Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia: 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS) population-based matched cohort

Abstract

Objectives: To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population.

Design: National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases.

Setting: The study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996.

Participants: 1082 5-year survivors of ALL diagnosed<15 years of age (1992-1996) and 2018 unaffected individuals; followed up to 15 March 2020.

Main outcome measures: Associations with hospital activity, cancer and mortality were assessed using incidence rate ratios (IRR) and differences.

Results: Mortality in the 5-year ALL survivor cohort was 20 times higher than in the comparison cohort (rate ratio 21.3, 95% CI 11.2 to 45.6), and cancer incidence 10 times higher (IRR 9.9 95% CI 4.1 to 29.1). Hospital activity was increased for many clinical specialties, the strongest associations being for endocrinology; outpatient IRR 36.7, 95% CI 17.3 to 93.4 and inpatient 19.7, 95% CI 7.9 to 63.2 for males, and 11.0, 95% CI 6.2 to 21.1 and 6.2 95% CI 3.1 to 13.5, respectively, for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology; ear, nose and throat; urology; and dermatology, while females were more likely to be seen in plastic surgery and less likely in midwifery.

Conclusions: Adding to excess risks of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years, which is not related to routine follow-up monitoring. Involving most clinical specialties, associations are striking, showing no signs of diminishing over time. Recognising that all survivors are potentially at risk of late treatment-associated effects, our findings underscore the need to take prior ALL diagnosis into account when interpreting seemingly unrelated symptoms later in life.

Keywords: epidemiology; leukaemia; paediatric oncology; public health.

Figure 1

Flow chart showing subjects targeted in the original United Kingdom Childhood Cancer case-control study and those included in the present cohort.

Figure 2

Outpatient activity hazard rates per year and 95% CIs (dotted lines) for childhood (<15 years) acute lymphoblastic leukaemia 5-year survivors and their matched controls: (A) paediatrics, haematology and oncology, (B) all other clinical specialties.

Figure 3

Cumulative incidence (%), incidence rates (per 1000 person years), attributable risks, and incidence rate ratios for the top 15 outpatient specialties (excluding paediatrics, haematology and oncology) with two or more face-to-face visits in the 5–25 years following diagnosis (cases diagnosed <15 years, 1992–1996) and their matched population controls.

Figure 4

Cumulative incidence (%), incidence rates (per 1000 person years), attributable risks and incidence rate ratios for the top 15 inpatient specialties (excluding paediatrics, haematology and oncology) with one or more admissions in the 5–25 years following diagnosis (cases diagnosed aged <15 years, 1992–1996) and their matched population controls. ENT, ear, nose and throat.