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Acute Lymphoblastic Leukemia

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Molecular Pathology in Clinical Practice

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Abstract

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of disorders which originate from various important genetic lesions in B and T progenitor cells, including mutations that lead to stage-specific developmental arrest and those that impart the capacity for unlimited self-renewal, resulting in clonal expansion of immature progenitor cells (Pui et al. Lancet 371:1030–43, 2008; Pui et al. Blood 120:1165–74, 2012; Morgolin et al. 2011). Different B- and T-cell ALLs can be recognized according to immunologic and molecular criteria (Pui et al. Blood 82:343–62, 1993; Yeoh et al. Cancer Cell 1:133–43, 2002; Pui et al. J Clin Oncol 29:551–65, 2011). The identification of the molecular events underlying the process of leukemia transformation has provided not only important biological information but also clinically significant genetic markers for the identification of prognostically relevant ALL subgroups and for the molecular monitoring of minimal residual disease (MRD). For ALL, immunoglobulin (IG) and T-cell receptor (TCR) gene rearrangement studies are used as markers of clonality and for MRD detection. In addition, the identification of different genetic variations is used to define different ALL subgroups and to refine treatment protocols tailored to the risk of relapse.

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References

  1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371:1030–43.

    Article  CAS  PubMed  Google Scholar 

  2. Pui CH, Mullighan CG, Evans WE, et al. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Margolin JF, Rabin KR, Steuber CP, et al. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, editors. Principles and practice of pediatric oncology. 6th ed. PA: Lippincott Williams & Wilkins; 2011. p. 518–65.

    Google Scholar 

  4. Pui CH, Behm FG, Crist WM. Clinical and biological relevance of immunologic marker studies in childhood acute lymphoblastic leukemia. Blood. 1993;82:343–62.

    CAS  PubMed  Google Scholar 

  5. Yeoh EJ, Roos ME, Shurtleff AS, et al. Classification, subtype discovery, and prediction outcome in pediatric acute lymphoblastic leukemia by gene expression profile. Cancer Cell. 2002;1:133–43.

    Article  CAS  PubMed  Google Scholar 

  6. Pui CH, Carroll WL, Meshinchi S, et al. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29:551–65.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302:575–81.

    Article  CAS  PubMed  Google Scholar 

  8. van Dongen JJM, Wolvers-Tettero ILM. Analysis of immunoglobulin and T cell receptor genes. Part I: basic and technical aspects. Clin Chim Acta. 1991;198:1–92.

    Article  PubMed  Google Scholar 

  9. van Dongen JJM, Wolvers-Tettero ILM. Analysis of immunoglobulin and T cell receptor genes. Part II: possibilities and limitations in the diagnosis and management of lymphoproliferative diseases and related disorders. Clin Chim Acta. 1991;198:93–174.

    Article  PubMed  Google Scholar 

  10. van Dongen JJM, Langerak AW. Immunoglobulin and T-cell receptor gene rearrangements. In: Pui CH, editor. Childhood leukemias. 2nd ed. Cambridge: Cambridge University Press; 2006. p. 210–34.

    Chapter  Google Scholar 

  11. Langerak AW, Groenen PJ, Brüggemann M, et al. EuroClonality/BIOMED-2 guidelines for interpretation and reporting of Ig/TCR clonality testing in suspected lymphoproliferations. Leukemia. 2012;2012(26):2159–71.

    Article  CAS  Google Scholar 

  12. van Zelm MC, van der Burg M, de Ridder D, et al. Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. J Immunol. 2005;175:5912–22.

    Article  PubMed  Google Scholar 

  13. Dik WA, Pike-Overzet K, Weerkamp F, et al. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med. 2005;201:1715–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Brisco MJ, Tan LW, Orsborn AM, et al. Development of a highly sensitive assay, based on the polymerase chain reaction, for rare B-lymphocyte clones in a polyclonal population. Br J Haematol. 1990;75:163–7.

    Article  CAS  PubMed  Google Scholar 

  15. Scrideli CA, Simoes AL, Defavery R, et al. Childhood B lineage acute lymphoblastic leukemia clonality study by the polymerase chain reaction. J Pediatr Hematol Oncol. 1997;19:516–22.

    Article  CAS  PubMed  Google Scholar 

  16. Pongers-Willemse MJ, Seriu T, Stolz F, et al. Primers and protocols for standardized MRD detection in ALL using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. Report of the BIOMED-1 Concerted Action: Investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13:110–8.

