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      Late Effects of Therapy in Childhood Acute Lymphoblastic Leukemia Survivors Translated title: Çocukluk Çağı Akut Lenfoblastik Lösemi Tedavisi Sonrası Geç Yan Etkiler

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          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.

          Translated abstract

          Son 50 yıldaki gelişmeler ile akut lenfoblastik lösemili (ALL) çocuklardaki tedavi sonrası sağkalım oranında belirgin derecede artış saptandı. Antilösemik ilaçların akılcı kullanımı, santral sinir sistemini hedefleyen lokal tedaviler ve destek tedavisindeki gelişmeler ile 5 yıllık olaysız sağkalım %85’e ve 5 yıllık genel sağkalım %90’a ulaştı. Uzamış sağkalım süreleri, tedavinin uzun dönem yan etkilerine olan farkındalığı da arttırdı. Geç dönem mortalite, ikincil maligniteler, nörolojik, kardiyak, endokrin ve psikososyal bozukluklar ALL tedavisi sonrası sık görülen yan etkilerdir. Son yıllarda Avrupa ve Amerika Birleşik Devletleri’ndeki birçok grup ALL tedavisi sonrası uzun dönem yan etkiler konusunda çalışmalar yaptı, takip için ve uzun dönem mortalite ve morbiditeyi azaltmak için yeni yaklaşımlar önerdiler. Günümüzde kullanımda olan protokoller uzun dönem yan etkileri önlemek için tedavinin yoğunluğunu azaltmaya çalışırken, sağkalımla iligili çalışmalarda da yan etkilerin öngörülmesi ve gerekli önlem ve tedavilerin sağlanması konusu irdeleniyor.

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          Treating childhood acute lymphoblastic leukemia without cranial irradiation.

          Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.) 2009 Massachusetts Medical Society
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            Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study.

            These studies were undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on ovarian function and reproductive outcomes. We reviewed the frequency of acute ovarian failure, premature menopause, live birth, stillbirth, spontaneous and therapeutic abortion and birth defects in the participants in the Childhood Cancer Survivor Study (CCSS). Acute ovarian failure (AOF) occurred in 6.3% of eligible survivors. Exposure of the ovaries to high-dose radiation (especially over 10 Gy), alkylating agents and procarbazine, at older ages, were significant risk factors for AOF. Premature nonsurgical menopause (PM) occurred in 8% of participants versus 0.8% of siblings (rate ratio = 13.21; 95% CI, 3.26 to 53.51; P < .001). Risk factors for PM included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score, and a diagnosis of Hodgkin's lymphoma. One thousand two hundred twenty-seven male survivors reported they sired 2,323 pregnancies, and 1,915 female survivors reported 4,029 pregnancies. Offspring of women who received uterine radiation doses of more than 5 Gy were more likely to be small for gestational age (birthweight < 10 percentile for gestational age; 18.2% v 7.8%; odds ratio = 4.0; 95% CI, 1.6 to 9.8; P = .003). There were no differences in the proportion of offspring with simple malformations, cytogenetic syndromes, or single-gene defects. These studies demonstrated that women treated with pelvic irradiation and/or increasing alkylating agent doses were at risk for acute ovarian failure, premature menopause, and small-for-gestational-age offspring. There was no evidence for an increased risk of congenital malformations. Survivors should be generally reassured although some women have to consider their potentially shortened fertile life span in making educational and career choices.
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              Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study.

              This study was undertaken to determine the effect, if any, of treatment for cancer diagnosed during childhood or adolescence on fertility. We reviewed the fertility of female participants in the Childhood Cancer Survivor Study (CCSS), which consisted of 5-year survivors, and a cohort of randomly selected siblings who responded to a questionnaire. Medical records of all members of the cohort were abstracted to obtain chemotherapeutic agents administered; the cumulative dose of drug administered for several drugs of interest; and the doses, volumes, and dates of administration of all radiation therapy. There were 5,149 female CCSS participants, and there were 1,441 female siblings of CCSS participants who were age 15 to 44 years. The relative risk (RR) for survivors of ever being pregnant was 0.81 (95% CI, 0.73 to 0.90; P or = 30 Gy (RR, 0.61; 95% CI, 0.44 to 0.83) or an ovarian/uterine radiation dose greater than 5 Gy were less likely to have ever been pregnant (RR, 0.56 for 5 to 10 Gy; 95% CI, 0.37 to 0.85; RR, 0.18 for > 10 Gy; 95% CI, 0.13 to 0.26). Those with a summed alkylating agent dose (AAD) score of three or four or who were treated with lomustine or cyclophosphamide were less likely to have ever been pregnant. This large study demonstrated that fertility is decreased among female CCSS participants. The risk factors identified may be utilized for pretreatment counseling of patients and their parents.
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                Author and article information

                Journal
                Turk J Haematol
                Turk J Haematol
                TJH
                Turkish Journal of Hematology
                Galenos Publishing
                1300-7777
                1308-5263
                March 2019
                7 February 2019
                : 36
                : 1
                : 1-11
                Affiliations
                [1 ]Istanbul University-Cerrahpaşa Faculty of Medicine, Department of Pediatric Hematology and Oncology, İstanbul, Turkey
                [2 ]Texas Children’s Hematology and Oncology Centers, Baylor College of Medicine, Department of Pediatrics, Division of Hematology and Oncology, Houston, TX, USA
                Author notes
                * Address for Correspondence: Istanbul University-Cerrahpaşa Faculty of Medicine, Department of Pediatric Hematology and Oncology, İstanbul, Turkey Phone: +90 323-361-5798 E-mail: handekizilocak2@ 123456yahoo.com
                Author information
                https://orcid.org/0000-0003-0323-2571
                https://orcid.org/0000-0001-9492-8675
                Article
                23415
                10.4274/tjh.galenos.2018.2018.0150
                6373511
                30398158
                62671e45-589c-4756-96e7-1c17e75afae1
                © Copyright 2019 by Turkish Society of Hematology / Turkish Journal of Hematology, Published by Galenos Publishing House.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 May 2018
                : 4 July 2018
                Categories
                Review

                acute lymphoblastic leukemia, cancer survivorship, late effects

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