Non‐endocrine late complications of bone marrow transplantation in childhood: part I

Current estimations indicate that greater than 30 000 allogeneic and autologous haematopoietic stem cell transplants (HSCT) are undertaken every year, worldwide, and that this figure is rapidly growing. Approximately one-fifth are performed in paediatric patients and it is estimated that a minimum of 1500–2000 of these annually will become long-term survivors (Boulad et al, 1998). Overall, autologous transplants, including those using peripheral blood stem cells, are commoner than allogeneic HSCT (Boulad et al, 1998; Horowitz, 1999), but in children the donor source is still mainly allogeneic marrow. This is confirmed by unpublished analysis of British paediatric data, taken from the United Kingdom Childrens’ Cancer Study Group Registry between 1993 and September 2000. Out of the 2331 transplantation procedures performed, 1700 were allogeneic. The commonest indication for allogeneic transplantation in children is leukaemia, with 62% undergoing bone marrow transplantation (BMT) for this or myelodysplasia, 36% for non-malignant conditions and 2% for other cancers. With increasing numbers of long-term survivors, delayed complications, often presenting years after BMT, are becoming a concern. Late sequelae may arise as a result of the disease for which transplantation was performed or from toxicity associated with the wide variety of conditioning regimens. Most of the latter will include high-dose chemotherapy, alone or accompanied by radiotherapy, in the form of total body irradiation (TBI) or total lymphoid irradiation (TLI) and ⁄ or agents to effect T-cell depletion. The total dose of TBI usually varies from 7Æ5 Gy given as a single fraction up to 15 Gy given in multiple fractions over a period of 3–4 d. Additional damage may be sustained through the toxic effects of some antibiotics and antifungals, or from immunosuppressive agents used for prevention and treatment of graft-versus-host disease (GVHD) or from the pathological process of chronic GVHD itself. Other potential variables influencing the impact of late sequelae are the total dose, dose rate and method of fractionation of the radiotherapy, the age and sex of the child, and genetic influences. Particularly difficult to disentangle from sequelae related to the BMT procedure itself, but integral to the outcome, is the effect of previous treatment, especially in the case of malignant disease. This review would be incomplete without relevant discussion of some of these important aspects. As many of the childhood studies are very small and in themselves inconclusive, larger, mixed studies and some adult data have been included when I have felt it to be important to the evidence. Part I of this review describes cardiac, pulmonary, renal, neurological and neuropsychological late sequelae of bone marrow transplantation. The second part deals with ocular, audiological, dental, salivary and skeletal delayed complications, second malignant neoplasms, overall morbidity, late mortality and quality of life. The endocrine system is particularly vulnerable to damage by radiation and alkylating agents in the growing child (Leiper et al, 1987; Boulad et al, 1998; Cohen et al, 1999), but endocrinopathy will not be included here. Deeg, Sanders, Kolb and BenderGotze have reviewed late complications of BMT in adults and children, covering the early period of transplantation up to the end of the eighties (Sanders et al, 1989; Deeg, 1990; Kolb and Bender-Gotze, 1990; Sanders, 1990; Bender-Gotze, 1991). This review focuses mainly on paediatric literature published over the last decade.