    Article  CAS  PubMed  Google Scholar 

  17. Szczepanski T, Beishuizen A, Pongers-Willemse MJ, et al. Crosslineage T-cell receptor gene rearrangements occur in more than ninety percent of childhood precursor-B-acute lymphoblastic leukaemias: alternative PCR targets for detection of minimal residual disease. Leukemia. 1999;13:196–205.

    Article  CAS  PubMed  Google Scholar 

  18. Assumpção JG, Ganazza MA, de Araújo M, et al. Detection of clonal immunoglobulin and T-cell receptor gene rearrangements in childhood acute lymphoblastic leukemia using a low-cost PCR strategy. Pediatr Blood Cancer. 2010;55:1278–86.

    Article  PubMed  Google Scholar 

  19. Tkachuck DC, Griesser H, Takirara Y, et al. Rearrangement of T-cell delta locus in lymphoproliferative disorders. Blood. 1988;72:353–7.

    Google Scholar 

  20. Biondi A, Francia de Celli P, Rossi V, et al. High prevalence of T-cell receptor V delta 2-(D)-D delta 3 or D delta 1/2-D delta 3 rearrangements in B-precursor acute lymphoblastic leukemias. Blood. 1990;75:1834–40.

    CAS  PubMed  Google Scholar 

  21. Trainor KJ, Brisco MJ, Wan JH, et al. Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction. Blood. 1991;78:192–6.

    CAS  PubMed  Google Scholar 

  22. Szczepanki T, LangeraK AW, Wolvers-Tettero IL, et al. Immunoglobulin and T cell receptor gene rearrangement patterns in acute lymphoblastic leukemia are less mature in adults than in children: implications for selection of PCR targets for detection of minimal residual disease. Leukemia. 1998;12:1081–8.

    Article  Google Scholar 

  23. Szczepanski T, van der Velden VH, Hoogeveen PG, et al. Vdelta2-Jalpha rearrangements are frequent in precursor-B-acute lymphoblastic leukemia but rare in normal lymphoid cells. Blood. 2004;103:3798–804.

    Article  CAS  PubMed  Google Scholar 

  24. Scrideli CA, Queiroz RG, Kashima S, et al. T cell receptor gamma (TCRG) gene rearrangements in Brazilian children with acute lymphoblastic leukemia: analysis and implications for the study of minimal residual disease. Leuk Res. 2004;28:267–73.

    Article  CAS  PubMed  Google Scholar 

  25. Scrideli CA, Queiroz RP, Takayanagui OM, et al. Molecular diagnosis of leukemic cerebrospinal fluid cells in children with newly diagnosed acute lymphoblastic leukemia. Haematologica. 2004;89:1013–5.

    CAS  PubMed  Google Scholar 

  26. van Dongen JJ, Macintyre EA, Gabert JA, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13:1901–28.

    Article  PubMed  CAS  Google Scholar 

  27. Yano T, Pullman A, Andade R, et al. A common Vd2-Dd2-Dd3 T cell receptor gene rearrangement in precursor B acute lymphoblastic leukemia. Br J Haematol. 1991;79:44–9.

    Article  CAS  PubMed  Google Scholar 

  28. Heerema NA, Sather HN, Sensel MG, et al. 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;18:1876–87.

    CAS  PubMed  Google Scholar 

  29. Harrison CJ. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol. 2009;144:147–56.

    Article  PubMed  Google Scholar 

  30. Meijerink JP, den Boer ML, Pieters R. New genetic abnormalities and treatment response in acute lymphoblastic leukemia. Semin Hematol. 2009;46:16–23.

    Article  PubMed  Google Scholar 

  31. Armstrong SA, Look AT. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol. 2005;23:6306–15.

    Article  CAS  PubMed  Google Scholar 

  32. Look AT. Oncogenic transcription factors in the human acute leukaemias. Science. 1997;278:1059–64.

    Article  CAS  PubMed  Google Scholar 

  33. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.

    Article  CAS  PubMed  Google Scholar 

  34. Borkhardt A, Cazzaniga G, Viehmann S, et al. Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster Study Group. Blood. 1997;90:571–77.

    CAS  PubMed  Google Scholar 

  35. Raynaud S, Mauvieux L, Cayuela JM, et al. TEL/AML1 fusion gene is a rare event in adult acute lymphoblastic leukemia. Leukemia. 1996;10:1529–30.

