Ibrutinib plus RICE or RVICI for relapsed/refractory mature B-cell non-Hodgkin lymphoma in children and young adults:SPARKLE trial

Part 1 results of the open-label, randomized, global phase 3 SPARKLE trial supported continued assessment of ibrutinib with either modified rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) in pediatric patients with relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). We report final results of Part 2 evaluating the efficacy of ibrutinib plus RICE or RVICI vs RICE/RVICI alone. Patients aged 1 to 30 years (initial diagnosis \u3c18 years) were randomized 2:1 to receive ibrutinib with or without RICE/RVICI. Primary endpoint was event-free survival (EFS) based on independent committee-confirmed events. Fifty-one patients were enrolled. Median age was 15 years; Burkitt lymphoma, Burkitt leukemia, and Burkitt-like lymphoma (total: 45%) and diffuse large B-cell lymphoma/primary mediastinal B-cell lymphoma (51%) were the most common subtypes. At the preplanned interim analysis, median EFS was 6.1 vs 7.0 months with ibrutinib plus RICE/RVICI vs RICE/RVICI, respectively (hazard ratio, 0.9; 90% confidence interval, 0.5-1.6; P = .387); further enrollment was ceased. With ibrutinib plus RICE/RVICI vs RICE/RVICI, median overall survival was 14.1 vs 11.1 months, overall response rate was 69% vs 81%, and 46% vs 44% proceeded to stem cell transplantation. In both treatment arms, 100% of patients experienced grade ≥3 treatment-emergent adverse events. No EFS benefit was seen with ibrutinib. Salvage was generally poor in patients who received prior rituximab, regardless of treatment arm. No new safety signals were observed. Ibrutinib exposure in pediatric patients fell within the target range of exposure in adults. Trial is registered on www.clinicaltrials.gov (NCT02703272)

Vaso-occlusive crisis as a predictor of symptomatic avascular necrosis in children with sickle cell disease

Avascular necrosis (AVN) is a chronic bone complication of sickle cell disease (SCD) resulting in significant morbidity. Understanding associated risk factors can facilitate risk-based screening, earlier identification, and prompt intervention. Between 1998 and 2014, 26 symptomatic cases with imaging evidence of AVN were compared 1:5 with age- and SCD genotype-matched controls (n = 128). Patients with 1–5 vaso-occlusive crisis (VOC) (OR 11.9, 95% CI, 1.4–99.9; P = 0.02) and more than 5 VOC (OR 53.6, 95% CI, 5.5–520.2; P = 0.0006) in a 5-year period were more likely to have AVN. Symptomatic patients with more than five VOC in 5 years may benefit from radiologic screening for AVN

Hydroxyurea Use and Hospitalization Trends in a Comprehensive Pediatric Sickle Cell Program

Background:A decline in hospitalizations and pain episodes among those with sickle cell disease (SCD) who take hydroxyurea (HU) has been shown when compared to pre-HU patterns but paradoxically, when compared to those who have never been treated, HU recipients often have more frequent hospitalizations. This analysis evaluates the impact of increasing usage of HU on trends in hospitalizations and blood transfusions within a large SCD treatment program.Methods:Eligibility was restricted to patients with Hb SS or Hb Sβ0-thalassemia who were 2-18 years old between 2006-2010 and received care at St. Jude Children\u27s Research Hospital (N = 508). Hospitalizations and blood transfusions were calculated for each of the years under study for those exposed and never exposed to HU. Differences in number of hospitalizations before and after HU initiation were compared.Results:The proportion of patients receiving HU increased by 4% per year on average. In the HU exposed group, a modest decline in mean per-patient hospitalizations and per-patient hospital days occurred, while those never exposed to HU trended toward a slight increase over time. Rates of blood transfusions declined among those on HU but not in patients never exposed to HU. Patients on HU had a median of one fewer hospital admission in the year after initiation of HU, compared to the year prior. Two deaths occurred in the patient population, both of whom were not exposed to HU.Conclusions:Increasing usage of HU was concurrent with decreased hospitalization rates and blood transfusions. Our results support the utility of HU on decreasing hospitalizations and transfusions for patients with SCD outside of the clinical trial setting. © 2013 Nottage et al

Prevalence of Vitamin D Deficiency in Sickle Cell Disease: A Systematic Review

<div><p>Vitamin D deficiency has emerged as a public health focus in recent years and patients with sickle cell disease (SCD) reportedly have a high prevalence of the condition. Our objectives were to summarize definitions of vitamin D deficiency and insufficiency used in the literature, and to determine the prevalence and magnitude of each in patients with SCD through a systematic review conducted according to PRISMA guidelines. From a PubMed search, 34 potential articles were identified and 15 met eligibility criteria for inclusion. Definitions of deficiency and insufficiency varied greatly across studies making direct comparisons difficult. This review provides evidence to suggest that suboptimal vitamin D levels are highly prevalent among those with SCD, far more so than in comparable non-SCD patients or matched control populations. Defining deficiency as vitamin D <20ng/mL, prevalence estimates in SCD populations range from 56.4% to 96.4%. When compared with results from the population-based National Health and Nutrition Examination Survey, however, the general African American population appeared to have a similarly high prevalence of vitamin D deficiency. African American patients with and without SCD were both substantially higher than that of Caucasians. What remains to be determined is whether there are adverse health effects for patients with SCD because of concurrent vitamin D deficiency.</p></div

Distance from an urban sickle cell center and its effects on routine healthcare management and rates of hospitalization

The St. Jude Childrens Research Hospital (St. Jude) comprehensive sickle cell center serves a 150 mile catchment radius around Memphis, TN, USA. Full travel expenses are provided for routine and acute care visits for sickle cell disease patients living ≥35 miles from St. Jude. We compared hospitalization rates to national estimates and assessed if driving distance was a barrier to sickle cell healthcare despite the travel reimbursement policy. We evaluated the associations between hospitalizations and routine clinic visits and distance from St. Jude using negative binomial models and we conducted bias analyses by Monte Carlo simulation. We followed 545 patients (2550 patient-years) aged ≤18 years with sickle cell disease (Hb SS only) from 2007 to 2012. The hospitalization rate per patient-year was 0.65 [95% CI (confidence interval): 0.62, 0.68), significantly lower than the national rate of 1.16 (95% CI: 1.14, 1.18). Children living \u3c35 miles from St. Jude had 1.75 (95% CI: 1.41, 2.17) times the rate of hospitalization and 1.22 (95% CI: 1.07, 1.39) times the rate of clinic visits compared to those ≥35 miles. Bias analysis suggested that under-reporting could explain the observed difference in hospitalization rates if 30.0% of patients who lived ≥35 miles from the hospital under-reported six hospitalizations over 6 years. The hospitalization rate at St. Jude in children with sickle cell disease was lower than expected from national rates. Greater distance from the sickle cell center (\u3e35 miles) was associated with decreased hospitalization rates, despite the travel allowances that are provided for those who live ≥35 miles from the hospital

PRISMA Flow Diagram.

<p>Flowchart of publications included in this systematic review.</p

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1–17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P \u3c 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI

Birth Prevalence of Sickle Cell Trait and Sickle Cell Disease in Shelby County, TN

BACKGROUND: Accurate quantification of the regional burden of sickle cell disease (SCD) is vital to allocating health-related resources. Shelby County, TN, which includes the city of Memphis and the regional pediatric SCD treatment center at St. Jude Children\u27s Research Hospital, is home to a large population of African Americans