Abstract
Over the last 50 years, the survival rates in children with acute lymphoblastic leukemia (ALL) have increased remarkably. The optimal use of antileukemic agents in cooperative group protocols, central nervous system-directed treatment, improvements in supportive care, and recognition of biological, clinical, and treatment response characteristics that predict patients with a higher or a lower risk of treatment failure have improved 5-year event-free survival rates, reaching more than 85%, and 5-year overall survival rates, reaching more than 90%. Consequently, it has become increasingly important to characterize the occurrence of long-term late effects. ALL treatments have been associated with increased risks for adverse outcomes such as late mortality, secondary malignancies, and neurological, cardiac, endocrine, and social/psychological disorders. In recent decades, cooperative groups in Europe and in the United States have provided essential information about the long-term effects of ALL therapy, giving recommendations for screening as well as facilitating new approaches for reducing late-term morbidity and mortality. Current frontline protocols continue to examine ways to lower the intensity and amount of therapy to reduce late effects, whereas survivorship studies attempt to predict such adverse effects precisely and develop targeted prevention and treatment strategies.
Highlights
In the last 50 years remarkable success in treating childhood acute lymphoblastic leukemia (ALL) has been achieved through modifications of chemotherapy and radiotherapy within cooperative group trials and improved supportive care [1]
The optimal use of antileukemic agents in cooperative group protocols, central nervous system-directed treatment, improvements in supportive care, and recognition of biological, clinical, and treatment response characteristics that predict patients with a higher or a lower risk of treatment failure have improved 5-year event-free survival rates, reaching more than 85%, and 5-year overall survival rates, reaching more than 90%
In this manuscript we present a comprehensive review of the epidemiology and burden of common late effects observed among childhood ALL survivors including secondary malignancies and neurological, cardiac, endocrine, and social/ psychological disorders
Summary
In the last 50 years remarkable success in treating childhood acute lymphoblastic leukemia (ALL) has been achieved through modifications of chemotherapy and radiotherapy within cooperative group trials and improved supportive care [1]. After the initial single agent (aminopterin) and two-drug combinations (mercaptopurine and methotrexate) produced breakthrough “temporary remissions” in the 1940s and 1950s [4,5] Pinkel and colleagues developed a multiphase ALL treatment protocol in 1962 [6] This included remission induction, CNS-directed therapy [including both cranial irradiation and intrathecal (IT) methotrexate], intensification (consolidation), and continuation treatment using a combination of 6-mercaptopurine and methotrexate. Craniospinal radiation led to several detrimental late effects including cognitive impairment, growth arrest, and panhypopituitarism in most of the patients [10,11] To reduce these adverse outcomes first spine radiation was eliminated, followed by reductions in the cranial radiation dose from 24 to 18 Gy and eventually to 12 Gy. in 1980s, cranial radiotherapy (CRT) became a standard component of successful multimodality therapy for treating and preventing CNS leukemia [12]. Many children were still left with neurocognitive impairment that manifested as impaired processing speed, global intellectual function, and executive
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