    CAS  PubMed  Google Scholar 

  36. Mullighan CG. Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest. 2012;122:3407–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012;2012:389–96.

    PubMed  Google Scholar 

  38. Greaves MF, Maia AT, Wiemels JL, et al. Leukemia in twins: lessons in natural history. Blood. 2003;102:2321–33.

    Article  CAS  PubMed  Google Scholar 

  39. Seeger K, Adams HP, Buchwald D, et al. TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin–Frankfurt–Munster Study Group. Blood. 1998;91:1716–22.

    CAS  PubMed  Google Scholar 

  40. Hunger SP, Fall MZ, Camitta BM, et al. E2A-PBX1 chimeric transcript status at end of consolidation is not predictive of treatment outcome in childhood acute lymphoblastic leukemias with a t(1;19)(q23;p13): a Pediatric Oncology Group study. Blood. 1998;91:1021–8.

    CAS  PubMed  Google Scholar 

  41. Privitera E, Luciano A, Ronchetti D, et al. Molecular variants of the 1;19 chromosomal translocation in pediatric acute lymphoblastic leukemia (ALL). Leukemia. 1994;8:554–9.

    CAS  PubMed  Google Scholar 

  42. Pui CH, Sandlund JT, Pei D, et al. Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA. 2003;290:2001–7.

    Article  CAS  PubMed  Google Scholar 

  43. Raimondi SC, Privitera E, Williams DL, et al. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood. 1991;77:2016–22.

    CAS  PubMed  Google Scholar 

  44. Behm FG, Raimondi SC, Frestedt JL, et al. Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood. 1996;87:2870–7.

    CAS  PubMed  Google Scholar 

  45. Biondi A, Cimino G, Pieters R, et al. Biological and therapeutic aspects of infant leukemia. Blood. 2000;96:24–33.

    CAS  PubMed  Google Scholar 

  46. Biondi A, Valsecchi MG, Seriu T, et al. Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM Study Group. Leukemia. 2000;14:1939–43.

    Article  CAS  PubMed  Google Scholar 

  47. Cazzaniga G, Lanciotti M, Rossi V, et al. Prospective molecular monitoring of BCR/ABL transcript in children with Ph+ acute lymphoblastic leukaemia unravels differences in treatment response. BrJ Haematol. 2002;119:445–53.

    Article  CAS  Google Scholar 

  48. Cazzaniga G, Rossi V, Biondi A. Monitoring minimal residual disease using chromosomal translocations in childhood ALL. Best Pract Res Clin Haematol. 2002;15:21–35.

    Article  CAS  PubMed  Google Scholar 

  49. Mann G, Attarbaschi A, Schrappe M, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study. Blood. 2010;116:2644–50.

    Article  CAS  PubMed  Google Scholar 

  50. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343–56.

    CAS  PubMed  Google Scholar 

  51. Scrideli CA, Cazzaniga G, Fazio G, et al. Gene expression profile unravels significant differences between childhood and adult Ph+ acute lymphoblastic leukemia. Leukemia. 2003;17:2234–7.

    Article  CAS  PubMed  Google Scholar 

  52. Scrideli CA, Queiroz RG, Bernardes JE, et al. PCR detection of clonal IgH and TCR gene rearrangements at the end of induction as a non-remission criterion in children with ALL: comparison with standard morphologic analysis and risk group classification. Med Pediatr Oncol. 2003;41:10–6.

    Article  PubMed  Google Scholar 

  53. Scrideli CA, Queiroz RP, Takayanagui OM, et al. Polymerase chain reaction on cerebrospinal fluid cells in suspected leptomeningeal involvement in childhood acute lymphoblastic leukemia: comparison to cytomorphological analysis. Diagn Mol Pathol. 2003;12:124–7.

    Article  PubMed  Google Scholar 

  54. Schrappe M, Arico M, Harbott J, et al. Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood. 1998;92:2730–41.

    CAS  PubMed  Google Scholar 

  55. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27:5175–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Biondi A, Schrappe M, De Lorenzo P, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13:936–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360:470–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10:125–34.

    Article  CAS  Google Scholar 

  59. Cline MJ. The molecular basis of leukaemia. N Engl J Med. 1994;330:328–36.

    Article  CAS  PubMed  Google Scholar 

  60. Scrideli CA, Tone LG. Molecular basis of acute lymphoblastic leukemia. In: Novak E, Rego EM, editors. Physiopathogenesis of hematological cancer. 1st ed. Sharjah: Bentham Science; 2012. p. 168–82.

