Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

Background

Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers.

Procedure

A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA.

Results

The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose.

Conclusions

REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation

Monosomy 7 is a well‐documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3‐year‐old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities.     

High Protein Intake Does Not Prevent Low Plasma Levels of Conditionally Essential Amino Acids in Very Preterm Infants Receiving Parenteral Nutrition

Background: We have shown that increasing protein intake using a standardized, concentrated, added macronutrients parenteral (SCAMP) nutrition regimen improves head growth in very preterm infants (VPIs) compared with a control parenteral nutrition (PN) regimen. VPIs are at risk of conditionally essential amino acid (CEAA) deficiencies because of current neonatal PN amino acid (AA) formulations. We hypothesized that the SCAMP regimen would prevent low plasma levels of CEAAs. Aim: To compare the plasma AA profiles at approximately day 9 of life in VPIs receiving SCAMP vs a control PN regimen. Methods: VPIs (<29 weeks' gestation) were randomized to receive SCAMP (30% more PN AA) or a control regimen. Data were collected to measure parenteral and enteral protein, energy, and individual AA intake and the first plasma AA profile. Plasma profiles of the 20 individual protogenic AA levels were measured using ion exchange chromatography. Results: Plasma AA profiles were obtained at median (interquartile range [IQR]) age of 9 (8–10) days in both SCAMP (n = 59) and control (n = 67) groups after randomizing 150 VPIs. Median (IQR) plasma levels of individual essential AAs were higher than the reference population mean (RPM) in both groups, especially for threonine. SCAMP infants had higher plasma levels of essential AAs than did the controls. Median (IQR) plasma levels of glutamine, arginine, and cysteine (CEAAs) were lower than the RPM in both groups. Conclusion: Plasma AA levels in PN‐dependent VPIs indicate there is an imbalance in essential and CEAA provision in neonatal PN AA formulations that is not improved by increasing protein intake.     

Percutaneously Inserted Central Catheter–Related Pleural Effusion in a Level III Neonatal Intensive Care Unit: A 5‐Year Review (2008–2012)

Background: Although peripherally inserted central catheters (PICCs) provide vascular access in newborns who require parenteral nutrition and medications, they can be associated with complications that lead to significant morbidity and mortality. Objectives: To describe the characteristics of pleural effusion (PLE) associated with PICC use in a large level III neonatal intensive care unit. Design/Methods: A retrospective review of PICC‐related PLE in newborns was conducted over a 5‐year period, from 2008–2012. Results: A total of 926 PICCs were inserted, accounting for 17,606 catheter days. PICC‐related PLE was identified in 7 infants, with an incidence of 0.4 per 1000 catheter days. Infants who developed PLE had a median gestational age of 28 weeks (range, 24–38 weeks) and birth weight of 735 g (range, 500–2975 g). PICCs were inserted at a median age of 4 days (range, 3–11 days). The median time from catheter insertion to the development of PLE was 16 days (range, 7–75 days). In all cases, the catheter tips were centrally located at the time of insertion but migrated to the subclavian veins or tributaries at the time of the events. Conclusion: PICC‐related PLE can be associated with the migration of PICC tips to noncentral locations, despite optimal positioning of the tip at the time of insertion. Attention should be paid to migration of catheter tips on subsequent x‐ray films. For PICCs inserted via upper limb or scalp, serial follow‐up x‐rays, beginning 1 week after insertion, may be helpful to detect migration of catheter tips and identify patients at risk.