Functional and Radiologic Assessment of the Brain after Reduced-Intensity Unrelated Donor Transplantation for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network Study 0601

Abstract

Stroke and cognitive decline are hallmarks of sickle cell disease (SCD). The natural history of SCD predicts progressive loss of 1 IQ point per year attributable to disease-related pathology. Hematopoietic cell transplantation (HCT) is curative by reverting to donor-derived erythropoiesis, but evidence that HCT can positively influence diseaseinduced cognitive decline is lacking. The Sickle Cell Unrelated Transplant Trial prospectively evaluated cognition and brain magnetic resonance imaging (MRI) findings at 2 years after reduced-intensity conditioning followed by unrelated donor HCT. Thirteen study participants completed pre-HCT and post-HCT assessments of intelligence. The mean age of participants was 12.5 § 3.3 years (range, 6.7 to 17.4 years). Eleven of the 13 recipients completed imaging studies at baseline and post-HCT. Seven had overt stroke pre-HCT, and 1 had an elevated transcranial Doppler velocity with abnormal MRI. The mean Full-Scale IQ was stable: 90.9 § 13 at baseline and 91.2 § 13 post-HCT. The mean Performance IQ was 89.9 § 13 at baseline versus 90.9 § 13 post-HCT, and mean Verbal IQ was 93.4 § 13 at baseline versus 93.2 § 13 post-HCT, respectively. Six recipients had stable MRI; 2 showed resolution of all areas of infarction. Three had additional infarcts post-HCT noted at the 2-year time point. This is the first report describing stabilization of IQ and central nervous system outcomes after unrelated donor HCT despite previous central nervous system morbidity and post-HCT posterior reversible encephalopathy syndrome. These preliminary results post-HCT suggest that HCT may stabilize the cognitive decline of SCD and should continue to be followed over the long term.

Why, Who, When, and How? Rationale for Considering Allogeneic Stem Cell Transplantation in Children with Sickle Cell Disease

“…In the Baby-Hug trial comparing hydroxyurea to placebo, no difference was found between groups and only a trend toward better cognitive performances was reported in those on hydroxyurea with baseline severe anemia [99]. Following SCT, stabilization with age of cognitive performances has been found [100], but the DREPAGREFFE trial comparing chronic transfusion to HSCT in children with abnormal-TCD history did not find any significant difference in cognitive performances between both groups at the 1 and 3-year follow-up. However, a significantly higher progression of the processing speed index was seen in the transplantation group from 1 to 3 years : 6.1 (12.9) vs. −3.1 (10.5) in the standard-care group, p = 0.02 [80].…”

Improvement in processing speed following haploidentical bone marrow transplant with posttransplant cytoxan in children and adolescents with sickle cell disease

“…Three published studies to date have assessed the effect of bone marrow transplantation (BMT) on cognition in SCD, and findings show that full-scale IQ remained stable after transplant. [3][4][5] King et al also found that verbal IQ and performance IQ also remain stable. However, these findings are based on very small samples, and replication is necessary across multiple domains of cognition including various transplant approaches.…”

“…Few studies have investigated whether therapeutic interventions to prevent cerebral infarction impact progressive neurocognitive benefits in individuals with SCD. Three published studies to date have assessed the effect of bone marrow transplantation (BMT) on cognition in SCD, and findings show that full‐scale IQ remained stable after transplant . King et al also found that verbal IQ and performance IQ also remain stable.…”

Hematopoietic Cell Transplantation for Sickle Cell Disease

“…Patients with severe cerebral vasculopathy or moyamoya disease may be considered for encephaloduroarteriosynangiosis (51). Cerebral blood flow velocity determined by transcranial Doppler velocity (age <16 years) and neurocognitive function may stabilize or improve posttransplant (52) and may be evaluated pre-HCT. Transfusional hemosiderosis and its effect are examined by the quantification of the liver and cardiac iron.…”

“…In more recent series, reduced toxicity/intensity (10,13,81) and NMA (18,20,67,103) conditioning regimens have been demonstrated to be safe and effective in ameliorating SCD clinical manifestations (10,13,81). Following HCT, the transcranial Doppler velocity returns to normal; there is a stabilization of organ function, stabilization of full-scale IQ, improved healthrelated QoL (HRQoL), decreased prescriptions of opioid pain medications, and improvement in splenic function (11,13,14,52,55,(104)(105)(106)(107). Adult patients followed in the 2nd year after a successful HCT for SCD, as compared to pre-HCT, and as compared to a group of SCD patients who had not undergone HCT, had significantly lower rates of healthcare utilization and healthcare costs (108).…”