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The trials and tribulations of chronic transfusion in pediatric sickle cell disease: progress from STOP to TWiTCH?

I n the 1990s, the prevalence of stroke or transient ischemic attack in children with sickle cell disease was 11%. The pivotal STOP trial showed that primary stroke prevention could be achieved by transcranial Doppler (TCD) screening and chronic transfusion therapy in children identified to have elevated TCD velocities. Adherence to this strategy has reduced the incidence of stroke by 90% (from 0.67 to 0.06 stroke per 100 patient-years). The price of this success is the well-known side effect profile of chronic transfusion: iron overload, alloimmunization, and the need for venous access. Compared to patients transfused for thalassemia major, patients with sickle cell disease and transfusional iron overload have fewer endocrine and cardiac effects and iron deposition in the liver leading to cirrhosis is the primary concern. The iron chelator deferoxamine—available since the late 1970s—is associated with poor adherence from the subcutaneous route of administration. Erythrocytapheresis—red blood cell (RBC) exchange via an automated cell separator—was demonstrated to reduce iron loading by 87% compared to simple transfusion, allowing some patients to maintain minimally elevated serum ferritin levels without iron chelation, in the pre-STOP era. RBC exchange in small children is technically challenging, even at tertiary academic medical centers. The availability of the oral iron chelator deferasirox in the mid-2000s facilitated the widespread adoption of chronic transfusion for primary stroke prevention in children with sickle cell disease at high risk of stroke by TCD. In parallel, a noninvasive standardized magnetic resonance imaging (MRI) method that correlates well with liver iron content by biopsy was validated. The article by Fasano and colleagues in this issue illustrates the gap between efficacy in clinical trials and real-world effectiveness. They conducted a retrospective review of the medical records of 28 patients with sickle cell disease (age 7-18.5 years) at a single pediatric center from 2011 to 2014. Inclusion criteria included chronic transfusion (>12 months) for primary or secondary stroke prevention, a stable deferasirox dose of 25 mg/kg/day, and more than 6 months of laboratory data while receiving one transfusion modality. The outcome measures were serum ferritin and/or liver iron content (LIC) by R2-MRI (Ferriscan) analysis, stratified by transfusion modality: simple transfusion, partial manual exchange (PME), or RBC exchange (RCE). Simple transfusion was the initial transfusion modality for most patients; patients were switched to PME or RCE for worsening iron overload or failure to achieve hemoglobin S targets on simple transfusion. The results of this study are sobering for two reasons. First, the serum ferritin increased by 15 ng/mL/month in the simple transfusion group and by 38 ng/mL/month in the PME group, highlighting the ineffectiveness of deferasirox, attributed by the authors to patient nonadherence. Only the RCE group achieved iron unloading (91 ng/mL/ month). The LIC data mirror the ferritin results: the RCE group (n 5 6) had a baseline median LIC of 21 mg/g dry weight (range, 6-32), which declined to 13 mg/g dry weight (range, 4-27) after 13 months. In contrast, the simple transfusion and PME group had a baseline LIC of 5.6 and 14.9 mg/g dry weight respectively, which increased to 8.4 and 15.9 mg/g dry weight after medians of 18 and 8 months, respectively. The second troubling observation is the 45% prevalence of alloimmunization at baseline in the simple transfusion group, which comprised the younger children (median age, 10.6 years). This observation is at least partially explained by the baseline transfusion protocol, which was not matched for C, E, or K antigens until alloantibodies developed. Prophylactic antigen matching was introduced 1 year into the study period. Three new alloantibodies and six new autoantibodies developed during the study period, without any significant difference noted across transfusion modality groups. As a point of comparison, the Cooperative Study of Sickle Cell Disease reported an alloimmunization rate of 18.6% more than two decades ago and the STOP trial sites using C, E, and K matching reported an alloimmunization rate of 8%. Although the sensitivity of antibody detection techniques may have improved over time, the study by Fasano and coworkers speaks to the practical barriers (operational and financial) to prophylactic antigen matching in the United States. It is known that prophylactic Rh antigen matching prevents some—but not all—Rh alloimmunization in patients with sickle cell disease. Venous access difficulties were not specifically discussed in the current TRANSFUSION study. Since the PME and RCE groups were older adolescents (median age, 17 years for both), one could surmise that the decision to switch to an exchange modality was at least doi:10.1111/trf.13662