Comprehensive Long Term Evaluation of End-Organ Function in Pediatric Patients Undergoing Matched Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease

Although early outcomes for sickle cell disease (SCD) after HCT have been well-reported, comprehensive long-term outcomes is limited.   We report the first prospective long-term follow up of pediatric patients that have undergone an HLA-identical sibling HCT for SCD at St. Jude. The median age for the 14 patients (11 SS, 2 SC and 1 Sb⁰) was 11.0±3.9 yrs. Patients received BU(500 mg/m²), CY(200 mg/kg), ATG (20 mg/kg) with CSA/MTX for GVHD prophylaxis. The median follow-up was 9.0±2.3 yrs. with OS of 93%, TRM of 7% and recurrence/graft failure of 0%. Median time to engraftment was 16±5 days. Incidence for acute and chronic GVHD was 34% and 21%, respectively. Hematologic parameters significantly improved after HCT (Hgb 7.5±1.0 to 14.1±1.5g/dl; HCT 25.5±4.7% to 42.2±5.0%). Indices of hemolysis significantly improved after HCT (retic. 0.19±0.20 to 0.06±0.12; bili. 3.0±4.6 to 0.4±0.3 mg/dl; LDH 1103±583 to 162±45 u/L; ferritin 1722±1068 to 122±613). MRI/MRA confirm previous finding that parenchymal changes continued despite normal erythropoiesis but stabilized 5 yrs. after HCT. Abnormal TCD velocities normalized after HCT (166±39 to 89±22). Comprehensive neuropsychiatric evaluations confirm stable cognitive function after HCT with no significant decrease in IQ (Full: 94±18 to 87 ±20; performance: 104±16 to 83±19; verbal 86±19 to 87±12).  Unexpectedly, 2 patients with no/low splenic function prior to HCT had evidence of splenic regeneration after HCT. Moreover, hepatomegaly resolved in all patients after HCT. Renal and cardiac function was stable with no significant decline in CrCl or SF. Patients did not have proteinuria or hematuria on UA or pulmonary hypertension on ECHO. PFTs showed stable spirometry but DLCO declined after HCT (99±6 to 77±6, p=0.02). Endocrine studies showed high risk for gonadal dysfunction. Of males, 55% had normal function, 33% were at high risk for hypogonadism and 11% developed hypogonadism requiring therapy. Of females, 50% had normal function and 50% developed ovarian failure requiring therapy.  Growth was monitored using bone age, growth velocity and IGF-1. Patients  with delayed growth (35%) were able to normalized growth by 3 yrs. after HCT if they did not have GVHD. Patients with GVHD had significant risk for continued delays. Bone density and DEXA scans showed no significant improvement in bone density and/or Z score for whole body or lumbar spine after HCT. Risk for osteoporosis or AVN were not decreased after HCT.  In summary, we show children with SCD with durable engraftment after HCT are protected from sickle-related pathophysiology with stabilization of renal, pulmonary, cardiac and CNS dysfunction.  Patients continue to be at risk for lung, bone and gonadal damage due to HCT. To better understand the risks associated with curative HCT we report one of the most comprehensive systematic prospective long-term follow up of pediatric patients that have undergone HCT for SCD.