Sickle cell disease (SCD) is a hereditary hemoglobinopathy that affects over 100,000 people in the United States. Patients with SCD are known to experience suboptimal health-related quality of life (HRQoL). In addition to the physical manifestations of SCD, psychological and social stress, along with academic difficulties, secondary to the chronicity of the disease and its complications often affect patients with SCD. Although medical therapy of SCD has improved, allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapy. The objective of this study was to measure HRQoL before and after allo-HCT by assessing physical, psychological, and social functioning in patients with SCD who have undergone reduced-toxicity conditioning (busulfan/fludarabine/alemtuzumab) followed by allo-HCT. Patients < 21 years of age undergoing allo-HCT (matched siblings and unrelated donors) for SCD and their primary caregiver were enrolled using either the English or Spanish version of the PedsQoL 4.0. Data were collected at 3 time points: before allo-HCT and on days 180 and 365 after allo-HCT. The change in HRQoL from baseline was assessed with unadjusted and adjusted mixed-effects models in which subjects were treated as random effects, and variance component structure was used. Seventeen patients and 23 primary caregivers were enrolled and reported a mean overall HRQoL of 66.05 (SD, 15.62) and 72.20 (SD, 15.50) at baseline, respectively. In the patient-reported analysis with adjusted mixed-effects models, the estimated improvements in overall HRQoL were 4.45 (SE, 4.98; P = .380) and 16.58 (SE, 5.06; P = .003) at 180 and 365 days, respectively, after allo-HCT. For parent-reported overall HRQoL, the estimated improvements were 1.57 (SE, 4.82; P = .747) and 9.28 (SE, 4.62; P = .053) at 180 and 365 days, respectively, after allo-HCT. Similar results were found across the physical, social, and emotional HRQoL domains with mixed-effects models after adjustment of demographic and medical variables. In addition to the alleviation of clinical manifestations of SCD, these patients demonstrated significant improvement in most aspects of HRQoL by 1 year after allo-HCT. These data represent the trajectory of HRQoL during the initial year of follow-up within this population and should be integrated into the decision-making process when considering allo-HCT in patients with SCD.

Purpose Using standard screening techniques, sickle retinopathy reportedly occurs in 10% of adolescents with sickle cell disease (SCD). We performed a prospective, observational clinical study to determine if ultra-widefield fluorescein angiography (UWFA), spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCT-A) detect more frequent retinopathy in adolescents with SCD. Design Cross-sectional study. Methods Setting Institutional. Subjects Sixteen adolescents with SCD, ages 10–19 years, (mean age 14.9 years) and 5 age-equivalent controls (mean age 17.4 years). Observation Procedures Examinations including acuity, standard slit-lamp biomicroscopy, UWFA, SD-OCT and OCT-A were performed. Main Outcome Measures Sickle retinopathy defined by biomicroscopic changes, Goldberg stages I–V, Penman scale, flow void on OCT-A, or macular thinning on SD-OCT. Results While 22/32 SCD eyes (68.8%) had retinopathy on biomicroscopy, by UWFA 4/24 (16.7%) SCD eyes had peripheral arterial occlusion (Goldberg I), and 20/24 eyes (83.3%) had peripheral arteriovenous anastomoses (Goldberg II) in addition. No patients had Goldberg stages III–V. By SD-OCT and OCT-A, thinning of the macula and flow voids in both the superficial and deep retinal capillary plexus were found in 6/30 (20%) eyes. Conclusions All 24 eyes with adequate UWFA studies demonstrated sickle retinopathy. SD-OCT and OCT-A, which have not been previously reported in the adolescent population, detected abnormal macular thinning and flow abnormalities undetected by biomicroscopy. These findings suggest that pediatric sickle retinopathy may be more prevalent than previously suspected. If these findings are confirmed with larger cross-sectional and prospective analyses, these approaches may enhance early screening for sickle retinopathy.

