Patients Treated for SCID (1968-Present)

Study Overview
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Brief Summary
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Individuals with a past diagnosis of severe combined immune deficiency (including many cases of leaky SCID, Omenn syndrome, and reticular dysgenesis) who have undergone blood and marrow transplant, gene therapy, or enzyme replacement in the past may be eligible for this study. The purpose of study is to look backwards at what has already been done in the. Over 800 patients with SCID are expected to be enrolled, making this one of the largest studies ever to describe outcomes for patients with SCID treated at many different hospitals around North America.

Detailed Description
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One of the most important components of this study is the cross sectional aspect. Patients who have received their treatments (BMT, gene therapy, enzyme replacement) many years ago are asked to come back to the hospital where they were treated. During this visit, additional research bloodwork is drawn, and information is gathered regarding long-term transplant outcomes such as infections, graft-versus-host disease, autoimmune diseases, and quality of life. This will allow PIDTC researchers to better understand long-term outcomes from procedures that occurred many years ago (sometimes over 30 years ago). This will help researchers to best design new treatments and clinical trials in the future for children with SCID.

Official Title
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A Retrospective and Cross-Sectional Analysis of Patients Treated for SCID Since January 1,1968 (RDCRN PIDTC-6902)

Conditions
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SCID, ADA-SCID, XSCID, Leaky SCID, Omenn Syndrome, Reticular Dysgenesis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Strata A, B, and C (Part 1 - Retrospective Study)- Individuals with Severe Combined Immune Deficiency (SCID) diagnosis who: --were treated at a location participating in this consortium from 1968 until present, and --are not enrolled in RDCRN PIDTC-6901 (ClinicalTrials.gov ID: NCT01186913). Subjects who received HCT/GT/ERT prior to the present date are eligible for the retrospective study. The enrollment criteria for subjects who died prior to definitive therapy are the same as for Strata A, B and C. Stratum A, Typical SCID: Individuals who meet the following inclusion criteria and who received HCT are eligible for enrollment into Stratum A of the study: Absence or very low number of T cells (CD3 T cells < 300/microliter), and no or very low T cell function (< 10% of lower limit of normal) as measured by response to phytohemagglutinin (PHA) or cells of maternal origin present. If maternal cells are present but the patient does not meet criteria for very low T cell function as defined, the assigned reviewers for the potential subject, and if necessary, the full PID-SCID RP will review the laboratory report to determine if criteria of maternal engraftment are met for Protocol 6902. Laboratory report of testing for maternal engraftment is required, for evaluation by the PID-SCID RP. Stratum B, Leaky SCID, Omenn Syndrome, Reticular Dysgenesis: Individuals who meet the following criteria are eligible for enrollment into Stratum B of the study: Leaky SCID- Maternal lymphocytes tested for and not detected and, Either one or both of the following (a,b): a) < 50% of lower limit of normal T cell function (as measured by response to PHA OR < 50% of lower limit of normal T cell function as measured by response to CD3/CD28 antibody, b) Absent or < 30% lower limit of normal proliferative responses to candida and tetanus toxoid antigens postvaccination or exposure, AND at least one of the following (a through e): Reduced number of CD3 T cells, > 80% of CD3+ or CD4 T cells are CD45RO+, AND/OR >80% of CD3+ or CD4+ T cells are,CD62L negative, AND/OR >50% of CD3+ or CD4+ T cells express HLA-DR (at < 4 years of age), AND/OR are oligoclonal T cells. c) Hypomorphic mutation in IL2RG in a male, or homozygous hypomorphic mutation or compound heterozygosity with at least one hypomorphic mutation in an autosomal SCID-causing gene. d) Low TRECs and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower limit of normal. e) Functional testing in vitro supporting impaired, but not