Outcome of acute lymphoblastic leukemia in children

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Oct 17, 2017 - throughout the therapy and deintensification of therapy in newly identified good-prognosis subgroups [2]. Similarly, the results published by ...
Pediatric Hematology and Oncology

ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20

Outcome of acute lymphoblastic leukemia in children with down syndrome—Polish pediatric leukemia and lymphoma study group report Joanna Zawitkowska, Teresa Odój, Katarzyna Drabko, Agnieszka ZauchaPrażmo, Julia Rudnicka, Michał Romiszewski, Michał Matysiak, Kinga Kwiecińska, Magdalena Ćwiklińska, Walentyna Balwierz, Joanna OwocLempach, Katarzyna Derwich, Jacek Wachowiak, Maciej Niedźwiecki, Elżbieta Adamkiewicz- Drożyńska, Joanna Trelińska, Wojciech Młynarski, Andrzej Kołtan, Mariusz Wysocki, Renata Tomaszewska, Tomasz Szczepański, Marcin Płonowski, Maryna Krawczuk-Rybak, Tomasz Ociepa, Tomasz Urasiński, Agnieszka Mizia-Malarz, Grażyna Sobol-Milejska, Grażyna Karolczyk & Jerzy Kowalczyk To cite this article: Joanna Zawitkowska, Teresa Odój, Katarzyna Drabko, Agnieszka ZauchaPrażmo, Julia Rudnicka, Michał Romiszewski, Michał Matysiak, Kinga Kwiecińska, Magdalena Ćwiklińska, Walentyna Balwierz, Joanna Owoc-Lempach, Katarzyna Derwich, Jacek Wachowiak, Maciej Niedźwiecki, Elżbieta Adamkiewicz- Drożyńska, Joanna Trelińska, Wojciech Młynarski, Andrzej Kołtan, Mariusz Wysocki, Renata Tomaszewska, Tomasz Szczepański, Marcin Płonowski, Maryna Krawczuk-Rybak, Tomasz Ociepa, Tomasz Urasiński, Agnieszka Mizia-Malarz, Grażyna Sobol-Milejska, Grażyna Karolczyk & Jerzy Kowalczyk (2017): Outcome of acute lymphoblastic leukemia in children with down syndrome—Polish pediatric leukemia and lymphoma study group report, Pediatric Hematology and Oncology, DOI: 10.1080/08880018.2017.1363837 To link to this article: http://dx.doi.org/10.1080/08880018.2017.1363837

Published online: 17 Oct 2017.

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Date: 18 October 2017, At: 01:37

PEDIATRIC HEMATOLOGY AND ONCOLOGY https://doi.org/./..

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Outcome of acute lymphoblastic leukemia in children with down syndrome—Polish pediatric leukemia and lymphoma study group report Joanna Zawitkowska, PhDa , Teresa Odój, PhDa , Katarzyna Drabko, PhDa , Agnieszka Zaucha-Pra˙zmo, PhDa , Julia Rudnicka, MDa , Michał Romiszewski, PhDb , ´ ´ ´ Michał Matysiakb , Kinga Kwiecinska, PhDc , Magdalena Cwikli nska, PhDc , c d Walentyna Balwierz , Joanna Owoc-Lempach, PhD , Katarzyna Derwich, PhDe , ´ f, Jacek Wachowiake , Maciej Nied´zwiecki, PhDf , El˙zbieta Adamkiewicz- Dro˙zynska g g h ´ Joanna Trelinska, PhD , Wojciech Młynarski , Andrzej Kołtan, PhD , Mariusz Wysockih , ´ i , Marcin Płonowski, PhDj , Renata Tomaszewska, PhDi , Tomasz Szczepanski j ´ k, Maryna Krawczuk-Rybak , Tomasz Ociepa, PhDk , Tomasz Urasinski l l Agnieszka Mizia-Malarz, PhD , Gra˙zyna Sobol-Milejska, PhD , Gra˙zyna Karolczyk, PhDm , and Jerzy Kowalczyka a

