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.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood.

BACKGROUND: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children's Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. PROCEDURES: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. RESULTS: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7-30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0 -thalassemia, 25.7% HbSC, 8.4% HbsB+ -Thalassemia, 1.7% HbS/HPFH, and 1.2% other. CONCLUSIONS: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD.

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 < 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's Research Hospital, is home to a large population of African Americans. PROCEDURE: We postulated that the regional birth prevalence of SCD in Shelby County, TN, would differ from national rates. Using data from 2002 to 2012, we estimated the birth prevalence of SCD and sickle cell trait (SCT) in Shelby County and evaluated the distribution of SCD cases by ZIP code of residence with geographic information systems (GIS). RESULTS: The prevalence of SCD in African Americans was 1/287 (95% confidence interval [CI]: 1/323, 1/256) live births, significantly higher than the nationally reported 1/350 -1/500. The prevalence of SCT in African Americans was 1/14.7 (95% CI: 1/15.0, 1/14.3) live births, significantly lower than the nationally reported 1/12. We found that 48% of the SCD cases resided in only six of the 37 residential ZIP codes, and using GIS mapping there were two clusters composed of two and four adjacent urban ZIP codes. SCT cases were also centered predominantly in the same two clusters, but slightly more dispersed. CONCLUSIONS: Recent Shelby County birth prevalence estimates differ substantially from national estimates with higher SCD and lower SCT than expected. Preliminary evidence suggests substantial clustering in two small geographic urban areas within Shelby County that may provide target areas for educational and outreach services.

Addressing challenges of clinical trials in acute pain: The Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study.

BACKGROUND/AIMS: Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. METHODS: In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. RESULTS: In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. LESSONS LEARNED: Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. CONCLUSION: This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies.

Distance from an Urban Sickle Cell Center and its Effects on Routine Healthcare Management and Rates of Hospitalization.

The St. Jude Children's 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 5 35 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 (4 35 miles) was associated with decreased hospitalization rates, despite the travel allowances that are provided for those who live 35 miles from the hospital.

Paroxysmal cold hemoglobinuria due to an IgA Donath-Landsteiner antibody.

Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath-Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described.

Severe Autoimmune Hemolytic Anemia in an Infant Caused by Warm-reactive IGM and IGA Autoantibodies: A Case Report and Review of the Literature.

Warm-reactive IgM autoimmune hemolytic anemia is uncommon and carries a poor prognosis in adults. There have been rare reports in children, generally associated with an underlying immunologic deficiency, and outcomes are quite variable. Warm IgM in combination with other antibodies has not been reported in children. We report the first case of severe, steroid-responsive autoimmune hemolytic anemia caused by both warm-reactive IgM and IgA autoantibodies in an otherwise healthy 3-month-old.

Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS. METHODS: CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income. RESULTS: Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines. CONCLUSIONS: Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS.

Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia - From the St. Jude Lifetime Cohort.

Adult survivors of childhood acute lymphoblastic leukaemia (ALL) have a four-fold excess risk of mortality from cardiovascular disease. This cardiovascular risk has not been fully characterized. ALL survivors [n = 784, median age 31·7 years (18·9-59·1)] in the St. Jude Lifetime Cohort Study underwent evaluation for cardiovascular risk and metabolic syndrome (MetS) according to National Cholesterol Education Program - Adult Treatment Panel III criteria. Comparisons were made to 777 age-, sex-, and race-matched controls from the National Health and Nutrition Examination Survey (NHANES). MetS was identified in 259 survivors (33·6%) and associated with older age in 5-year increments (relative risk [RR] 1·13, 95% confidence interval [CI] 1·06-1·19) and prior cranial radiotherapy (CRT) (with craniospinal radiation: RR 1·88, 95%CI 1·32-2·67; without: RR 1·67, 95%CI 1·26-2·23). Measures of obesity were highly prevalent among female survivors and CRT recipients. Compared to NHANES controls, ALL survivors had a higher risk of MetS (RR 1·43, 95%CI 1·22-1·69), hypertension (RR 2·43, 95%CI 2·06-2·86), low high-density lipoprotein (RR 1·40, 95%CI 1·23-1·59), obesity (RR 1·47, 95%CI 1·29-1·68) and insulin resistance (1·64, 95%CI 1·44-1·86). This large study of clinically evaluated ALL survivors identified a high prevalence of MetS, obesity and cardiovascular risk, particularly in CRT recipients, underscoring the need for screening and aggressive reduction of modifiable risks.

Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea.