Progressive neurovasculopathy in children with sickle cell disease (SCD) results in decreased cognitive function and quality of life (QoL). Hematopoietic cell transplantation (HCT) is believed to halt progression of neurovasculopathy. Quantitative analysis of T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) for white matter hyperintensity (WMH) burden provides a meaningful estimate of small vessel cerebrovascular disease. We asked if quantitative analysis of WMH could complement standardized clinical assessment of MRI/magnetic resonance angiography (MRA) for assessing SCD central nervous system vasculopathy before and after HCT. Retrospective longitudinal clinical examination of scheduled annual MRI/MRA and quantitative analysis of WMH were performed before and 1 to 7 years after HCT at scheduled annual intervals, along with QoL measurements, in children who had engrafted after HCT. Of 18 patients alive and persistently engrafted (median age, 9.1 years), pretransplantation MRI demonstrated that 9 and 5 had sickle-related stroke and/or small infarcts, respectively. Patients were divided into WMH severity tertiles based on pretransplantation WMH volumes. MRI and WMH were assessed 1 to 7 years after HCT. MRI/MRA and WMH volume were stable or slightly better in 17 of 18 patients. By parent- and self-report, post-HCT QoL improved for children in the lowest WMH tertile significantly more than in the other groups. Based on this single-institution retrospective sample, we report that WMH appears to quantitatively support MRI-based findings that HCT stabilizes long-term small and large vessel cerebrovascular changes and is associated with the degree of improved QoL. While confirmation in larger prospective studies and evaluation by neurocognitive testing are needed, these findings suggest that WMH is a useful biomarker of neurovasculopathy after transplantation for SCD.

To ensure optimal clinical outcomes for patients while retaining adequate protection for donors, the National Marrow Donor Program developed guidelines specifying that up to 20 mL/kg of bone marrow can be harvested from donors. These guidelines, originally developed for unrelated adult donors, are followed in children as well. We studied the impact of granulocyte colony-stimulating factor (G-CSF) priming on the cellular composition of harvested bone marrow, sought to develop an algorithm to optimize bone marrow harvest volume from pediatric matched sibling donors, and studied the impact of CD34 cell dose on clinical outcomes. We analyzed data from 92 bone marrow harvests and clinical outcomes for 69 sibling recipient-donor duos, The mean age of recipients was 9.85 ± 5.90 years, and that of donors was 11.85 ± 6.36 years. G-CSF priming was not associated with higher yield of CD34 cells/µL. The median CD34 cell count obtained from donors was 700 cells/µL (range, 400-1700 cells/µL) in donors age <6 years, 360 cells/µL (range, 100-1100 cells/µL) in donors age 6 to 12 years, and 300 cells/µL (range, 80-800 cells/µL) in donors age >12 years (P < .001). The number of CD34 cells infused had no impact on traditional clinical outcomes; however, it was significantly related to graft-versus-host disease/relapse/rejection-free survival. Our investigation revealed that ultimately, a CD34 cell count of approximately 3 to 5 × 10/kg was a threshold beyond which increasing CD34 cell dose did not impact outcome. In this study, we addressed the broad question of whether harvesting up to 20 mL/kg of bone marrow from a child donor is truly necessary for optimal outcomes in every pediatric case.

Methods: Pediatric patients (<21 years old, n¼34) on a research protocol between 4/2006 and 6/2014 receiving myeloablative conditioning (FLU/CY/13.2 Gy TBI) with or without expanded CB HSPC (fresh or cryopreserved) were included. Duration of initial hospitalization, use of opiate pain medications (by continuous infusion or PCA), and use of TPN were determined for each patient. All blood stream infections occurring during initial hospitalization were also recorded. Statistical comparisons between groups were made with two-tailed, unpaired t-tests. Results: 11 patients received expanded CB HSPC in addition to 1-2 unmanipulated CB units while a concurrent cohort of 23 patients received the same conditioning regimen without expanded cell infusion. The mean time to neutrophil count of 500/ml was 16.5 v. 22.1 days in patients receiving expanded cells or not, respectively (p¼0.026). The mean duration of initial hospitalization was 43.2 v. 55.6 days (p¼0.05) (Fig. 1), mean duration for continuous opiate medications 9.7 v. 18.1 days (p¼0.07), and mean time receiving TPN was 20.7 v. 30.1 days (p¼0.06) (Fig. 2). Although not statistically significant, bacterial blood stream infections were identified during their initial hospitalization in 3 patients receiving expanded CB HSPC compared to 10 in the standard treatment group. Conclusions: In addition to reduce time to ANC recovery, these results suggest that administration of expanded CB HSPC may significantly reduce initial hospitalization and may also reduce utilization of pain medications and nutritional support in the pediatric population receiving CBT. Thus, this cellular therapy has the potential to decrease the risk of morbidity and mortality post-CBT by reducing regimen related toxicities that directly result from delayed hematopoietic recovery.