Department of Pediatric Hematology, Oncology and Transplantology, Medical University, Lublin, Poland; Department of Hematology and Pediatrics, Children’s Hospital, Warsaw, Poland; c Department of Pediatric Oncology and Hematology, Children’s University Hospital, Kraków, Poland; d Department of Pediatric Transplantology, Oncology, Hematology, Medical University, Wrocław, Poland; e Department of Pediatric ´ Poland; f Department of Pediatrics, Oncology, Hematology and Transplantology, Medical University, Poznan, ´ Poland; g Department of Pediatrics, Hematology, Oncology and Endocrinology, Medical University, Gdansk, Oncology, Hematology and Diabetology, Medical University, Łód´z, Poland; h Department of Pediatrics, Hematology and Oncology, Collegium Medicum, Bydgoszcz, Poland; i Department of Pediatrics, Hematology and Oncology, Medical University, Zabrze, Poland; j Department of Pediatric Oncology, Hematology, Medical University, Białystok, Poland; k Department of Pediatrics, Hematology and Oncology, Medical University, Szczecin, Poland; l Department of Pediatric Oncology, Hematology and Chemotherapy, Medical University, Katowice, Poland; m Department of Pediatric Oncology and Hematology, Children’s Hospital, Kielce, Poland b

ABSTRACT

ARTICLE HISTORY

Children with Down syndrome (DS) have a 20-fold increased risk of developing leukemia compared with the general population. The aim of the study was to analyze the outcome of patients diagnosed with Down syndrome and acute lymphoblastic leukemia (ALL) in Poland between the years 2003 and 2010. A total of 1848 children were diagnosed with ALL (810 females and 1038 males). Of those, 41 (2.2%) had DS. The children were classified into three risk groups: a standard-risk group—14 patients, an intermediate-risk group—24, a high-risk group—3. All patients were treated according to ALLIC 2002 protocol. The median observation time of all patients was 6.1 years, and in patients with DS 5.3 years. Five-year overall survival (OS) was the same in all patients (86% vs 86%, longrank test, p = .9). The relapse-free survival (RFS) was calculated as 73% in patients with DS and 81% in patients without DS during a median observation time (long-rank test, p = .3). No statistically significant differences were found in the incidence of nonrelapse mortality between those two groups of patients (p = .72). The study was based on children with ALL

Received  January  Revised  July  Accepted  July  KEYWORDS

ALL; chemotherapy; children; Down syndrome

CONTACT Joanna Zawitkowska PhD jzawitkowska@o.pl Department of Pediatric Hematology, Oncology and Transplantology, Medical University,  Professor Antoni Gebala Street, - Lublin, Poland. ˛ Color versions of one or more of the figures in the article can be found online at www.tandonline.com/ipho. ©  Taylor & Francis Group, LLC

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J. ZAWITKOWSKA ET AL.

and Down syndrome who were treated with an identical therapy schedule as ALL patients without DS, according to risk group. This fact can increase the value of the presented results.

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Introduction Children with Down syndrome (DS) have a 20-fold increased risk of developing leukemia compared to the general population. Patients with DS are estimated to represent 2% of all acute lymphoblastic leukemia (ALL) cases in children [3, 9]. Clinical features of ALL in children with DS include a lower incidence of hyperdiploidy and ETV6-RUNX1(TEL-AML1), rare occurrence of T-cell ALL, excessive toxicity of methotrexate, an increased incidence of infections compared to patients without DS [2, 9]. Individuals with DS without leukemia were reported to have functional defects in B-cell, T-cell, and phagocytic cell systems. Therefore, they have a higher risk of death from bacterial sepsis. Additionally, the metabolism of drugs in patients with DS may be distinct from that in healthy counterparts. A limited number of studies suggested that patients with DS and ALL had an increased risk of mucositis from methotrexate (MTX), myelosuppression from anthracyclines, and hyperglycemia from glucocorticoids [2, 6, 7, 8]. Both higher treatment-related mortality (TRM) and a higher relapse rate contributed to an inferior outcome of children with DS and ALL compared to patients without DS [2, 9]. The aim of the study was to analyze the outcome measured as overall survival (OS) and relapse free survival (RFS) of patients diagnosed with Down syndrome and acute lymphoblastic leukemia in Poland from 2003 to 2010.

