Chapter 133 Late Effects of HSCT

Many children who receive hematopoietic stem cell transplantation (HSCT) become long-term survivors. Besides chronic graft versus host disease (GVHD), long-term complications include impaired growth, neuroendocrine dysfunction, delayed puberty, infertility, second malignancies, cataracts and other ocular complications, leukoencephalopathy, and cardiac and pulmonary dysfunction (see Table 133-1 on the Nelson Textbook of Pediatrics website at www.expertconsult.com).

Children who receive HSCT before puberty may develop growth impairment, precluding achievement of the genetic target for adult height. The decrease in growth velocity is similar for boys and girls and is more frequently observed in patients given total body irradiation (TBI) as part of the preparative regimen. Fractionation of irradiation has less adverse impact on height than single-dose TBI, whereas the use of craniospinal radiotherapy before transplantation plays a synergistic detrimental role with TBI in favoring growth impairment. A study of 175 children <6 yr of age, 6-12 yr of age, or 12-15 yr of age receiving TBI-based regimens and not treated with growth hormone reported a mean final adult height of 3.49, 1.92, and 0.37 SD below average, respectively. Chronic GVHD and its treatment with corticosteroids may also contribute to growth impairment. Serial studies of children given a busulfan-based preparative regimen indicate that busulfan has much less impact on growth but produces the same gonadal failure as TBI-based regimens. Preparative regimens using only cyclophosphamide for children transplanted for aplastic anemia have little, if any, detrimental effect on growth and development.

Growth impairment of patients given TBI is mainly due to direct damage of cartilage plates and to the effect of TBI on the hypothalamic-pituitary axis, which leads to an inappropriately low production of growth hormone (GH). GH deficiency is susceptible to at least partial correction through administration of hormonal replacement therapy. Annual growth evaluation should be performed in all children after HSCT. Children showing a decreased growth velocity should be further investigated through evaluation of bone age and secretion of GH in response to pharmacologic stimulus. Current studies are aimed at identifying children with GH deficiencies at an earlier age and administering hormonal replacement therapy. Initial concerns about potential risks of favoring disease recurrence or promoting development of second malignancies with GH therapy have not been confirmed and GH replacement therapy is widely employed.

The use of TBI during the preparative regimen involves the thyroid gland in the irradiation field and may result in hypothyroidism. Some children who have received single-dose TBI develop either compensated or overt hypothyroidism. The use of fractionated TBI reduces the incidence of both compensated and overt hypothyroidism. Children <7 yr old at time of allograft are at greater risk of developing hypothyroidism. Chemotherapy-only preparative regimens have far fewer adverse effects on normal thyroid function. The site of injury by irradiation is at the level of the thyroid gland rather than at the pituitary or hypothalamus. Therapy with thyroxine is very effective for overt hypothyroidism, but treatment of compensated hypothyroidism is more controversial, although there is evidence that hormonal replacement therapy may reduce the risk of thyroid carcinoma through a suppression of thyroid-stimulating hormone (TSH). Despite treatment of hypothyroidism, the incidence of thyroid carcinoma is not negligible. An annual echo of the thyroid gland is indicated for timely identification of nodules in the thyroid gland suspected to be of neoplastic origin. The cumulative incidence of hypothyroidism increases over time, underscoring the importance of annual thyroid function studies.

Gonadal hormones are essential for normal pubertal growth, as well as for development of secondary sexual characteristics. A significant proportion of patients receiving TBI-containing preparative regimens show delayed development of secondary sexual characteristics, resulting from primary ovarian or testicular failure. Laboratory evaluation of these patients reveals elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels with depressed estradiol and testosterone serum levels. These patients benefit from careful follow-up with evaluation of annual Tanner scores and endocrine function. Supplementation of gonadal hormones is useful for primary gonadal failure and is administered with growth hormone to promote pubertal growth. The incidence of sex hormone deficiency is lower in patients given a busulfan-based regimen. Infertility during adulthood is a common problem both in patients who receive busulfan and in those prepared with TBI.

The overall risk of developing a secondary form of cancer is significantly higher after HSCT than in the general population. Although few studies have specifically analyzed pediatric patients, available evidence indicates that the cumulative incidence of second malignancies gradually increases over time. Several types of secondary tumors have been identified in patients given HSCT. The most frequently diagnosed neoplasms are thyroid carcinoma, brain tumors, and epithelial cancers. Young age at transplantation, male gender, use of TBI during the preparative regimen, chronic GVHD, and an intrinsic genetic predisposition to develop cancer (Fanconi anemia) have been reported to be risk factors for development of secondary malignancies after HSCT.

Cataracts mainly occur in children given a radiotherapy-based preparative regimen. The incidence of cataracts is particularly high if TBI is delivered as a single-fraction (800-1,000 cGy). The introduction of fractionated TBI has led to a marked reduction of this complication to ≈10-20% of patients, one third of whom require surgical intervention. Corticosteroids, frequently employed for treating GVHD, have also been demonstrated to promote development of cataracts. A dry eye syndrome called keratoconjunctivitis sicca may also affect HSCT recipients. It is often related to chronic GVHD and postradiotherapy fibrosis of the lacrimal gland and is treated with artificial tears and lubricants.