    Google Scholar 

  61. Mullighan CG, Downing JR. Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia. 2009;23:1209–18.

    Article  CAS  PubMed  Google Scholar 

  62. Ferrando AA, Look AT. Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin Hematol. 2003;40:274–80.

    Article  CAS  PubMed  Google Scholar 

  63. Ferrando AA, Look AT. DNA microarrays in the diagnosis and management of acute lymphoblastic leukemia. Int J Hematol. 2004;80:395–400.

    Article  CAS  PubMed  Google Scholar 

  64. Van Vlierberghe P, Pieters R, Beverloo HB, et al. Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br J Haematol. 2008;143:153–68.

    Article  PubMed  CAS  Google Scholar 

  65. Van Vlierberghe P, van Grotel M, Tchinda J, et al. The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood. 2008;111:4668–80.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Ferrando AA, Neuberg DS, Staunton J, et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 2002;1:75–87.

    Article  CAS  PubMed  Google Scholar 

  67. Meijerink JP. Genetic rearrangements in relation to immunophenotype and outcome in T-cell acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2010;23:307–18.

    Article  CAS  PubMed  Google Scholar 

  68. Homminga I, Vuerhard MJ, Langerak AW, et al. Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements. Haematologica. 2012;97:258–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Heerema NA, Sather HN, Sensel MG, et al. Frequency and clinical significance of cytogenetic abnormalities in pediatric T-lineage acute lymphoblastic leukemia: a report from the Children’s Cancer Group. J Clin Oncol. 1998;16:1270–8.

    CAS  PubMed  Google Scholar 

  71. Karrman K, Forestier E, Heyman M, et al. Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome. Genes Chromosomes Cancer. 2009;48:795–805.

    Article  CAS  PubMed  Google Scholar 

  72. Soulier J, Clappier E, Cayuela JM, et al. HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood. 2005;106:274–86.

    Article  CAS  PubMed  Google Scholar 

  73. Jotta PY, Ganazza MA, Silva A, et al. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia. 2010;24:239–42.

    Article  CAS  PubMed  Google Scholar 

  74. Zenatti PP, Ribeiro D, Li W, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43:932–9.

    Article  CAS  PubMed  Google Scholar 

  75. Biojone E, Queiróz Rde P, Valera ET, et al. Minimal residual disease in cerebrospinal fluid at diagnosis: a more intensive treatment protocol was able to eliminate the adverse prognosis in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2012;53:89–95.

    Article  CAS  PubMed  Google Scholar 

  76. Cave H, van der Werff Ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. N Engl J Med. 1998;339:591–8.

    Article  CAS  PubMed  Google Scholar 

  77. van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731–8.

    Article  PubMed  Google Scholar 

  78. Flohr T, Schrauder A, Cazzaniga G, et al. 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 ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia. 2008;22:771–82.

    Article  CAS  PubMed  Google Scholar 

  79. Scrideli CA, Assumpção JG, Ganazza MA, et al. A simplified minimal residual disease polymerase chain reaction method at early treatment points can stratify children with acute lymphoblastic leukemia into good and poor outcome groups. Haematologica. 2009;94:781–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115:3206–14.

    Article  CAS  PubMed  Google Scholar 

  81. Gabert J, Beillard E, van der Velden VH, et al. Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003;17:2318–57.

    Article  CAS  PubMed  Google Scholar 

  82. Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status as a predictor of relapse after allogeneic bone marrow transplantation for children with acute lymphoblastic leukaemia. Br J Haematol. 1998;102:860–71.

    Article  CAS  PubMed  Google Scholar 

  83. Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status before allogeneic bone marrow transplantation is an important determinant of successful outcome for children and adolescents with acute lymphoblastic leukemia. Blood. 1998;92:4072–9.

    CAS  PubMed  Google Scholar 

  84. van der Velden VHJ, Joosten SA, Willemse MJ, et al. Real-time quantitative PCR for detection of minimal residual disease before allogeneic stem cell transplantation predicts outcome in children with acute lymphoblastic leukemia. Leukemia. 2001;15:1485–7.

    Article  PubMed  Google Scholar 

  85. Paganin M, Zecca M, Fabbri G, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed ‘high-risk’ acute lymphoblastic leukemia. Leukemia. 2008;22:2193–200.