No abstract

Introduction: Sickle cell retinopathy (SCR) reflects disease-related vascular injury. Previous studies of pediatric SCR using standard imaging approaches reported retinopathy in <15% of children (Estepp JH, Br J Haematol 161:402;2013). Sensitive clinical retinal imaging modalities of ultra-widefield fluorescein angiography (UWFA), spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCT-A) may better characterize early retinal changes in pediatric SCR. Fluorescein angiography detects retinopathy through dynamic visualization of retinal blood flow. UWFA captures up to twice as much retinal area as conventional fluorescein angiography and is more sensitive in identifying peripheral vascular changes in SCR (Friberg TR, Ophthalmic Surg Lasers Imaging 39:304;2008). SD- OCT and OCT-A utilize reflected light to produce detailed cross-sectional images of the retina and allow visualization of blood flow in retinal layers. To our knowledge, this is the first case series using these technologies in pediatric SCR. Methods: A consecutive series of children with sickle cell disease (SCD) of any phenotype, ages 10-19 years, accepting enrollment are described. Examinations including acuity, standard slit-lamp examination (biomicroscopy), UWFA, SD- OCT and OCT-A were performed according to standard acquisition protocols. Testing is non-invasive except fluorescein angiography, which requires a small volume of intravenous dye. Results: Eight children (mean age 16.3 years; 5 HbSS, 2 HbSC,1 HbS-Beta thalassemia0) were evaluated. Three were on hydroxyurea therapy, 1 on chronic transfusion, 1 on both and 3 on no therapy. No patient had vision disturbance at the time of examination. Biomicroscopic examination revealed sunburst lesions in the mid-peripheral retina in 3 patients and subtle vascular changes in the far periphery of all patients. In contrast, UWFA detected extensive capillary non- perfusion of the peripheral retina with abnormal vascular loops (Goldberg Stage I) in all 8 patients; 3 patients had peripheral arteriovenous anastomoses (Goldberg Stage II) that were undetectable by biomicroscopy. No patient had Goldberg Stages III-V. SD-OCT demonstrated thinning of the temporal macula in 2 patients, and OCT-A of both patients revealed flow voids in both the superficial and deep retinal capillary plexus in the area of thinned retina. Both the SD- OCT and OCT-A abnormalities were undetectable with standard biomicroscopy. Conclusions: All 8 children with SCD in this case series demonstrated evidence of SCR using the combination of standard biomicroscopy, UWFA, SD-OCT, and OCT-A imaging. Findings from these sensitive imaging modalities suggest that pediatric SCR is more prevalent than previously suspected. Additional patients and age-equivalent controls will be included in this report to validate the specificity of findings to SCD. Larger cross-sectional and prospective analyses using sensitive retina imaging are needed to confirm our findings and identify their significance for detecting pathology. If confirmed, these approaches may enhance early screening for patients at risk of vision-threatening consequences of SCR. Supported by the Irving Institute CTSA at CUMC and by 2T35HL007616 (DP). Retinal findings in pediatric sickle cell disease patients SD-OCT: Spectral-domain optical coherence tomography; OCT-A: Optical coherence tomography angiography; UWFA: Ultra-widefield fluorescein angiography. Retinal findings in pediatric sickle cell disease patients. / SD-OCT: Spectral-domain optical coherence tomography; OCT-A: Optical coherence tomography angiography; UWFA: Ultra-widefield fluorescein angiography. Disclosures No relevant conflicts of interest to declare.

