A Population-Based Cohort Study of Malignancies and Late Mortality in Children Treated by Allogeneic Stem Cell Transplantation for Non -Malignant Conditions

Background:

Characterisation of late effects in children undergoing hematopoietic stem cell transplant (HSCT) for non-malignant diseases is challenging due to the small numbers of rare diseases, variations in cancer susceptibility and organ toxicity associated with primary diagnosis as well as non-uniform clinical practice. In addition, limited  follow-up in previous studies may have underestimated the risk of second cancers and late deaths in this group of transplant recipients.  Our study used population-based registry data to determine the risk of malignancy and late mortality in pediatric patients transplanted for non-malignant conditions.

Methods:

318 Australian allogeneic transplant recipients aged less than 15 years, treated from 1982-2007 for non-malignant conditions, were identified from children’s hospitals and the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR).  Clinical and demographic data were obtained from the ABMTRR and medical records.  Linkage with the Australian Cancer Database and National Death Index was performed to identify all primary invasive cancers and deaths in this cohort. Standardised incidence ratios (SIRs) were generated for second malignancies and deaths in 2-year survivors.

Results:

Indications for HSCT included; primary immunodeficiencies (n=130), aplastic anemia (SAA, n=71), inherited marrow failure syndromes (n=51), thalassemia (n=14) and hemophagocytic lymphohistiocytosis (n=14). Over two thirds of recipients were male (69%), while the median age at transplant was 3 years (range 0-14y)  A total of 43 patients received radiation therapy as part of their conditioning regimen.

Six malignancies were identified in male patients with various diseases including Fanconi Anemia (2), Severe Aplastic Anemia (1), severe combined immune deficiency (1), Thalassemia (1) and chronic granulomatous disease (n=1). The most common second cancer was squamous cell carcinoma of the tongue.  Overall there was a 15-fold increased risk of malignancy compared to the Australian general population (SIR=15.37, 95%CI=6.91-34.21).

Two thirds of patients (62%) survived for more than 2 years after HSCT, while the cumulative incidence of late death was 2.1% at 5 years from HSCT and 6.3% at 10 years from HSCT. Overall, the rate of death was 17 times greater than expected compared to the general population, with cancer being the most common cause of death.

Conclusion:

These findings show an increased rate of malignancy and late death in Australian pediatric patients transplanted for non-malignant conditions compared to the general population.  This confirms the need for long term surveillance to maximize the early detection of subsequent malignancies, which may occur a decade or more after HSCT.

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