Patients Treated for Wiskott-Aldrich Syndrome (WAS) Since 1990

Study Overview
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Brief Summary
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Wiskott - Aldrich syndrome (WAS) is a rare serious medical condition that causes problems both with the immune system and with easy bruising and bleeding. The immune abnormalities cause patients with WAS to be very susceptible to infections. Depending on the specific type of primary immune deficiency diseases, there are effective treatments, including antibiotics, cellular therapy and gene therapy, but studies of large numbers of patients are needed to determine the full range of causes, natural history, or the best methods of treatment for long term success. This multicenter study combines retrospective, prospective and cross-sectional analyses of the transplant experiences for patients with WAS who have already received HCT since 1990, or who will undergo Hematopoietic cell transplant (HCT) during the study period. The retrospective and prospective portions of the study will address the impact of a number of pre and post-transplant factors on post-transplant disease correction and ultimate benefit from HCT and the cross-sectional portion of the study will assess the benefit of HCT 2 years post-HCT in consenting surviving patients.

Official Title
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Analysis of Patients Treated for Wiskott-Aldrich Syndrome Since January 1, 1990 (RDCRN PIDTC-6904)

Conditions
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Wiskott-Aldrich Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: WAS participants will be defined as males who have: thrombocytopenia (< 100K) AND EITHER molecular diagnosis of WAS OR reduced WASP expression; OR thrombocytopenia (< 100K) AND positive family history consistent with WAS diagnosis; OR chronic thrombocytopenia (< 100K for minimum of 3 months) AND low mean platelet volume (MPV below normal range for age) AND EITHER recurrent and/or severe infections requiring treatment and/or eczema OR lack of antibody response to polysaccharide antigens or low IgM. Longitudinal Analysis (Retrospective and Prospective) Stratum A. Participants with WAS who have or will Receive HCT Participants with WAS who have received an HCT since January 1, 1990 Stratum B. Participants with WAS who have or will Receive Gene Transfer Participants in which the intention is to treat with gene transfer with autologous modified cells Cross-Sectional Analysis (Strata A and B) 1. Participants with WAS who are surviving and at least 2 years after the most recent HCT or gene therapy. Exclusion Criteria: As this is a natural history study, for both the Longitudinal Analysis and the Cross-Sectional Analysis we will not exclude any patients due to race or age who fit the inclusion criteria.
Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Retrospective Cohort (Longitudinal Analysis)<br>Participants with WAS treated at consortium centers since 1990 who have received transplant (Stratum A) or gene therapy (Stratum B) | |
| Prospective Cohort (Longitudinal Analysis)<br>Participants treated at consortium centers since 1990 who will receive transplant (Stratum A) or gene therapy (Stratum B) | |
| Cross-Sectional Cohort (Cross-sectional Analysis)<br>Living participants with WAS who have received transplant (Stratum A) or gene therapy (Stratum B) at Consortium Centers 1990-Present And >= 2 Years Post-Transplant | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longitudinal Analysis: Overall Survival From Time of HCT/Gene Therapy | The event analyzed is death from any cause. The time to this event is the time from HCT/gene therapy to death or last follow-up. | an expected average of 5 years | 
| Cross-Sectional Analysis: Proportion of Participants Achieving Full T Cell Reconstitution | Full T cell reconstitution is defined by all of the following: CD3 cell count within normal range for age. CD4 cell count within normal range for age. CD8 cell count within normal range for age Donor T cell chimerism > 95% Lymphocyte proliferation to PHA. Proliferative responses to PHA within the normal range (at or above the lower limit of normal). When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory; alternatively, the lower limit of normal controls for the day may be used | an expected average of 5 years | 
| Cross-Sectional Analysis: Proportion of Participants Achieving Full B Cell Reconstitution | Full B cell reconstitution is defined by all of the following: Quantitative immunoglobulins (IgG, IgM, and IgA) within normal range; each immunoglobulin level will be assessed separately. Serologic confirmation of post immunization tetanus titer in protective range. Serologic confirmation of post immunization pneumococcal titers in protective range (protective titers for > 50% of the serotypes contained in the vaccine) following immunization | an expected average of 5 years | 
| Cross-Sectional Analysis: Proportion of Participants Achieving Resolution of thrombocytopenia | Resolution of thrombocytopenia defined by Platelets ≥ 150,000/microliter (transfusion independent for at least 7 consecutive days) | an expected average of 5 years | 
| Cross-Sectional Analysis: Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL | Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL is defined as the first day of at least 3 different days the ANC is measured as 500 / uL or greater | an expected average of 5 years | 
| Cross-sectional Analysis: Day of Recovery of Platelet Count to 20,000 / uL | Day of Recovery of Platelet Count to 20,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 20,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day. | an expected average of 5 years | 
| Cross-sectional Analysis: Day of Recovery of Platelet Count to 50,000 / uL | Day of Recovery of Platelet Count to 50,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 50,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day. | an expected average of 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longitudinal Analysis: Proportion of Participants Achieving Hematologic Reconstitution | Hematologic Reconstitution is defined as attainment of each of the following lab test values: Hemoglobin within normal range for age WBC count within normal range for age Absolute neutrophil count (ANC) within normal range for age Platelet count ≥ 150,000/microL and without transfusion for at least 7 consecutive days | an expected average of 5 years | 
