBSC With T Cell Depletion | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 2 Participants | 0 Participants | 0 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | — | — | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | — | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | — | — | 6 Participants |
| Race (NIH/OMB) White | 2 Participants | 0 Participants | — | — | 2 Participants |
| Region of Enrollment United States | 7 participants | 2 participants | — | — | 9 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | — | — | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | — | — | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 7 | 1 / 2 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 5 / 7 | 1 / 2 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 1 / 7 | 1 / 2 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With Engraftment
Engraftment is defined as recovery of blood counts (neutrophil and platelet engraftment) with cells of donor origin, documented by either bone marrow or peripheral blood chimerism assays after hematopoietic stem cell transplant.
Time frame: 100 day
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated BM With T Cell Depletion | Number of Participants With Engraftment | 7 Participants |
| Unrelated Cord Blood | Number of Participants With Engraftment | 2 Participants |
Secondary
Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3
Absolute number of donor-derived CD3+ T lymphocytes \>/= 100/mm3 in participating subjects.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated BM With T Cell Depletion | Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3 | 7 Participants |
| Unrelated Cord Blood | Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3 | 1 Participants |
| Haplo BM With T Cell Depletion | Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3 | 0 Participants |
| Unrelated PBSC With T Cell Depletion | Number of Participants With Donor-derived CD3+ T Lymphocytes >/= 100/mm3 | 0 Participants |
Other Pre-specified
Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV
GVHD disease surveillance done by clinical evaluation, to include history, physical examination, specifically for rash, jaundice, liver dysfunction, nausea and vomiting, diarrhea and failure to thrive.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated BM With T Cell Depletion | Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV | 1 Participants |
| Unrelated Cord Blood | Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV | 0 Participants |
| Haplo BM With T Cell Depletion | Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV | 0 Participants |
| Unrelated PBSC With T Cell Depletion | Number of Participants With Graft Versus Host Disease (GVHD) - Grade III or IV | 0 Participants |
Other Pre-specified
Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe
Evaluation of veno-occlusive disease determined by the presence of the following features; fluid retention, weight gain, leaky capillary syndrome, painful liver enlargement, refractoriness to platelet tranfusion and hyperbilirubinemia
Time frame: 100 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated BM With T Cell Depletion | Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe | 2 Participants |
| Unrelated Cord Blood | Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe | 1 Participants |
| Haplo BM With T Cell Depletion | Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe | 0 Participants |
| Unrelated PBSC With T Cell Depletion | Number of Participants With Veno-occlusive Disease (VOD) - Moderate and Severe | 0 Participants |
Other Pre-specified
Overall Survival
Overalls survival of patient at 1 year post transplant
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Unrelated BM With T Cell Depletion | Overall Survival | 6 Participants |
| Unrelated Cord Blood | Overall Survival | 1 Participants |
| Haplo BM With T Cell Depletion | Overall Survival | 0 Participants |
| Unrelated PBSC With T Cell Depletion | Overall Survival | 0 Participants |