absent, activity of the mutant protein, AND does not meet criteria for Omenn Syndrome, AND does not have known selective loss of lymphocytes, Ataxia- Telangiectasia, or congenital heart defect associated with lymphopenia, unless a SCID genotype is also present. Omenn Syndrome (OS): Generalized skin rash, Maternal engraftment tested for and not detected, Absent or low (up to 30% of normal) T cell proliferation to antigens to which the patient has been exposed. If the proliferation to antigen was not performed, but at least 4 of the following 10 supportive criteria, at least one of which must be among those marked with an asterisk (*) are present, the patient is eligible: hepatomegaly; splenomegaly; lymphadenopathy; elevated IgE; elevated absolute eosinophil count; *oligoclonal T cells measured by CDR3 length or flow cytometry >80% of CD4+ T cells are CD45RO+ ;*proliferation to PHA is reduced <50% of lower limit of normal or SI <30; *proliferative response in mixed leukocyte reaction is reduced to increment cpm < 20% or SI <20; hypomorphic mutation to SCID causing gene; low TRECs and/or percentage of CD 4+/ RA+/CD31+; or CD4+/RA+/CD62L+ cells below the lower limit of normal. Reticular Dysgenesis (RD): Absence or very low number of T cells (CD3 T cells <300/microliter), No or very low (<10% of lower limit of normal) T cell function (as measured by response to phytohemagglutinin (PHA), Severe congenital neutropenia (absolute neutrophil count <200/microliter), AND at least one of the following: Sensorineural deafness and/or absence of granulopoiesis at bone marrow examination and/or a deleterious AK2 mutation, absence of granulopoiesis on bone marrow examination; a pathogenic mutation in the adenylate kinase 2 (AK2) gene identified. Stratum C, SCID with Non-HCT Treatments: -Individuals who meet the following criteria and were treated with PEG-ADA or gene therapy with autologous modified cells are eligible for enrollment into Stratum C (SCID with non-HCT treatments) of the study- - Any SCID patient previously treated with a thymus transplant (includes intention to treat with HCT, as well as PEG-ADA ERT or gene therapy). Strata A, B, and C (Part 2 - Cross-Sectional Study): Patient inclusion criteria for the cross sectional study: Eligibility for Strata A, B and C are the same as for the retrospective study except that all the patients in the cross-sectional study are currently surviving and are at least 2 years post the most recent class of therapy. Exclusion Criteria: Parts 1 and 2 - Retrospective and Cross-Sectional Studies - Lack of appropriate testing to rule out HIV infection after 1997 (p24 antigen or more sensitive) or other cause of secondary immunodeficiency, Presence of DiGeorge syndrome, Most patients with other PIDs such as nucleoside phosphorylase deficiency, ZAP70 deficiency, CD40 ligand deficiency, NEMO deficiency, XLP, cartilage hair hypoplasia or ataxia telangiectasia will not meet the inclusion criteria for Stratum A, B, or C above; however, a patient with one of the above may meet the inclusion criteria for Stratum B and if so will be included- MHC Class I and MHC Class II antigen deficiency are excluded, Metabolic conditions that imitate SCID or related disorders such as folate transporter deficiency, severe zinc deficiency, transcobalamin deficiency.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Stratum A -Typical SCID<br>Typical Severe Combined Immunodeficiency (SCID), Adenosine Deaminase-Deficient ADA SCID, and X-linked SCID (XSCID) who received a transplant | |
| Stratum B - Atypical SCID<br>Leaky SCID, Omenn Syndrome, and Reticular Dysgenesis who received a transplant | |
| Stratum C - SCID w/Non-HCT Treatments<br>SCID who received Polyethylene Glycol -Adenosine Deaminase Enzyme Replacement Therapy (PEG-ADA ERT) or gene therapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retrospective Study - Part 1 | Overall survival | 1, 5, 10, 20, >20 years | 
| Cross-Sectional Study - Part 2 | Full immune reconstitution | 2 to > 20 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retrospective Study Part 1 | Immune reconstitution and clinical outcomes | 1 year to > 20 years | 
| Retrospective Study - Part 1 | Engraftment | 3 months to >20 years | 
| Cross-Sectional Study - Part 2 | Current state of lineage-specific chimerism | 2 to >20 years | 
| Cross-Sectional Study - Part 2 | Current status of health | 2 to >20 years |