Late Venous Thromboembolic Events in Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study

Introduction: Survivors of childhood cancer are at risk for late adverse sequelae related to prior cancer and its therapies, including an increased risk for venous thromboembolic events (VTE) throughout their lifespans (Madenci, Weil et al. 2018). We investigated the prevalence of and risk factors for late VTE (≥ 5 years from initial cancer diagnosis) in the St. Jude Lifetime (SJLIFE) Cohort (Howell, Bjornard et al. 2021). An improved understanding of risk factors for late VTE may help identify high-risk survivors who may benefit from surveillance or prophylaxis. Methods: Cancer survivors (N=5229), ≥5 years from diagnosis, previously treated for a pediatric malignancy at St. Jude Children's Research Hospital, returned for a comprehensive on-campus health evaluation, including history/physical examination, laboratory analysis, detailed testing of organ function, and patient-reported outcomes. Medical record abstraction was performed for each participant, documenting treatment exposures and validating medical events during and following therapy. Age-, sex- and race-frequency matched individuals without a history of childhood cancer (N=737) were recruited as a reference population. Demographic characteristics and prevalence of late VTE at a fixed time were compared between cancer survivors and the reference population with a Chi-squared/ Fisher Exact test, and associations with treatment and clinical risk factors were assessed in multivariable logistic regression models. Results: Among cancer survivors [84% non-Hispanic White, median age at diagnosis 6.4 years (range: 0.0-24.8) and median age at evaluation 29.6 years (range: 7.4-71)], there were 94 late VTEs (1.8 [95% CI: 1.46-2.20]), compared to 5 (0.7 [95% CI: 0.22-1.58]) (p=0.02) among community controls (80% non-Hispanic White, median age at evaluation 31.1 years (range: 12.1-70.2). Most late VTEs occurred among survivors of ALL and Hodgkin lymphoma (n=25 each), followed by other hematologic malignancies (n=11), Wilms tumor (n=6), soft tissue sarcomas (n=6), central nervous system tumors (n=5), retinoblastoma (n=5), neuroblastoma (n=4), and other (n=7). Most events (n=65, 56%) were located in an extremity (upper=8, lower=57) followed by pulmonary artery (39, 33.6%), abdomen (n=5, 4.3%), neck (n=3, 2.6%), cerebral sinus (n=1, 0.9%), and other (n=3, 2.6%). No association with an early/on-therapy VTE was identified (p=0.7). Adjusting for sex, race, age at diagnosis, follow-up time since diagnosis, body mass index, and physical activity (meeting/not meeting Center for Disease Control recommendations), risk of late VTE was associated with chest/abdominal/pelvis radiation exposure (OR 2.04 [95% CI: 1.2-3.5]), and hormone use (OR 2.01 [95% CI: 1.2-3.5]). Conclusions: The prevalence of and risk for VTE is elevated among cancer survivors many years following therapy, particularly among those treated with chest/abdomen/pelvis radiation therapy and on subsequent hormone replacement. Heightened awareness and potentially prophylactic measures may be warranted among these survivors in high-risk situations.