F. Lennie Wong

Cancer Incidence After Retinoblastoma: Radiation Dose and Sarcoma Risk

CONTEXT There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. OBJECTIVE To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. DESIGN Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. SETTING/PARTICIPANTS A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. RESULTS Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). CONCLUSIONS Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

Inherited NUDT15 Variant Is a Genetic Determinant of Mercaptopurine Intolerance in Children With Acute Lymphoblastic Leukemia

PURPOSE Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. PATIENTS AND METHODS The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model. RESULTS MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others. CONCLUSION We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Cardiovascular Disease Risk Profiles in Survivors of Adolescent and Young Adult (AYA) Cancer: The Kaiser Permanente AYA Cancer Survivors Study

PURPOSE To describe the epidemiology and risk factors for cardiovascular disease (CVD) in survivors of adolescent and young adult (AYA) cancer. METHODS We identified a retrospective cohort of 2-year survivors of AYA cancer who were diagnosed between the ages of 15 to 39 years (1998 to 2009) at Kaiser Permanente Southern California. A comparison group without cancer was selected and matched 10:1 to cancer survivors on the basis of age, sex, Kaiser Permanente Southern California membership, and calendar year. Patients were followed through December 31, 2012, for coronary artery disease, heart failure, and stroke. Time-dependent Poisson regression was used to evaluate the effect that cancer survivorship had on the risk of developing CVD, adjusted for cardiovascular risk factors (CVRFs; ie, diabetes, hypertension, and dyslipidemia), ethnicity, smoking, and overweight/obesity. Among cancer survivors, mortality risk by CVD status was examined using Cox regression. RESULTS A total of 5,673 2-year survivors of AYA cancer and 57,617 comparison patients were included, representing 24,839 and 239,073 person-years of follow-up, respectively. Overall, cancer survivors had more than two-fold risk of developing CVD (adjusted incidence rate ratio, 2.37; 95% CI, 1.93 to 2.93) when compared with patients without cancer; survivors of leukemia and breast cancer were at the highest risk (adjusted incidence rate ratio, 4.23; 95% CI, 1.73 to 10.31; and 3.63; 95% CI, 2.41 to 5.47, respectively) of developing CVD. Having any of the CVRFs increased the risk of CVD in cancer survivors. Cancer survivors who developed CVD had an 11-fold increased overall mortality risk (hazard ratio, 10.9; 95% CI, 8.1 to 14.8) when compared with survivors without CVD. CONCLUSION Survivors of AYA cancer are at increased risk for developing CVD. Survival after CVD onset is compromised, and CVRFs are independent modifiers of CVD risk. These data form the basis for identifying high-risk individuals and proactive management of CVRFs.

Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study

Purpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency-matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect-adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post-HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions.

Prediction of cardiovascular disease among hematopoietic cell transplantation survivors

Cardiovascular disease (CVD) is a leading cause of late morbidity and mortality in hematopoietic cell transplantation (HCT) survivors. HCT-specific CVD risk prediction models are needed to facilitate early screening and prevention. In the current study, patients who underwent HCT at City of Hope (COH) and survived 1-year free of clinically evident CVD (N = 1828) were observed for the development of heart failure (HF) or coronary artery disease (CAD) by 10-years from index date (1 year from HCT). CVD occurred in 135 individuals (92 HF, 43 CAD). Risk prediction models were developed for overall CVD (HF and/or CAD) using COH-derived integer risk scores. Risk scores based on selected variables (age, anthracycline dose, chest radiation, hypertension, diabetes, smoking) achieved an area under the curve (AUC) and concordance (C) statistic of 0.74 and 0.72 for CVD; these varied from 0.70 to 0.82 according to CVD subtype (HF or CAD). A Fred Hutchinson Cancer Research Center case cohort (N = 580) was used to validate the COH models. Validation cohort AUCs ranged from 0.66 to 0.75. Risk scores were collapsed to form statistically distinct low-, intermediate-, and high-risk groups, corresponding to 10-year cumulative incidences of CVD of 3.7%, 9.9%, and 26.2%, respectively. Individuals in the high- and intermediate-risk groups were at 7.8-fold (95% confidence interval, 5.0-12.2) and 2.9-fold (95% confidence interval, 1.9-4.6) risk of developing CVD (referent group: low risk). These validated models provide a framework on which to modify current screening recommendations and for the development of targeted interventions to reduce the risk of CVD after HCT.