Stable to Improved Neurocognitive Outcomes in Children, Adolescents & Young Adults with High-Risk Sickle Cell Disease (SCD) Who Have Undergone Familial Haploidentical (FHI) Stem Cell Transplantation: A Prospective Study from Pre HSCT Period to 2 Years Post HSCT (IND 14359)

Introduction The cognitive and neurological impairments associated with SCD that are due to cerebral vascular injury have been well documented (DeBaun et al, Blood, 2012). Brain abnormalities are evident on neuroimaging and cognitive domains in the areas of attention, memory, processing speed, executive functioning, and lower general intellectual functioning. Processing speed in particular is a vulnerable domain, with deficits mediating difficulties across other domains and is independently decreased in SCD patients unrelated to overt or silent infarctions (Stotesbury et al, Neurology, 2018). Van der Land et al suggests that there is a relationship between white matter tissue integrity and cognitive morbidity in SCD patients (British Journal of Hematology, 2015). Previous studies following reduced toxicity conditioning and matched sibling BMT in patients with SCD have demonstrated stable to improved CNS functioning (Walters et al, 2010, Biol BMT; Bhatia et al, BMT, 2014). Objectives We aimed to determine changes in neuroimaging and neurocognitive sequelae in individuals with high-risk SCD prior to and following myeloimmunoablative conditioning (MIAC) and FHI AlloSCT utilizing CD34 enrichment and T cell addback. Methods Haploidentical stem cell transplant with MIAC with CD34 enrichment was performed as previously described by Cairo et al (JAMA Peds, 2019). Participants had a baseline, 1 year and 2 year MRI that were reviewed by blinded central neuroimaging, neurocognitive screener (DIVERGT, Krull, et al) and an abbreviated, standardized neurocognitive test battery (IQ, memory, attention, language, motor, processing speed) over three time points (baseline, Day +365 and Day +730). Neurocognitive domain scores were calculated for each area of functioning in patients at each timepoint. Results Nineteen SCD patients were enrolled and received transplant (12 males, 7 females, mean age, 13.5, range 3-21). At baseline, seven patients had evidence of an overt stroke and four patients had evidence of a silent infarct. At 1 and 2 years post-transplant, there were no new overt and/or silent infarcts, and no new cerebral vasculopathy. Intellectual functioning, memory, language and attention/executive function remained stable to improved at year one and two, respectively (Table 1). Most importantly, processing speed was significantly improved at 2 years versus baseline (p Conclusions These preliminary studies suggest that MIAC followed by FHI AlloSCT utilizing CD34 enrichment and CD3 addback is protective against further CNS injury. Early HSCT has the potential to decrease or prevent cognitive decline and even improve neurocognitive functioning in high risk SCD recipients (supported by R01FD004090).