In 1973, patients with sickle cell disease (SCD) due to homozygosity for hemoglobin S (HbSS) were estimated to have a median life expectancy of slightly more than 14 years,1 and thus, the disease was essentially a disease of childhood. However, in the observational Cooperative Study of Sickle Cell Disease (CSSCD), data collected between 1977 and 1988 showed that approximately 85% of children with HbSS lived to adulthood.2 Furthermore, in the CSSCD, child mortality peaked early, occurring among children aged 1 to 3 years, and was due predominantly to infections such as Streptococcus pneumoniae sepsis. Since the CSSCD natural history study, hallmark interventional clinical trials have significantly impacted the disease’s natural history by establishing standards of care, helping prevent serious complications, and improving quality of life and survival in SCD. In this chapter, we first review those clinical trials that have had major impact on clinical practice and patient survival (Figure 24-1 and Table 24-1). We also summarize the major observational studies that have substantially affected clinical practice in the care of patients with SCD in Table 24-2. Subsequent sections in this chapter address the key achievements and challenges of clinical trials in SCD.
Major clinical trials in sickle cell disease (SCD). Many contemporary efforts endeavor to find and validate new therapeutic targets, often one or more of the many abnormalities observed in red blood cells containing predominantly hemoglobin S. Others, however, focus on downstream effects on various organs or physiologic pathways, attempting to prevent or slow organ damage. ACS, acute chest syndrome; Hb, hemoglobin; HbS, sickle hemoglobin; HSCT, hematopoietic stem cell transplantation; SCI, silent cerebral infarction; TCD, transcranial Doppler; VOC, vaso-occlusive crisis.
TABLE 24-1Landmark clinical trials with major clinical practice impact in SCD ||Download (.pdf) TABLE 24-1 Landmark clinical trials with major clinical practice impact in SCD
|Trial and reference ||Major findings ||Lessons learned |
|Prophylaxis With Oral Penicillin in Children With Sickle Cell Anemia (PROPS)3 ||Oral penicillin prophylaxis significantly decreased morbidity (84% relative risk reduction) and mortality due to IPD in children with HbSS disease or HbS-β0 thalassemia; 2 episodes of IPD occurred in the penicillin group (n = 105) vs 13 episodes of IPD in the placebo group (n = 110). ||The study led to the recommendation of instituting universal newborn screening for SCD to permit early penicillin prophylaxis. However, this trial did not include patients with other SCD genotypes such as HbSC and HbS-β+ thalassemia that are at risk of developing delayed, severe IPD due to functional asplenia. |
|Prophylaxis With Oral Penicillin in Children With Sickle Cell Anemia II (PROPS II)4...|