    Article  CAS  PubMed  Google Scholar 

  86. Ruggeri A, Michel G, Dalle JH, et al. Impact of pre-transplant minimal residual disease after cord blood transplantation for childhood acute lymphoblastic leukemia in remission. An Eurocord, PDWP-EBMT analysis. Leukemia. 2012;26:2455–61.

    Article  CAS  PubMed  Google Scholar 

  87. Buckley SA, Appelbaum FR, Walter RB. Prognostic and therapeutic implications of minimal residual disease at the time of transplantation in acute leukemia. Bone Marrow Transplant. 2013;48:630–41.

    Article  CAS  PubMed  Google Scholar 

  88. Sklar J. Polymerase chain reaction: the molecular microscope of residual disease. J Clin Oncol. 1991;1:1521–23.

    Google Scholar 

  89. Eckert C, Scrideli CA, Taube T, et al. Comparison between TaqMan and LightCycler technologies for quantification of minimal residual disease by using immunoglobulin and T-cell receptor genes consensus probes. Leukemia. 2003;17:2517–24.

    Article  CAS  PubMed  Google Scholar 

  90. Cazzaniga G, Biondi A. Molecular monitoring of childhood acute lymphoblastic leukemia using antigen receptor gene rearrangements and quantitative polymerase chain reaction technology. Haematologica. 2005;90:382–90.

    CAS  PubMed  Google Scholar 

  91. van der Velden VH, Hochhaus A, Cazzaniga G, et al. Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia. 2003;17:1013–34.

    Article  PubMed  CAS  Google Scholar 

  92. van der Velden VH, Cazzaniga G, Schrauder A, et al. Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21:604–11.

    PubMed  Google Scholar 

  93. Garand R, Beldjord K, Cavé H, et al. Flow cytometry and IG/TCR quantitative PCR for minimal residual disease quantitation in acute lymphoblastic leukemia: a French multicenter prospective study on behalf of the FRALLE, EORTC and GRAALL. Leukemia. 2013;27:370–6.

    Article  CAS  PubMed  Google Scholar 

  94. Brüggemann M, Gökbuget N, Kneba M. Acute lymphoblastic leukemia: monitoring minimal residual disease as a therapeutic principle. Semin Oncol. 2012;39:47–57.

    Article  PubMed  CAS  Google Scholar 

  95. Pongers-Willemse MJ, Verhagen OJ, Tibbe GJ, et al. Real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia using junctional region specific TaqMan probes. Leukemia. 1998;12:2006–14.

    Article  CAS  PubMed  Google Scholar 

  96. Verhagen OJ, Willemse MJ, Breunis WB, et al. Application of germline IgH probes in real-time quantitative PCR for the detection of minimal residual disease in acute lymphoblastic leukemia. Leukemia. 2000;14:1426–35.

    Article  CAS  PubMed  Google Scholar 

  97. Beillard E, Pallisgaard N, van der Velden VH, et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using “real-time” quantitative reverse- transcriptase polymerase chain reaction (RQ-PCR)—a Europe Against Cancer program. Leukemia. 2003;17:2474–86.

    Article  CAS  PubMed  Google Scholar 

  98. Guidal C, Vilmer E, Grandchamp B, et al. A competitive PCR- based method using TCRD, TCRG and IGH rearrangements for rapid detection of patients with high levels of minimal residual disease in acute lymphoblastic leukemia. Leukemia. 2002;16:762–4.

    Article  CAS  PubMed  Google Scholar 

  99. Landman-Parker J, Aubin J, Delabesse E, et al. Simplified strategies for minimal residual disease detection in B cell precursor acute lymphoblastic leukaemia. Br J Haematol. 1996;95:281–90.

    Article  CAS  PubMed  Google Scholar 

  100. Evans PA, Short MA, Owen RG, et al. Residual disease detection using fluorescent polymerase chain reaction at 20 weeks of therapy predicts clinical outcome in childhood acute lymphoblastic leukemia. J Clin Oncol. 1998;16:3616–27.

    CAS  PubMed  Google Scholar 

  101. Bottaro M, Berti E, Biondi A, et al. Heteroduplex analysis of T-cell receptor gamma gene rearrangements for diagnosis and monitoring of cutaneous T-cell lymphomas. Blood. 1994;83:3271–8.

