The goals of Project 4 (PIDTC Protocol 6904) are to identify key clinical factors and biologic markers that predict the outcome of children undergoing hematopoietic cell transplantation (HCT) for Wiskott-Aldrich Syndrome (WAS), and provide a comprehensive assessment ofthe long term outcomes, late effects, and quality of life (QoL) in these children. While the potenfial benefits of HCT in WAS are clear the opfimal conditioning regimens are not known and the minimal levels of lineage-specific donor chimerism necessary for disease correction remain to be defined. At present, there are little data on long-term immune and hematologic status and even less informafion regarding late effects and QoL post-HCT. In addifion, autoimmunity has been frequently observed after HCT, especially in pafients with mixed chimerism. However, the molecular mechanisms involved remain pooriy defined. The PIDTC provides a unique opportunity to bring together data from the vast majority of centers in North America with expertise in treating this rare disease. The standardized compilation of results after HCT for this pafient populafion will permit a comprehensive analysis of mulfiple outcomes.
The Specific Aims of Project 4 are to: 1) Characterize the biologic factors that determine survival, immune reconstitution, and long term outcomes in WAS. We will perform a detailed retrospective, cross-sectional, and prospective analysis of outcomes after HCT. Survival factors to be assessed in a multi-factorial analysis include HLA matching, donor type and source, cell dose, age, clinical status at HCT and condifioning regimen. Post-HCT factors will include acute and chronic GVHD and lineage-specific chimerism. We will also evaluate hematologic and immunologic reconstitufion, QoL and late effects following HCT. In addifion, we will evaluate the minimum level of multilineage donor engraftment required for disease correcfion including: the level of myeloid (and/or circulafing peripheral blood CD34+ cell) chimerism required to restore normal platelet numbers;and the level of lymphoid (B cell and T cell) chimerism required to restore T cell and B cell numbers and funcfion, prevent severe infecfions, and eliminate autoimmune manifestations and allergic complicafions. 2) Identify biomarkers that may predict the development of autoimmunity post-HCT. We will determine whether development of autoimmune disease post-HCT: 1) Correlates with skewed B (or myeloid) vs. T cell donor chimerism;2) Correlates with serum BAFF or APRIL levels;and 3) Is preceded by B cell activation, rising serum autoanfibodies, and/or an altered B and T cell repertoire.

Public Health Relevance

Overall, Project 4 will provide a comprehensive assessment of outcomes in patients with WAS. This longitudinal, retrospective and cross-sectional study is anticipated to identify new rationales for the design of future multi-center prospective clinical trials leading to optimal outcomes.

National Institute of Health (NIH)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1)
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University of California San Francisco
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