Severe/Life-Threatening/Fatal Chronic Health Conditions (CHCs) after Allogeneic Blood or Marrow Transplantation (BMT) in Childhood – a Report from the BMT Survivor Study (BMTSS)

Background: Allogeneic BMT is a curative option for children with malignant and non-malignant diseases. Nonetheless, the high intensity of therapeutic exposures at a young age increases the risk of organ compromise and thereby the risk of developing CHCs. Yet, there is limited information regarding CHC risk after allogeneic BMT performed in childhood. We address this gap in patients undergoing allogeneic BMT between 1974 and 2014 at 3 participating transplant centers.

Methods: BMT recipients and a sibling comparison group (or the parents of participants <18y) completed a 255-item questionnaire that included sociodemographics and health conditions. A severity score (grades 3 [severe] or 4 [life-threatening]) was assigned to CHCs using CTCAE, v. 5.0. Deceased BMT recipients received a CHC-specific grade 5. Risk of severe/life-threatening CHC in BMT survivors vs. siblings: We calculated the cumulative incidence of CHCs for survivors and siblings as a function of attained age. We used logistic regression for estimating the risk of grade 3-4 conditions in survivors compared to siblings, adjusting for sex, age at study, race/ethnicity, education, household income, and health insurance. Risk of severe/life-threatening/fatal CHC in BMT recipients: We used proportional subdistribution hazards model (Fine-Gray) for competing risks to identify predictors of grade 3-5 CHCs, adjusting for demographics, primary disease, conditioning agents, disease status at BMT and chronic GvHD status.

Results: 848 patients had received allogeneic BMT at age ≤22 and survived ≥2y after BMT (563 alive at study; 285 deceased after surviving ≥2y). Primary diagnoses included ALL (29%), AML/MDS (28%), SAA (13%), other (30%); median age at BMT: 11.5y (range: 0.4-22.0); median length of follow-up 10.7y (2.0-41.4). Risk of severe/life-threatening CHC in 563 BMT survivors vs. 515 siblings: Cumulative incidence of grade 3-4 condition by age 30y among BMT recipients was significantly higher than that among siblings (38.5±2.7% vs. 5.4±1.0%, p<0.0001), Figure 1. The adjusted odds of developing grade 3-4 CHCs were 8.9-fold higher in BMT survivors (95%CI 6.4-12.5). Higher odds were observed for developing cataracts (OR=48.2; 95%CI 17.9-129.5), heart disease (OR=11.4, 95%CI, 3.9-33.3), diabetes (OR=11.1; 95%CI 3.5-34.8), thyroid nodules (OR=6.6, 95%CI, 2.6-17.0), joint replacement (OR=4.4, 85%CI, 1.7-10.9), and sensorineural disorders (hearing loss/balance disorder/legally blind); OR=3.2, 95%CI, 1.5-6.8). Risk of severe/life-threatening/fatal CHCs in 848 BMT recipients: cumulative incidence of grades 3-5 CHCs was 60.5±3.0% at 40y (Figure 2). The most prevalent grade 3-5 CHCs were second malignancy (11.8%), cataract (5.9%), cardiovascular disease (5.8%), sensorineural disorder (4.4%), diabetes (3.4%), and joint replacement (2.9%). The risk of grades 3-5 CHCs was higher among females (HR=1.3, 95%CI 1.0-1.6), age >12y at BMT (HR=1.4, 95%CI 1.1-1.8) and among those exposed to TBI (HR=1.7, 95%CI 1.2-2.3).

Conclusions: Two-year survivors of allogeneic BMT performed in childhood had an almost 10-fold higher risk of severe/life-threatening CHCs compared to siblings. By age of 30, 39% of the survivors had developed a severe or life-threatening CHC. The results of the present study call for close follow-up, from the time of transplantation continuing throughout life.