    CAS  PubMed  Google Scholar 

  102. Langerak AW, Szczepański T, van der Burg M, et al. Heteroduplex PCR analysis of rearranged T cell receptor genes for clonality assessment in suspect T cell proliferations. Leukemia. 1997;11:2192–9.

    Article  CAS  PubMed  Google Scholar 

  103. Kitchingman GR, Mirro J, Stass S, et al. Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin. Blood. 1986;67:698–703.

    CAS  PubMed  Google Scholar 

  104. Kuang S, Gu L, Dong S, et al. Long-term follow-up of minimal residual disease in childhood acute lymphoblastic leukemia patients by polymerase chain reaction analysis of multiple clone-specific or malignancy-specific gene markers. Cancer Genet Cytogenet. 1996;88:110–7.

    Article  CAS  PubMed  Google Scholar 

  105. Green E, McConville CM, Powell JE, et al. Clonal diversity of Ig and T-cell-receptor gene rearrangements identifies a subset of childhood B-precursor acute lymphoblastic leukemia with increased risk of relapse. Blood. 1998;92:952–8.

    CAS  PubMed  Google Scholar 

  106. Scrideli CA, Defavery R, Bernardes JE, et al. Prognostic significance of bi/oligoclonality in childhood acute lymphoblastic leukemia as determined by polymerase chain reaction. Sao Paulo Med J. 2001;119:175–80.

    Article  CAS  PubMed  Google Scholar 

  107. Brumpt C, Delabesse E, Beldjord K, et al. The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype. Blood. 2000;96:2254–61.

    CAS  PubMed  Google Scholar 

  108. Beishuizen A, Verhoeven MA, Van Wering ER, et al. Analysis of Ig and T cell receptor genes in 40 childhood acute lymphoblastic leukemia at diagnosis and subsequent relapse: implications for the detection of minimal residual disease by polymerase chain reaction analysis. Blood. 1994;83:2238–47.

    CAS  PubMed  Google Scholar 

  109. Steward CG, Goulden NJ, Katz F, et al. A polymerase chain reaction study of the stability of Ig heavy-chain and T cell receptor delta gene rearrangements between presentation and relapse of childhood B-lineage acute lymphoblastic leukemia. Blood. 1994;83:1355–62.

    CAS  PubMed  Google Scholar 

  110. Ghali DW, Panzer S, Fischer S, et al. Heterogeneity of the T cell receptor delta gene indicating subclone formation in acute precursor B cell leukemias. Blood. 1995;85:2795–801.

    CAS  PubMed  Google Scholar 

  111. Hara J, Benedict SH, Yumura K, et al. Rearrangement of variable region T cell receptor γ genes in acute lymphoblastic leukemia. Vγ gene usage differs in mature and immature T cells. J Clin Invest. 1999;83:1277–83.

    Article  Google Scholar 

  112. Marshall GM, Kwan E, Haber M, et al. Characterization of clonal immunoglobulin heavy chain and I cell receptor gamma gene rearrangements during progression of childhood acute lymphoblastic leukemia. Leukemia. 1995;9:1847–50.

    CAS  PubMed  Google Scholar 

  113. Scrideli CA, Kashima S, Cipolloti R, et al. Minimal residual disease in Brazilian children with acute lymphoid leukemia: comparison of three detection methods by PCR. Leuk Res. 2002;26:431–8.

    Article  PubMed  Google Scholar 

  114. Scrideli CA, Kashima S, Cipolloti R, et al. Clonal evolution as the limiting factor in the detection of minimal residual disease by polymerase chain reaction in children in Brazil with acute lymphoid leukemia. J Pediatr Hematol Oncol. 2002;24:364–7.

    Article  PubMed  Google Scholar 

  115. Steenbergen EJ, Verhagen OJ, Van Leeuwen EF, et al. Distinct ongoing Ig heavy chain rearrangement processes in childhood B-precursor acute lymphoblastic leukemia. Blood. 1993;82:581–9.

    CAS  PubMed  Google Scholar 

  116. Lo Nigro L, Cazzaniga G, Di Cataldo A, et al. Clonal stability in children with acute lymphoblastic leukemia (ALL) who relapsed five or more years after diagnosis. Leukemia. 1999;13:190–5.

    Article  CAS  PubMed  Google Scholar 

  117. Choi Y, Greenberg SJ, Du TL, Ward PM, et al. Clonal evolution in B- lineage acute lymphoblastic leukemia by contemporaneous VH-VH gene replacements and VH-DJH gene rearrangements. Blood. 1996;87:2506–12.

