Sickle cell disease (SCD) afflicts millions of people worldwide but is referred to as an orphan disease in the United States. Over the past several decades, there has been an increasing understanding of the pathophysiology of SCD and its complications. While most individuals with SCD in resource-rich countries survive into adulthood, the life expectancy of patients with SCD remains substantially shorter than for the general African-American population. SCD can be cured using hematopoietic stem cell transplantation and possibly gene therapy, but these treatment approaches are not available to most patients, the majority of whom reside in low- and middle-income countries. Until relatively recently, only one drug, hydroxyurea, was approved by the US Food and Drug Administration to ameliorate disease severity. Multiple other drugs (L-glutamine, crizanlizumab, and voxelotor) have recently been approved for the treatment of SCD, with several others at various stages of clinical testing. The availability of multiple agents to treat SCD raises questions related to the choice of appropriate drug therapy, combination of multiple agents, and affordability of recently approved products. The enthusiasm for new drug development provides opportunities to involve patients in low- and middle-income nations in the testing of potentially disease-modifying therapies and has the potential to contribute to capacity building in these environments. Demonstration that these agents, alone or in combination, can prevent or decrease end-organ damage would provide additional evidence for the role of drug therapies in improving outcomes in SCD.

Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial or ethnic disparities, and none have assessed potential genetic factors contributing to this outcome. In this study, childhood cancer survivors of African ancestry exposed to cardiotoxic therapies (anthracyclines and/or heart radiation) (n=246) were compared to cardiotoxic-exposed survivors of European ancestry (n=1645) in the St. Jude Lifetime Cohort. Genetic variants were examined using whole-genome sequencing data among survivors of African ancestry, first based on ejection fraction (EF) as a continuous outcome, followed by clinical history of cardiomyopathy. Survivors of African ancestry showed 1.53-and 2.47-fold risks of CTCAE grade 2-4 and grade 3-4 cardiomyopathy than survivors of European ancestry. A novel locus at 1p13.2 showed significant association with EF [rs6689879*C: EF reduction=4.2%; P=2.8×10 −8 ] in 246 survivors of African ancestry, which was successfully replicated in 1645 survivors of European ancestry but with attenuated magnitude

Elevated tricuspid regurgitant velocity (TRV) ≥2.5 m/s is a predictor of disease severity in adults and children with sickle cell anemia (SCA), but how disease-modifying therapies (DMTs) affect this biomarker is incompletely understood. We investigated the effect of DMTs on TRV elevation in children. In a prospective single-center study, 204 subjects with HbSS or HbSβ0 thalassemia (mean age, 10.6 years; range, 5-18) had echocardiograms with assessment of TRV, with repeat evaluations after 2 years of observation. One-hundred and twelve participants received DMTs (hydroxyurea, n = 72; monthly erythrocyte transfusions, n = 40), 58 did not receive any DMT, and 34 were begun on hydroxyurea during this observation period. In the entire cohort, an increase in hemoglobin of 1.0 g/dL was associated with a 0.03-m/s decrease in TRV (P = .024), and a decrease in absolute reticulocyte count of 1.0 × 106/mL was associated with a 0.34-m/s decrease in TRV (P = .034). Compared with baseline, hydroxyurea exposure (continuous or newly started) was associated with an average 5% decline in mean TRV at the 2-year evaluation. Among participants newly started on hydroxyurea (mean treatment duration 1.2 ± 0.6 years), an increase in hemoglobin of 1.0 g/dL was associated with a 0.06-m/s decrease in TRV (P = .05). We conclude that hydroxyurea therapy may mitigate TRV elevation in children with SCA, possibly as a result of a reduction in hemolysis and improvement in anemia.

Anemia, hemolysis-driven vasculopathy, and intrinsic myocardial injury have been proposed as predisposing factors to cardiac disease in sickle cell anemia (SCA). The individual impact of these mechanisms on the cardiac features of SCA and the way they influence complications such as sudden death and dysrhythmias have been unclear. Recent findings of an acquired restrictive SCA-related cardiomyopathy, driven by myocardial fibrosis, may explain some of these cardiac features. Given the complexity of cardiac pathology in SCA, using additional parameters to tricuspid regurgitant jet velocity (left atrial volume, diastolic parameters, NT-proBNP) may improve the accuracy of noninvasive screening for cardiopulmonary complications in SCA.

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Hepatoblastoma is rarely reported to metastasize to the brain. A comprehensive review of the literature was undertaken to characterize such patients and to examine the various therapies utilized to treat them. We identified 39 patients, including 1 previously unreported case from our institution. Although only 19 of these patients had much demographic information reported, it is notable that 24% (4/17) were older than 4 years at their original primary tumor diagnosis and 63% (7/11) had evidence of pulmonary metastases (at original diagnosis or recurrence) before the occurrence of brain metastasis. On the basis of the limited data published about this rare presentation and the known association of poor outcome with older age at diagnosis, we recommend additional neuroimaging in older hepatoblastoma patients when they present for evaluation of a pulmonary recurrence even when they are neurologically asymptomatic, with the aim of early identification and surgical resection of these lesions. The role of radiotherapy as an adjunct treatment for multiple cerebral lesions looks promising and needs to be explored further.

