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.
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