Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.7)
Index Copernicus  – 161.11; MNiSW – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2014, vol. 23, nr 3, May-June, p. 469–474

Publication type: review article

Language: English

How Have Advances in Our Understanding of the Molecular Genetics of Paediatric Leukaemia Led to Improved Targeted Therapies for These Diseases?

Elwira Szychot1,A,B,C,D,E,F, Andrzej Brodkiewicz2,E,F, Jarosław Peregud-Pogorzelski3,E,F

1 Haematology and Oncology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

2 Department of Pediatrics, Nephrology with Dializotheraphy and Management of Acute Poisoning, Pomeranian Medical University, Szczecin, Poland

3 Department of Pediatrics, Hematology and Pediatric Oncology, Pomeranian Medical University, Szczecin, Poland

Abstract

The term “leukaemia” refers to a large and heterogenous group of diseases, with treatment response and outcome dependent on the specific type of malignancy. New molecular methods allow us to specifically evaluate the type of disorder, and provide treatment of necessary intensity. The aim of this review is to provide insight into the progress in leukaemia treatment that had been possible due to advances in molecular genetics over the last few decades. Those new sophisticated diagnostic methods have allowed us not only to predict patients’ prognosis but also to provide a specific therapy depending on the molecular and genetic characteristics of patients. Our review is based on 25 articles regarding novel diagnostic and therapeutic methods as well as prognostic factors, released between 1992 and 2011. Those articles focus mostly on molecular and cytogenetic testing allowing revolutionary methods of patient classification and individual therapy for this highly heterogeneous group of disorders. Implementation of molecular genetic testing to evaluate the type of leukaemia allowed paediatric oncologists and haematologists to adjust the intensity of treatment, improve outcome, minimize toxicity of therapies and considerably lower the risk of side effects. In the last few decades there has been a great improvement in survival among children suffering from haematopoietic malignancies. Progress made in molecular genetics allowed the creation of new treatment protocols that are designed to maintain a high cure rate for children with leukaemia while reducing toxicity.

Key words

children, leukaemia, genes, targeted therapy.

References (25)

  1. Margolin JF: Molecular diagnosis and risk-adjusted therapy in pediatric hematologic malignancies: a primer for pediatricians. Eur J Pediatr 2011, 170, 419–425.
  2. Pieters R, Carroll WL: Biology and treatment of acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2010, 24, 1–18.
  3. Winter SS: Pediatric acute leukemia therapies informed by molecular analysis of high-risk disease. Hematology Am Soc Hematol Educ Program 2011, 366–373.
  4. Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, Kung AL, Armstrong SA: MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 2008, 22, 66–77.
  5. Harris MB, Shuster JJ, Carroll A, Look AT, Borowitz MJ, Crist WM, Nitschke R, Pullen J, Steuber CP, Land VJ: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 1992, 79, 3316–3324.
  6. Heerema NA, Sather HN, Sensel MG, Heerema NA, Zhang T, Hutchinson RJ, Nachman JB, Lange BJ, Steinherz PG, Bostrom BC, Reaman GH, Gaynon PS, Uckun FM: Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes). J Clin Oncol 2000, 18, 1876–1887.
  7. Li ZY, Liu DP, Liang CC: New insight into the molecular mechanisms of MLL-associated leukemia. Leukemia 2005, 19, 183–190.
  8. Chauvenet AR, Martin PL, Devidas M, Chauvenet AR Linda SB, Bell BA, Kurtzberg J, Pullen J, Pettenati MJ, Carroll AJ, Shuster JJ, Camitta B: Antimetabolite therapy for lesser-risk B-lineage acute lymphoblastic leukemia of childhood: a report from Children’s Oncology Group Study P9201. Blood 2007, 110, 1105–1111.
  9. Hunger SP, Winick NJ, Sather HN, Carroll WL: Therapy of low-risk subsets of childhood acute lymphoblastic leukemia: when do we say enough? Pediatr Blood Cancer 2005, 45, 876–880.
  10. Flohr T, Schrauder A, Cazzaniga G, Flohr T, Panzer-Grümayer R, van der Velden V, Fischer S, Stanulla M, Basso G, Niggli FK, Schäfer BW, Sutton R, Koehler R, Zimmermann M, Valsecchi MG, Gadner H, Masera G, Schrappe M, van Dongen JJ, Biondi A, Bartram CR; International BFM Study Group (I-BFM-SG): Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM A
  11. Rubnitz JE, Gibson B, Smith FO: Acute myeloid leukemia. Hematol Oncol Clin North Am 2010, 24, 35–63.
  12. Schultz KR, Bowman WP, Aledo A, Slayton WB, Sather H, Devidas M, Wang C, Davies SM, Gaynon PS, Trigg M, Rutledge R, Burden L, Jorstad D, Carroll A, Heerema NA, Winick N, Borowitz MJ, Hunger SP, Carroll WL, Camitta B: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol 2009, 27, 5175–5181.
  13. Pui CH, Robison LL, Look AT: Acute lymphoblastic leukaemia. Lancet 2008, 371, 1030–1043.
  14. Campana D: Molecular determinants of treatment response in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2008, 366–373.
  15. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, Linda S, Martin PL, Pullen DJ, Viswanatha D, Willman CL, Winick N, Camitta BM; Children’s Oncology Group: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood 2008, 111, 5477–5485.
  16. Mullighan CG, Downing JR: Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia 2009, 23, 1209–1218.
  17. Ensor HM, Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, Jones L, Kinsey SE, Vora AJ, Mitchell CD, Harrison CJ, Moorman AV: Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 2011, 117, 2129–2136.
  18. Lee-Sherick AB, Linger RM, Gore L, Keating AK, Graham DK: Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development. Br J Haematol 2010, 151, 295–311.
  19. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D: Early T-cell precursor leukaemia: a subtype of very highrisk acute lymphoblastic leukaemia. Lancet Oncol 2009, 10, 147–156.
  20. Lugthart S, Cheok MH, den Boer ML, Yang W, Holleman A, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE: Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia. Cancer Cell 2005, 7, 375–386.
  21. Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM, Pei D, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R, Evans WE: Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 2004, 351, 533–542.
  22. Peregud-Pogorzelski J, Tetera-Rudnicka E, Kurzawski M, Brodkiewicz A, Adrianowska N, Mlynarski W, Januszkiewicz D, Drozdzik M: Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: the Polish multicenter analysis. Pediatr Blood Cancer 2011, 57, 578–582.
  23. Meshinchi S, Arceci RJ: Prognostic factors and risk-based therapy in pediatric acute myeloid leukemia. Oncologist 2007, 12, 341–355.
  24. Kondo M, Horibe K, Takahashi Y, Matsumoto K, Fukuda M, Inaba J, Kato K, Kojima S, Matsuyama T: Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med Pediatr Oncol 1999, 33, 525–529.
  25. Wiernik PH: FLT3 inhibitors for the treatment of acute myeloid leukemia. Clin Adv Hematol Oncol 2010, 8, 429–436, 444.