Introduction Human papilloma virus (HPV) infection can cause cervical, anal, penile, vaginal, and oropharyngeal cancer. The CDC recommends HPV vaccination as a 2 or 3-dose series at <15 or ≥15 years, respectively. Completion of the vaccine series decreases rates of cervical cancer in young women by 29%(Guo, F. et al. American Journal of Preventive Medicine 2018). For this reason, focus is currently on vaccinating younger patients to optimize benefit. Historically, adolescents have had low rates of completion of the HPV vaccine series. African Americans, in particular, have significantly lower rates than whites in receiving the full series (De, P. and H. Budhwani. Public Health 2017). Vaccine hesitancy in sickle cell disease (SCD) patients exists and is exemplified by a lower uptake in teenagers with SCD compared to non-SCD counterparts (Beverung, L. et al. American Journal of Hematology 2018). However, completion of 23-pneumococcal vaccine polyvalent (PPSV-23), which is routinely administered as a series during well-child visits, has notably been high. SCD programs serve as medical homes where primary care may also be provided. With this in mind, we introduced a quality improvement (QI) intervention to improve the uptake of HPV vaccination in the adolescent SCD clinic. A bundle intervention was developed including 1) provider education about HPV vaccination importance, 2) nurse review of each adolescent's vaccine records prior to clinic visit, 3) provider notification by the nurse regarding the need for HPV during the visit, 4) discussion of the vaccine benefits with the family, 5) provision of the vaccine in the SCD clinic after parent consent, and 6) offering of MOC points as incentive to providers for project participation. We sought to evaluate the impact of the QI bundle on completion of the HPV vaccine series. We hypothesized that implementation of the QI bundle would increase the rate of completion of the HPV vaccine series among adolescents with SCD. Secondary objectives included association between completion of the HPV vaccine series and frequency of outpatient visits to the SCD clinic, quality of life (QoL), SCD-specific knowledge, completion of the PPSV-23 series, and markers of socio-economic status (SES). Methods Retrospective data was collected using the Sickle Cell Clinical Research and Intervention Program (SCCRIP) study database (Hankins JS, et al. Pediatr Blood Cancer 2018). Patients aged 12-18 years between October 1, 2018 and December 31, 2019 with any SCD genotype and who were enrolled on the SCCRIP study were included in analysis. The following variables were extracted: age, sex, race, ethnicity, age, economic hardship index (EHI), parental education level, household income, genotype, SCD-specific knowledge, and distance to healthcare facility. The prevalence of completed HPV series, defined as 2 doses ages <15 years and 3 doses ages ≥15 years, in the 12 months prior to implementation of the bundle vaccination program (before October 1, 2018) and after implementation of program (October 2, 2018 to December 31, 2019) was calculated using Fisher's exact. Demographic characteristics and QoL were compared between patients who completed the vaccine series and those who did not. Results In total, 373 patients met inclusion criteria. Their median age was 15.2 (range 12-19), 50% were female, 225 (60.3%) had HbSS/Sβ 0-thalassemia, and 114 (29.7%) had HbC/Sβ +-thalassemia. The mean SES index was 70% (±27%) and the mean QoL score 73 (±14.6). HPV vaccine completion rates increased from 31% to 56.2% after the bundle implementation (Figure 1, p<0.01). Completion of the series was associated with higher SES index, completion of the PPSV-23 series, and higher frequency of outpatient visits. There was no significant association between completion of the vaccine series and QoL, distance from healthcare facility, and disease-specific knowledge (Table 1). Discussion Prevention of communicable diseases such as HPV is imperative in the general population. However, baseline vaccination rates in adolescents with SCD is low. A QI intervention that includes provider education and incentives, active verification of HPV vaccination status, and promotes coordinated communication between the nurse, providers, and patients effectively increased completion of the HPV vaccine series among adolescents with SCD. Continued strategies are needed to further increase the rates of vaccine completion. Figure 1 Figure 1. Disclosures Hankins: Vindico Medical Education: Consultancy; Global Blood Therapeutics: Consultancy; UpToDate: Consultancy; Bluebird Bio: Consultancy.

Gene therapy by either gene insertion or editing is an exciting curative therapeutic option for monogenic hemoglobin disorders like sickle cell disease and β-thalassemia. The safety and efficacy of gene transfer techniques has markedly improved with the use of lentivirus vectors. The clinical translation of this technology has met with good success, although key limitations include number of engraftable transduced hematopoietic stem cells and adequate transgene expression that results in complete correction of β0 thalassemia major. This highlights the need to identify and address factors that might be contributing to the in-vivo survival of the transduced hematopoietic stem cells or find means to improve expression from current vectors. In this review, we briefly discuss the gene therapy strategies specific to hemoglobinopathies, the success of the preclinical models and the current status of gene therapy clinical trials.