Due to improvements in treatment and care, the life expectancy of patients with sickle cell disease (SCD) has improved over the last 50 years1 such that many patients now survive to an age where they are at an increased risk for cancer. 2 Previously reported small case series3-6 or surveys7 have suggested an increased cancer risk in patients with SCD. In addition, an increased cancer incidence of hematologic cancers and some solid tumors was recently observed among 7512 SCD patients in England compared with patients hospitalized with minor medical and surgical conditions. 8 However, cancer incidence rates of SCD patients were not compared with the general population of England. There is limited understanding as to whether the risk of certain cancers among those with SCD differs from the general population. Therefore, we used 27 years of population-based data from California to determine cancer incidence in SCD patients compared with the general population. As previously described, the SCD study cohort was identified using serial records from the California Patient Discharge Data and the Emergency Department Utilization databases from the Office of Statewide Health Planning and Development. 9, 10 SCD patients were identified using a search algorithm informed by the Registry and Surveillance System for Hemoglobinopathies project11 and validated by the Public Health Research, Epidemiology, and Surveillance for Hemoglobinopathies study. 2 Although genotype is available by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, 69% had multiple genotypes coded across different admissions; therefore, genotype was deemed unreliable. 12 Patients with an average of $3 visits per year (across all study years in the cohort) were defined as having severe SCD; all other patients were defined as having less severe SCD. 9, 10 Cancer occurrence among SCD patients was obtained through a linkage with the population-based California Cancer Registry (1988-2014). 13 Cancer-specific data, including date of diagnosis, primary site, and histology, and patient demographics are collected for all malignant and selected in situ cancers in California. Standardized incidence ratios (SIRs) are commonly used to compare specific cohorts, cancer incidence to the general population and are adjusted for demographic differences in the population distributions. Additionally, SIRs are designed to handle smaller sample sizes. 14 SIRs with 95% confidence intervals (CIs) were calculated as observed cancers in SCD patients to expected cancers using California cancer rates for all cancers combined and specific cancers with $5 observed cases in all SCD patients. Additional SIR stratifications by sex, age, and time period of diagnosis were calculated for leukemia because of the fear of association with hyroxyurea, 15, 16 which was approved for use in 1998. This study was approved by the California Health and Human Services Agency Committee for the Protection of Human Subjects and the University of California, Davis Institutional

Review Boards. Additional details on methods are presented in supplemental Methods (available on the Blood Web site). There were 6423 SCD patients identified from 1991 to 2014 (supplemental Table 1). SCD patients were observed for a total of 141752 person-years, with a median length of follow-up of 22.2 person-years. A total of 115 SCD patients were diagnosed with first primary cancers at a median age of 46 years. Compared with the California population, SCD patients had a 72% increased risk of hematologic malignancies and a 38% reduced risk of solid tumors …