| Longitudinal Analysis: Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL | Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL is defined as the first day of at least 3 different days the ANC is measured as 500 / uL or greater. | an expected average of 5 years | 
| Longitudinal Analysis: Day of Recovery of Platelet Count to 20,000 / uL | Day of Recovery of Platelet Count to 20,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 20,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day. | an expected average of 5 years | 
| Longitudinal Analysis: Day of Recovery of Platelet Count to 50,000 / uL | Day of Recovery of Platelet Count to 50,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 50,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day. | an expected average of 5 years | 
| Longitudinal Analysis: Proportion of Participants Achieving Full T Cell Immune Reconstitution | Absolute CD3 T cell count within normal range for age Absolute CD4 T cell count within normal range for age Absolute CD8 T cell count within normal range for age Proliferative responses to PHA within the normal range (at or above the lower limit of normal). When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory; alternatively, the lower limit of normal controls for the day may be used. | an expected average of 5 years | 
| Longitudinal Analysis: Proportion of Participants Achieving Full B Cell Immune Reconstitution | Quantitative immunoglobulins (IgG, IgM, and IgA) within normal range for age; each immunoglobulin level will be assessed separately. Serologic confirmation of post immunization tetanus titer in protective range. Serologic confirmation of post immunization pneumococcal titers in protective range (protective titers for > 50% of the serotypes contained in the vaccine) following immunization. Patients who remain on IVIG will be considered not B cell reconstituted. Normalization of isohemagglutinin titers. | an expected average of 5 years | 
| Longitudinal Analysis: State of Lineage Specific Chimerism (HCT Stratum) | Peripheral blood chimerism will be assessed by FISH XX/XY, STRs, or WASP expression. | an expected average of 5 years | 
| Longitudinal Analysis: Definition of Graft Failure / Rejection | Less than 5% of donor cells in all lineages or in whole blood by 100 days post-HCT using standard PCR based or in situ hybridization techniques OR Second transplant by 100 days post-HCT (unless > 5% CD3 and purpose is to boost immune recovery). Failure to achieve ≥5% donor cells in all lineages or in whole blood by 100 days post-HCT will be defined as graft failure/rejection. Patients who receive a second transplant by day 100 will be considered graft failure. | an expected average of 5 years | 
| Longitudinal Analysis: Severe bleeding episodes | Any severe bleeding episode requiring platelet and/or RBC transfusion(s) | an expected average of 5 years | 
| Longitudinal Analysis: Malignancy | New onset or relapse of lymphoid malignancy confirmed by relevant pathologic and genetic features. | an expected average of 5 years | 
| Longitudinal Analysis: Growth | Z score of weight and height pre-HCT/gene therapy and post-HCT/gene therapy. | an expected average of 5 years | 
| Longitudinal Analysis: Incidence of Acute GVHD | The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of Grades IIIV or grades III-IV acute GVHD1 are considered events. Death is a competing risk, and patients alive without acute GVHD will be censored at the time of last follow-up. | an expected average of 5 years | 
| Longitudinal Analysis: Incidence of Chronic GVHD | Chronic GVHD will be graded as limited or extensive.2 Occurrence of symptoms in any organ system that meet the criteria of chronic GVHD will be recorded. Death is a competing risk, and patients alive without chronic GVHD will be censored at time of last follow-up. | an expected average of 5 years | 
| Longitudinal Analysis: Autoimmunity disorders | Incidence of documented autoimmunity disorders | an expected average of 5 years | 
| Longitudinal Analysis: Infections / blood borne infections | Clinical resolution of any pre-HCT opportunistic infections including but not limited to CMV, HSV1, adenovirus, EBV, and VZV. Approximate time to resolution (clinically well, off treatment, and/or negative culture/PCR assay) will be measured from the day of HCT. Incidence of documented severe (requiring hospitalization or resulting in death) and/or recurrent bacterial, viral or fungal infection post HCT. These will be reported by site of disease, organism, date of onset post HCT, and whether or not the infection resolved. Presence and resolution of severe warts (verruca vulgaris, flat warts) from the day of HCT. Whether the subject had complete resolution, partial resolution, persistent or recurrent warts will be recorded. New episodes of infections due to meningococcus, pneumococcus or hemophilus. Lymphoproliferative disease due to EBV. | an expected average of 5 years | 
| Cross-sectional Analysis: Current State of Lineage Specific Chimerism (HCT Stratum) | Peripheral blood donor chimerism will be assessed by FISH XX/XY, STR, and/or WASP expression | an expected average of 5 years | 
| Cross-sectional Analysis: Current frequency and severity of infections |  | an expected average of 5 years | 
| Cross-sectional Analysis: Current Status of Growth | Current Z score of weight and height pre-HCT/gene therapy and post-HCT/gene therapy. | an expected average of 5 years | 
| Cross-Sectional Analysis: Graft-versus-host Disease (GvHD) | Presence of chronic GVHD, current assessment; graded as limited or extensive | an expected average of 5 years | 
| Cross-Sectional Analysis: Autoimmunity Disorders | Presence of autoimmunity disorders | an expected average of 5 years | 
| Cross-sectional Analysis: Severe Bleeding Episodes | Any severe bleeding episode requiring platelet and/or RBC transfusion(s) during the previous year. | an expected average of 5 years | 
| Cross-sectional Analysis: fertility | Whether the subject has biological offspring will be recorded. | an expected average of 5 years | 
| Cross-sectional Analysis: malignancy | New onset or relapse of lymphoid malignancy confirmed by relevant pathologic and genetic features. | an expected average of 5 years | 
| Cross-sectional Analysis: Quality of Life Questionnaire | Age appropriate testing will be performed at the cross-sectional visit inpatients surviving at least two years post-transplant | an expected average of 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wiskott-Aldrich Syndrome, Hematopoietic Stem Cell Transplantation, Genetic Therapy