    CAS  PubMed  Google Scholar 

  118. Height SE, Swanbury GJ, Matute E, et al. Analysis of clonal rearrangements of the Ig heavy chain locus in acute leukemia. Blood. 1996;87:5242–50.

    CAS  PubMed  Google Scholar 

  119. Bose S, Deininger M, Gora-Tybor J, et al. The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood. 1998;92:3362–67.

    CAS  PubMed  Google Scholar 

  120. Uckun FM, Herman-Hatten K, Crotty ML, et al. Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation. Blood. 1998;92:810–21.

    CAS  PubMed  Google Scholar 

  121. Campana D, Pui CH. Detection of minimal residual disease in acute leukaemia: methodological and clinical significance. Blood. 1995;85:1416–34.

    CAS  PubMed  Google Scholar 

  122. Szczepanski T. Why and how to quantify minimal residual disease in acute lymphoblastic leukemia? Leukemia. 2007;21:622–6.

    CAS  PubMed  Google Scholar 

  123. Fronkova E, Mejstrikova E, Avigad S, et al. Minimal residual disease (MRD) analysis in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: is it possible to avoid MRD testing? Leukemia. 2008;22:989–97.

    Article  CAS  PubMed  Google Scholar 

  124. Moppett J, Burke GA, Steward CG, et al. The clinical relevance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia. J Clin Pathol. 2003;56:249–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Bjorklund E, Mazur J, Soderhall S, et al. Flow cytometric follow-up of minimal residual disease in bone marrow gives prognostic information in children with acute lymphoblastic leukemia. Leukemia. 2003;17:138–48.

    Article  CAS  PubMed  Google Scholar 

  126. Coustan-Smith E, Sancho J, Behm FG, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002;100:52–8.

    Article  CAS  PubMed  Google Scholar 

  127. Coustan-Smith E, Ribeiro RC, Stow P, et al. A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood. 2006;108:97–102.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Porwit-MacDonald A, Bjorklund E, Lucio P, et al. BIOMED-1 concerted action report: flow cytometric characterization of CD7+ cell subsets in normal bone marrow as a basis for the diagnosis and follow-up of T cell acute lymphoblastic leukemia (T-ALL). Leukemia. 2000;14:816–25.

    Article  CAS  PubMed  Google Scholar 

  129. Lucio P, Gaipa G, van Lochem EG, van Wering ER, Porwit-MacDonald A, Faria T, et al. BIOMED-I concerted action report: flow cytometric immunophenotyping of precursor B-ALL with standardized triple-stainings. BIOMED-1 Concerted Action Investigation of Minimal Residual Disease in Acute Leukemia: International Standardization and Clinical Evaluation. Leukemia. 2001;15:1185–92.

    Article  CAS  PubMed  Google Scholar 

  130. Malec M, van der Velden VH, Bjorklund E, et al. Analysis of minimal residual disease in childhood acute lymphoblastic leukemia: comparison between RQ-PCR analysis of Ig/TcR gene rearrangements and multicolor flow cytometric immunophenotyping. Leukemia. 2004;18:1630–6.

    Article  CAS  PubMed  Google Scholar 

  131. Kerst G, Kreyenberg H, Roth C, et al. Concurrent detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukaemia by flow cytometry and real-time PCR. Br J Haematol. 2005;128:774–82.

    Article  CAS  PubMed  Google Scholar 

  132. Schrappe M. Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient. Hematology Am Soc Hematol Educ Program. 2012;2012:137–42.

    PubMed  Google Scholar 

  133. Szczepanski T, Orfao A, van der Velden VH, et al. Minimal residual disease in leukaemia patients. Lancet Oncol. 2001;2:409–17.

    Article  CAS  PubMed  Google Scholar 

  134. Zhou J, Goldwasser MA, Li A, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood. 2007;110:1607–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood. 2007;109:926–35.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Panzer-Grumayer ER, Schneider M, Panzer S, et al. Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood. 2000;95:790–4.

    CAS  PubMed  Google Scholar 

  137. Sutton R, Venn NC, Tolisano J, et al. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2009;146:292–9.

    Article  CAS  PubMed  Google Scholar 

  138. Borowitz MJ, Devidas M, Hunger SP, et al. 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;111:5477–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  139. Bruggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116–23.

