REVIEW DOI: 10.4274/tjh.galenos.2018.2018.0150 Turk J Hematol 2019;36:1-11 Late Effects of Therapy in Childhood Acute Lymphoblastic Leukemia Survivors Çocukluk Çağı Akut Lenfoblastik Lösemi Tedavisi Sonrası Geç Yan Etkiler Hande Kızılocak1, Fatih Okcu2 1Istanbul University-Cerrahpaşa Faculty of Medicine, Department of Pediatric Hematology and Oncology, İstanbul, Turkey 2Texas Children’s Hematology and Oncology Centers, Baylor College of Medicine, Department of Pediatrics, Division of Hematology and Oncology, Houston, TX, USA Abstract Öz Over the last 50 years, the survival rates in children with acute Son 50 yıldaki gelişmeler ile akut lenfoblastik lösemili (ALL) lymphoblastic leukemia (ALL) have increased remarkably. The optimal çocuklardaki tedavi sonrası sağkalım oranında belirgin derecede artış use of antileukemic agents in cooperative group protocols, central saptandı. Antilösemik ilaçların akılcı kullanımı, santral sinir sistemini nervous system-directed treatment, improvements in supportive hedefleyen lokal tedaviler ve destek tedavisindeki gelişmeler ile 5 care, and recognition of biological, clinical, and treatment response yıllık olaysız sağkalım %85’e ve 5 yıllık genel sağkalım %90’a ulaştı. characteristics that predict patients with a higher or a lower risk of Uzamış sağkalım süreleri, tedavinin uzun dönem yan etkilerine olan treatment failure have improved 5-year event-free survival rates, farkındalığı da arttırdı. Geç dönem mortalite, ikincil maligniteler, reaching more than 85%, and 5-year overall survival rates, reaching nörolojik, kardiyak, endokrin ve psikososyal bozukluklar ALL tedavisi more than 90%. Consequently, it has become increasingly important to sonrası sık görülen yan etkilerdir. Son yıllarda Avrupa ve Amerika characterize the occurrence of long-term late effects. ALL treatments Birleşik Devletleri’ndeki birçok grup ALL tedavisi sonrası uzun dönem have been associated with increased risks for adverse outcomes such yan etkiler konusunda çalışmalar yaptı, takip için ve uzun dönem as late mortality, secondary malignancies, and neurological, cardiac, mortalite ve morbiditeyi azaltmak için yeni yaklaşımlar önerdiler. endocrine, and social/psychological disorders. In recent decades, Günümüzde kullanımda olan protokoller uzun dönem yan etkileri cooperative groups in Europe and in the United States have provided önlemek için tedavinin yoğunluğunu azaltmaya çalışırken, sağkalımla essential information about the long-term effects of ALL therapy, iligili çalışmalarda da yan etkilerin öngörülmesi ve gerekli önlem ve giving recommendations for screening as well as facilitating new tedavilerin sağlanması konusu irdeleniyor. approaches for reducing late-term morbidity and mortality. Current Anahtar Sözcükler: Akut lenfoblastik lösemi, Kanser tedavisi sonrası frontline protocols continue to examine ways to lower the intensity sağkalım, Geç yan etkiler 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. Keywords: Acute lymphoblastic leukemia, Cancer survivorship, Late effects Introduction late effects related to therapy (summarized in Table 1). In recent decades, cooperative groups in Europe and in the United States In the last 50 years remarkable success in treating childhood have prioritized development of treatment regimens aimed at acute lymphoblastic leukemia (ALL) has been achieved through reducing the risk for late effects without adversely impacting modifications of chemotherapy and radiotherapy within the cure rates. While traditional and molecular epidemiology cooperative group trials and improved supportive care [1]. As studies are pursued to describe the growing spectrum of late a result, it has become obvious that survivors of childhood ALL effects seen in such survivors, development of interventions have, in the long term, increased risks of life-threatening severe to prevent and treat late effects associated with significant ©Copyright 2019 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House Address for Correspondence/Yazışma Adresi: Hande KIZILOCAK, M.D., Received/Geliş tarihi: May 02, 2018 Istanbul University-Cerrahpaşa Faculty of Medicine, Department of Pediatric Hematology and Oncology, İstanbul, Turkey Accepted/Kabul tarihi: July 04, 2018 Phone : +90 323-361-5798 E-mail : [email protected] ORCID-ID: orcid.org/0000-0003-0323-2571 1 Kızılocak H and Okcu F: Late Effects in Childhood Acute Lymphoblastic Leukemia Turk J Hematol 2019;36:1-11 mortality and morbidity has emerged as an important field of 6-mercaptopurine and methotrexate. Such success inspired of research. In this manuscript we present a comprehensive the development of similar clinical trials around the world, review of the