BACKGROUND: More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. METHODS: Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc(99) m liver-spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake, <10% uptake, decreased but ≥10% uptake, and normal. RESULTS: Mean age (N = 40) was 9.1 yrs, range 2.3-17.0. After 3 yrs of treatment, 13 (33%) had uptake on LS scan. These 13 children were younger (median age 6.0 vs. 10.6 yrs, P = 0.008), had a higher HbF at baseline (mean 10.2% vs. 5.8%, P = 0.004) and after 3 yrs (22.9% vs. 13.9%, P < 0.001), achieved MTD more rapidly (median 288 vs. 358 d, P = 0.021), and were more likely to have baseline splenic uptake (P < 0.001). CONCLUSIONS: Hydroxyurea at MTD is associated with preserved or improved splenic filtrative function, with 33% demonstrating LS scan uptake after 3 yrs. Younger age, higher %HbF, and baseline splenic function are associated with a favorable outcome.

Clinical ascertainment of health outcomes among adults treated for childhood cancer.

IMPORTANCE: Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions. OBJECTIVE: To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer. DESIGN, SETTING, AND PARTICIPANTS: Presence of health outcomes was ascertained using systematic exposure-based medical assessments among 1713 adult (median age, 32 [range, 18-60] years) survivors of childhood cancer (median time from diagnosis, 25 [range, 10-47] years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012. MAIN OUTCOMES AND MEASURES: Age-specific cumulative prevalence of adverse outcomes by organ system. RESULTS: Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% [95% CI, 60.4%-69.8%]), auditory (hearing loss, 62.1% [95% CI, 55.8%-68.2%]), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% [95% CI, 59.5%-64.6%]), cardiac (any cardiac condition, such as heart valve disorders, 56.4% [95% CI, 53.5%-59.2%]), and neurocognitive (neurocognitive impairment, 48.0% [95% CI, 44.9%-51.0%]) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% [95% CI, 10.8%-15.3%]), skeletal (osteoporosis, 9.6% [95% CI, 8.0%-11.5%]), renal (kidney dysfunction, 5.0% [95% CI, 4.0%-6.3%]), and hematopoietic (abnormal blood cell counts, 3.0% [95% CI, 2.1%-3.9%]) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition. CONCLUSIONS AND RELEVANCE: Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.

State of the Art Management of Acute Vaso-occlusive Pain in Sickle Cell Disease.

Acute vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD). Multiple complex pathophysiological processes can result in pain during a VOC. Despite significant improvements in the understanding and management of SCD, little progress has been made in the management of pain in SCD, although new treatments are being explored. Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay of treatment of VOC pain, but new classes of drugs are being tested to prevent and treat acute pain. Advancements in the understanding of the pathophysiology of SCD and pain and the pharmacogenomics of opioids have yet to be effectively utilized in the management of VOC. Opioid tolerance and opioid-induced hyperalgesia are significant problems associated with the long-term use of opioids, and better strategies for chronic pain therapy are needed. This report reviews the mechanisms of pain associated with acute VOC, describes the current management of VOC, and describes some of the new therapies under evaluation for the management of acute VOC in SCD.

Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia.

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.

Prevalence of vitamin D deficiency in sickle cell disease: a systematic review.

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 < 20 ng/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.

Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.

Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA.

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 S߰-thalassemia who were 2-18 years old between 2006-2010 and received care at St. Jude Children's 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.

Granulocyte-macrophage colony stimulating factor and immunosuppression in the treatment of pediatric acquired severe aplastic anemia.

BACKGROUND: Immunosuppressive therapy (IS) is effective in the treatment of patients with acquired severe aplastic anemia (SAA). An enhanced myeloid response and decreased infection risk may be possible with the addition of a hematopoietic cytokine. Published data on the combination of cytokines and IS in patients with SAA are limited. The addition of G-CSF to IS shortens the time to neutrophil count recovery, but may not improve overall survival. Because GM-CSF acts differently than G-CSF, its use in combination with IS may be different. PROCEDURE: A retrospective chart review was performed on patients diagnosed with SAA and treated with IS and GM-CSF at St. Jude Children's Research Hospital. Hematologic recovery, prognostic factors, and infection data were collected. RESULTS: Eighteen patients were included in this study. The median age at diagnosis was 7.2 years (range 1.8-17.0). Ten patients (56%) had a complete response, four (22%) a partial response, and four (22%) no response. Median time to erythrocyte and platelet transfusion independence were 90 (18,243) and 64 days (18-243), and to discontinuation of treatment 287 days (90-730). Median time to partial (ANC > 500) and full (ANC > 1,500) neutrophil recovery were 41 and 51 days, respectively. Seventeen documented discrete infections occurred in six patients over 36 patient years. CONCLUSIONS: GM-CSF, in addition to IS, may shorten time to neutrophil count recovery, may be beneficial in decreasing infection rates, and may improve platelet response in patients with SAA. However, consistent with studies utilizing G-CSF, GM-CSF probably does not affect overall response rate. To fully answer whether or not cytokine therapy is of added value to IS in pediatric patients, a multi-institutional randomized trial is needed.