Introduction: Sickle cell disease (SCD) CNS vasculopathy (SCNSV) is a frequent indication for hematopoietic stem cell transplantation (HSCT). Untreated, SCNSV can be progressive and impair quality of life (QoL) and cognitive functioning. By clinical MRI/MRA assessment, HSCT is thought to halt progression of SCNSV. Quantitative analysis of T2-weighted FLAIR MRI for white matter hyperintensity (WMH) can provide a meaningful estimate of small vessel cerebrovascular burden. Adding WMH assessment, we asked whether HSCT for SCD halted long-term progression of SCNSV, including small vessel involvement, despite transplant-associated CNS risks. QoL assessment can track school functioning and physical, emotional and social functioning. Methods: This retrospective single site study compared MRI analyses pre-transplant to 1-7-years post-HSCT. Subject eligibility required availability of clinical MRI scans from within 2 months pre-HSCT and at 1-year intervals for at least one year post-HSCT. Interim scans performed for acute clinical indications were not included in the analysis. MRI scans were evaluated independent to the initial clinical read by one neuroradiologist, and via in-house developed software to quantitate WMH burden. QoL was completed by parent- and child-report pre-HSCT and annually thereafter using the Peds QL 4.0TM with scores 0-100; higher numbers reflected higher QoL. Results: 25 patients who received HSCT for SCD between 2003-2014 were evaluated. Median age at HSCT was 9.9 years (1.4-21.9); male:female 18:7; HbSS (17), HbSC (3), HbS-Bthalassemia (5). Donors were related (14) or unrelated (11). Stem cell sources were: related bone marrow (BM) (10), unrelated BM (5), related cord blood (CB) (3), unrelated CB (6), or related peripheral blood stem cells (1). Eight patients had CNS pathology as the indication for HSCT. Transplant complications were: PRES (2), stroke (1), graft failure (2), death (1). Duration of follow-up was: 1 yr (9), 2 yrs (10), >2 yrs (6). Only a minority of patients had normal pre-HSCT MRI (5) and normal MRA (11; 6 had 1-2 stenoses <2mm and were rated as ambiguous). At 1 to 7 yrs post-HSCT, 5 originally normal MRIs were unchanged, 15 MRIs were stable and 4 were improved at 1 year post-HSCT, without subsequent changes by clinical assessment. One MRI worsened due to peri-HSCT hemorrhagic stroke. MRAs were unchanged following HSCT. Preliminary analysis of 18 patients at pre-HSCT revealed that 5 did not have elevated WMH, while elevated WMH was detected in 13 patients. WMH remained stable in 16 of 18 patients over subsequent annual assessments. In the 2 patients with markedly elevated WMH pre-HSCT, values decreased at follow-up, corresponding to the resolution of acute or recent infarction. Overall pre-HSCT QoL by parent-report (N=19) was 65.3 (SD16.3); while child self-report (N=14) was 67.6, (SD13.1). After mean follow-up of 3 years, parent-report QoL improved to 78.8 (SD15.8), and self-report to 78.7 (SD15.2). Conclusions: Most children in this retrospective cohort had MRI abnormalities pre-HSCT, and all but 1 were stable or improved post-HSCT, despite PRES and other potential CNS complications. Pre-HSCT WMH appeared to be unchanged for most of these patients, while stroke-induced WMH appears to decrease over time, suggesting stable small vessel SCNSV following transplantation. Overall, by MRI/MRA and by preliminary WMH, HSCT appears to have stabilized large and small vessel SCNSV in all but 1 of 25 children. While only a modest number of patients were assessed, WMH was reproducible at multiple annual time points. Long-term parent and self-reported QoL indicated improvement from HSCT. Chronically transfused SCD patients could not be compared due to lack of annualized assessment. Future transplant protocols will include enhanced MRI-based tracking, in conjunction with QoL and neuropsychological assessments. These data could be useful for decision-making about SCD transplantation. Disclosures No relevant conflicts of interest to declare.