    Article  PubMed  CAS  Google Scholar 

  140. Raff T, Gokbuget N, Luschen S, et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood. 2007;109:910–5.

    Article  CAS  PubMed  Google Scholar 

  141. Specchia G, Liso A, Pannunzio A, et al. Molecular detection of minimal residual disease is associated with early relapse in adult acute lymphoblastic leukemia. Haematologica. 2004;89:1271–3.

    CAS  PubMed  Google Scholar 

  142. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14:199–209.

    Article  CAS  PubMed  Google Scholar 

  143. Ryan J, Quinn F, Meunier A, et al. Minimal residual disease detection in childhood acute lymphoblastic leukaemia patients at multiple time-points reveals high levels of concordance between molecular and immunophenotypic approaches. Br J Haematol. 2009;144:107–15.

    Article  PubMed  Google Scholar 

  144. Bader P, Kreyenberg H, Henze GH, ALL-REZ BFM Study Group, et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol. 2009;27:377–84.

    Article  PubMed  Google Scholar 

  145. Eckert C, Biondi A, Seeger K, et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet. 2001;358:1239–41.

    Article  CAS  PubMed  Google Scholar 

  146. Coustan-Smith E, Gajjar A, Hijiya N, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia. 2004;18:499–504.

    Article  CAS  PubMed  Google Scholar 

  147. Pallisgaard N, Clausen N, Schroder H, et al. Rapid and sensitive minimal residual disease detection in acute leukaemia by quantitative real-time RT-PCR exemplified by t(12;21) TEL-AML1 fusion transcript. Genes Chromosomes Cancer. 1999;26:355–65.

    Article  CAS  PubMed  Google Scholar 

  148. Cimino G, Elia L, Rapanotti MC, et al. A prospective study of residual-disease monitoring of the ALL1/AF4 transcript in patients with t(4;11) acute lymphoblastic leukemia. Blood. 2000;95:96–101.

    CAS  PubMed  Google Scholar 

  149. van der Velden VH, Corral L, Valsecchi MG, et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23(6):1073–9.

    Article  PubMed  CAS  Google Scholar 

  150. de Haas V, Breunis WB, Dee R, et al. The TEL-AML1 real-time quantitative polymerase chain reaction (PCR) might replace the antigen receptor-based genomic PCR in clinical minimal residual disease studies in children with acute lymphoblastic leukaemia. Br J Haematol. 2002;116:87–93.

    Article  PubMed  Google Scholar 

  151. Madzo J, Zuna J, Muzíková K, et al. Slower molecular response to treatment predicts poor outcome in patients with TEL/AML1 positive acute lymphoblastic leukemia: prospective real-time quantitative reverse transcriptase-polymerase chain reaction study. Cancer. 2003;97:105–13.

    Article  CAS  PubMed  Google Scholar 

  152. Taube T, Eckert C, Korner G, et al. Real-time quantification of TEL-AML1 fusion transcripts for MRD detection in relapsed childhood acute lymphoblastic leukaemia. Comparison with antigen receptor-based MRD quantification methods. Leuk Res. 2004;28:699–706.

    Article  CAS  PubMed  Google Scholar 

  153. van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257–317.

    Article  PubMed  Google Scholar 

  154. Bruggemann M, van der Velden VH, Raff T, et al. Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia. Leukemia. 2004;18:709–19.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Milano-Bicocca, Monza, Italy

    Andrea Biondi M. D.

  2. Pediatrics, Pediatric Oncology and Hematology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, SP, Brazil

    Carlos Alberto Scrideli M. D., Ph.D.

  3. Pediatrics, Centro Ricerca Tettamanti, Università di Milano Bicocca, Fondazione MBBS/Ospedale San Gerardo, Monza, Italy

    Giovanni Cazzaniga Ph.D.

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  1. Andrea Biondi M. D.
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  2. Carlos Alberto Scrideli M. D., Ph.D.
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  3. Giovanni Cazzaniga Ph.D.
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Correspondence to Andrea Biondi M. D. .

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  1. Pathology and Laboratory Medicine, University of Vermont College of Medicine and University of Vermont Medical Center, Burlington, Vermont, USA

    Debra G.B. Leonard

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Biondi, A., Scrideli, C.A., Cazzaniga, G. (2016). Acute Lymphoblastic Leukemia. In: Leonard, D. (eds) Molecular Pathology in Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-19674-9_41

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