Expected Outcome including Late Effects

Late effects among survivors of AML during childhood and adolescence may have a significant impact on their quality of life. Long-term sequelae of treatments can include impaired intellectual and psychomotor functioning, neuroendocrine abnormalities, impaired reproductive capacity, and second malignancies [44]. However, most of these late effects, especially side effects after CNS irradiation (neurocognitive deficits, growth hormone deficiency, and secondary CNS tumor) given in the AML-BFM studies for all age groups, but not in other AML trials, affect the younger age group. Anthracycline cardiotoxicity is also seen at lower cumulative doses (<300 mg/m2) in patients younger than 18 years but rather at 550 mg/m2 in those over 18 years [45].

The risk of endocrine dysfunction is relatively low in AML patients who are treated with standard chemotherapy only (without alkylating agents), however after stem-cell transplantation there is an increased risk of endocrine dysfunction [44]. Impairment of growth rates after busulfan/cyclophosphamide or cyclophosphamide/total body irradiation (TBI) conditioning regimens is a problem in children treated before or during their growth period. Gonadal toxicity is seen in all age groups, mainly as gonadal dysfunction; however, it is relatively low with modern conventional therapy [44]. Gonadal toxicity may cause disorder of pubertal development, infertility, sexual dysfunction, and the need for long-lasting hormone substitution. In adult women, high doses of alkylating agents and TBI increase the risk of ovarian failure and the probability of restoring the ovarian function decreases by a factor of 0.8 per year of age [46]. The addition of busulfan to cyclophosphamide causes permanent ovarian failure in nearly all female patients. In males the effects of both cytotoxic chemotherapy and TBI will damage the germinal epithelium of the testis, and for the majority of males in all age groups, permanent infertility is likely after TBI schedules [46].

Therefore, in the future, prior to stem-cell transplantation germ cells or gonadal tissue should be collected and stored with the aim of enabling patients to become parents later on [46].

Second malignant neoplasms have been described mainly in ALL patients, with a cumulative incidence of approximately 2-3% at 15 years of age [12, 44]. Data regarding second malignancies following treatment for AML are scarce, probably because the number of long-term survivors is much lower. Within the AML-BFM studies, only 12 second malignancies have been observed among 928 children, who were alive at least 3 years after treatment. Most of these patients had received chemotherapy only. After stem-cell transplantation, the risk of second malignancies is higher for any disease (standard incidence ratio from 6.7 to 11.6 in different studies compared to patients given chemotherapy only) [47]. AML and myelodysplastic syndrome are often reported as second malignancies after chemotherapy with alkylating agents or topoi-somerase inhibitors, therefore it might be difficult to distinguish between relapse or second malignancy in primary AML patients.

In all age groups with leukemia and lymphoma, more depression and somatic distress were reported in comparison with sibling controls [44].

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