Sickle cell disease (SCD) is an orphan disease (75-85,000 in USA) and patients with high-risk features, including those with a history of cerebral vasculopathy and/or pulmonary and/or pulmonary vascular complications portend to have a poor prognosis with a high tendency toward serious chronic morbidities and premature death. The only curative and organ stabilizing therapy is allogeneic stem cell transplantation (AlloSCT) from unaffected HLA matched sibling donors. However, only approximately 15% of SCD patients have such donors. An alternate allogeneic donor source includes unaffected familial haploidentical (FHI) donors. The use of this donor source is limited by increased risks of GVHD and/or graft failure. However, these risks can be minimized by the use of T cell depletion (TCD) through positive selection of CD34+ hematopoietic stem cells followed by minimal T cell addback. FHI TCD AlloSCT utilizing CD34+ hematopoietic stem cell positive selection has been demonstrated to be successful in patients with high-risk hematological malignancies. Currently there is no FDA indication for this device/procedure for non-malignant diseases, such as SCD. We hypothesize that adequate host myeloimmunsuppression (MIC) followed by FHI TCD AlloSCT by positive CD34+ hematopoietic stem cell selection in patients with high-risk SCD, will be safe, result in sustained donor chimerism, prompt hematopoietic engraftment, timely donor immune reconstitution, stabilization of neurological and pulmonary function, result in overall improved health-related quality of life (HRQL) and lead to an approved FDA indication in the orphan disease, SCD. The specific objectives include (Brief): 1) to determine safety and feasibility of MIC followed by FHI TCD AlloSCT in high-risk patients with SCD;2) sustained donor whole blood and RBC chimerism;3) quality and quantity of immune cell reconstitution and function;4) changes in neurological and neurocognitive sequelae;5) differences in pulmonary and pulmonary vascular function;and 6) changes in HRQL. The methodologies include (Brief): Probability of EFS, OS, hematopoietic reconstitution and AGVHD/CGVHD by Kaplan Meier statistics; measurement of donor chimerism by STR methodology;qualitative and quantitative T, B, NK cell immune reconstitution and function by flow cytometry, intracytokine staining, detection of donor-specific HLA antibodies using micro-arrays, opsonization and cytotoxicity studies;neurovasculopathy and cognitive functioning by cerebral MRI/MRA and neurocognitive testing;pulmonary and pulmonary vascular function by pulmonary function tests, echocardiogram and Doppler;and HQRL using CHRIs-General and -HSCT questionnaires in recipients and parents. The overarching long-term objectives include determining safety and feasibility, long- term EFS and organ stability following this experimental design, assemble a multidisciplinary research team, establish and centralize critical cores and lead to an FDA approved indication in this orphan disease, SCD.

Public Health Relevance

Sickle cell disease (SCD) affects approximately 80,000 patients in the U.S. (an orphan disease) in which, high- risk populations have been identified that portend a high-risk for serious chronic morbidity and early mortality. The only curative therapy at the present time is allogeneic stem cell transplantation from unaffected tissue matched family donors. The proposed research will determine the safety and feasibility of utilizing an experimental cell depletion procedure in non-tissue matched unaffected family donors as an alternate donor source for allogeneic stem cell transplantation with the intent of disease and organ stabilization, improvement in quality of life, long-term cure and FDA approval of this experimental device/procedure for this orphan disease (SCD).

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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New York Medical College
Schools of Medicine
United States
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Talano, Julie-An; Cairo, Mitchell S (2014) Smoothing the crescent curve: sickle cell disease. Hematology Am Soc Hematol Educ Program 2014:468-74