Patients and methods The study included children treated for ALL in 14 pediatric hematology centers in Poland between the years 2003 and 2010. A total of 1848 children were diagnosed with ALL (810 females and 1038 males). Of those, 41 (2.2%) had DS. The percentage of DS patients was comparable to that reported in the literature. The median age at diagnosis of patients with DS was 5.5 (range 2–18) years, in patients without DS 5.2 (range 1–18) years, p > .05. Cytogenetic aberrations BCR/ABL (t 9; 22) or KMT2A (MLL-AF4), which are important in classification into risk groups, were not found in any DS patient included in the study. A detection of those mutations could change the risk groups of particular patients. Band karyotyping and fluorescence in situ hybridization (FISH) were used to detect those abnormalities. The predominant immunophenotype of leukemia was pre-B-, common-positive. The infiltration of central nervous system at diagnosis was observed in three children and the testes were not involved in any child with DS and ALL. Minimal residual disease (MRD) was not routinely evaluated in the study group. Distribution of all the study population into risk groups was as follows: SR 536 patients (29%), IR 924 pts (50%), and HR 388 pts (21%). The clinical details of children with DS included in the analysis are presented in Table 1. All patients were treated according to ALL IC-BFM 2002 protocol—a randomized trial of the I-BFM-SG (International Berlin-Frankfurt-Munster Study Group) for the Management of Childhood Acute Lymphoblastic Leukemia, excluding Burkitt’s leukemia. This program did not provide a separate treatment protocol for patients with DS; therefore, they were treated with the same measures as patients without DS. In centers participating in the study, there was no other first line treatment for ALL.

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Table . Clinical features of Down syndrome patients included in the study.

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No. of patients



Sex Female Male Median age (years) Median WBC at diagnosis [µl] Median Hb [g/dl] Median PLT [µl] Median % blast (BM) day  Median % blast (BM) day  Immunophenotype Pre-B Common positive Common negative Pre-T Prednisone response good poor Risk Group SR IR HR

 (%)  (%) . (–) , (,–,) . (.–.) , (,—,) . (–) . (–.)   (%)  (%)  (%)  (%)  (%)  (%)  (%)  (%)

WBC, white blood cells; Hb, hemoglobin; PLT, thrombocytes; BM, bone marrow; SR, standard risk; IR, intermediate risk; HR, high risk.

Prognostic factors of ALL IC BFM 2002 included: age, white blood cell count (WBC) at diagnosis, response to prednisone at day 8, results of bone marrow evaluation on day 15 or 33 of therapy and, finally, the presence of specific genetic aberrations (BCR/ABL, MLL/AF4). CNS status and testicular involvement at diagnosis had no input on the initial risk classification. At diagnosis, the patients were classified into three groups: a standard-, intermediate-, and high-risk groups. Risk group definitions are shown in Table 2. The treatment plan included: induction of remission (Protocol I or I’), consolidation (protocol mM/M or HR-blocks), reinduction (protocol II), and maintenance therapy. The treatment protocol medications for each risk group is presented in Table 3. For HR-patients after the third HR-block bone marrow transplantation was indicated when a matching related donor was available. The maintenance therapy was obligatory to all children, except those who underwent transplantation. Standard supportive care of acute toxicities as well as infection and metabolic complications was conducted according to recommendations included in the therapeutic schedule. Survival was estimated using the Kaplan-Meier method; differences were analyzed by means of a log-rank test. The value of p < .05 was considered statistically significant. Table . Risk group definitions.

Age WBC Prednisone response BM ( day) BM ( day) t (;) [BCR/ABL] t (;) [MLL/AF]

SR

IR—first population

IR—second population

HR

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