epidemiology and burden of common late effects including two particularly important studies in the 1970s [7,8]. observed among childhood ALL survivors including secondary First the Berlin-Frankfurt-Munster group presented its “Protocol malignancies and neurological, cardiac, endocrine, and social/ II” treatment, specifying a reinduction phase (i.e. the repetition psychological disorders. of the initial remission induction therapy, which is now referred to as delayed intensification). Secondly, the Dana-Farber Cancer Evolution of Acute Lymphoblastic Leukemia Therapy Center added weekly asparaginase at a high dose into its multiagent protocol. The optimal use of antileukemic agents in cooperative group protocols, central nervous system (CNS)-directed treatment, Simultaneously, in the 1970s, the use of prophylactic improvements in supportive care, and recognition of biological, craniospinal radiation was the next major step in the evolution clinical, and treatment response characteristics able to predict of treatment of ALL [9]. While only 2% of children with ALL have patients at higher or lower risks of treatment failures have overt leukemia in the spinal fluid at diagnosis, approximately increased 5-year event-free survival (EFS) rates to above 85% half will experience a CNS relapse if given systemic therapy and 5-year overall survival (OS) rates to above 90% [2], while alone. Craniospinal radiation led to several detrimental late few children survived 50 years ago [3]. effects including cognitive impairment, growth arrest, and panhypopituitarism in most of the patients [10,11]. To reduce After the initial single agent (aminopterin) and two-drug these adverse outcomes first spine radiation was eliminated, combinations (mercaptopurine and methotrexate) produced followed by reductions in the cranial radiation dose from breakthrough “temporary remissions” in the 1940s and 24 to 18 Gy and then eventually to 12 Gy. Thus, in 1980s, 1950s [4,5] Pinkel and colleagues developed a multiphase cranial radiotherapy (CRT) became a standard component of ALL treatment protocol in 1962 [6]. This included remission successful multimodality therapy for treating and preventing induction, CNS-directed therapy [including both cranial CNS leukemia [12]. However, many children were still left irradiation and intrathecal (IT) methotrexate], intensification with neurocognitive impairment that manifested as impaired (consolidation), and continuation treatment using a combination processing speed, global intellectual function, and executive Table 1. Summary of late effects in childhood acute lymphoblastic leukemia. Late effects Associated variables Frequency Screening methods References Radiation, cardiopulmonary Death from any Lifelong periodic ROS*/ Late mortality [15,16,17,18,19] diseases, SN, recurrences cause, 13% physical exam Radiation, chemotherapy Secondary Lifelong periodic ROS/ (alkylating agents, 1%-6% [20,21,22,23,24,25,26,27,28,29] Malignancy physical exam anthracyclines, and etoposide) Lifelong periodic ROS/ Neurological/ Cranial or craniospinal radiation, physical exam; neurological [30,31,32,33,34,35,36,37,38,39,40, Neurocognitive methotrexate (IT/IV), IT ARA-C, 20%-40% examination, imaging as 41,42,43,44,45,46,47,48,49,50] disorders vincristine, steroids needed Anthracycline Lifelong periodic ROS/ <500 mg/m2, physical exam focused on Anthracycline therapy, [52,53,54,55,56,57,58,59,60,61, Cardiotoxicity CHF 10%, cardiac system, periodic overweight 62,63,64] >600 mg/m2: echocardiography, blood CHF 36% pressure monitoring Endocrine disorders (growth hormone Clinical dietician evaluation, [66,67,68,69,70,71,72,73,74,75,76, Cranial radiation, younger age Obesity, deficiency, healthy diet, and regular 77,78,79,80,81,82,83,84,85,86, at diagnosis, female sex precocious puberty, 12%-28% physical exercise 87,88,89] obesity) High-dose methotrexate, Bone disorders mercaptopurine, glucocorticoids, Symptomatic Increased physical activity [90,91,92,93,94,95,96,97,98,99, (osteoporosis, cranial radiation, low calcium osteonecrosis, and calcium intake 100,101,102,103] osteonecrosis) intake, decreased physical 1%-38% activity, obesity Social/Psychological Young age at diagnosis, Consultancy and education Not measured well [15,23,104,105,106] disorders female sex to parents and survivors ROS: Review of systems, SN: secondary neoplasm, IT: intrathecal. 2 Turk J Hematol 2019;36:1-11 Kızılocak H and Okcu F: Late Effects in Childhood Acute Lymphoblastic Leukemia function. Ultimately a number of randomized studies showed years from the initial diagnosis, those ALL patients still surviving that IT chemoprophylaxis with methotrexate or “triple” therapy are seen