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Blood, Vol. 92 No. 7 (October 1), 1998: pp. 2322-2333

The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial

David Grimwade, Helen Walker, Fiona Oliver, Keith Wheatley, Christine Harrison, Georgina Harrison, John Rees, Ian Hann, Richard Stevens, Alan Burnett, and Anthony Goldstone on behalf of the Medical Research Council Adult and Children's Leukaemia Working Parties

From the Departments of Haematology, University College London; the Royal Free and Great Ormond St Children's Hospitals, London; Royal Manchester Children's Hospital, Manchester; University of Cambridge and University of Wales College of Medicine, Cardiff; the Division of Medical and Molecular Genetics, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London; and the Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK.

Cytogenetics is considered one of the most valuable prognostic determinants in acute myeloid leukemia (AML). However, many studies on which this assertion is based were limited by relatively small sample sizes or varying treatment approach, leading to conflicting data regarding the prognostic implications of specific cytogenetic abnormalities. The Medical Research Council (MRC) AML 10 trial, which included children and adults up to 55 years of age, not only affords the opportunity to determine the independent prognostic significance of pretreatment cytogenetics in the context of large patient groups receiving comparable therapy, but also to address their impact on the outcome of subsequent transplantation procedures performed in first complete remission (CR). On the basis of response to induction treatment, relapse risk, and overall survival, three prognostic groups could be defined by cytogenetic abnormalities detected at presentation in comparison with the outcome of patients with normal karyotype. AML associated with t(8;21), t(15;17) or inv(16) predicted a relatively favorable outcome. Whereas in patients lacking these favorable changes, the presence of a complex karyotype, -5, del(5q), -7, or abnormalities of 3q defined a group with relatively poor prognosis. The remaining group of patients including those with 11q23 abnormalities, +8, +21, +22, del(9q), del(7q) or other miscellaneous structural or numerical defects not encompassed by the favorable or adverse risk groups were found to have an intermediate prognosis. The presence of additional cytogenetic abnormalities did not modify the outcome of patients with favorable cytogenetics. Subgroup analysis demonstrated that the three cytogenetically defined prognostic groups retained their predictive value in the context of secondary as well as de novo AML, within the pediatric age group and furthermore were found to be a key determinant of outcome from autologous or allogeneic bone marrow transplantation (BMT) in first CR. This study highlights the importance of diagnostic cytogenetics as an independent prognostic factor in AML, providing the framework for a stratified treatment approach of this disease, which has been adopted in the current MRC AML 12 trial.


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F. Dayyani, J. Wang, J.-R. J. Yeh, E.-Y. Ahn, E. Tobey, D.-E. Zhang, I. D. Bernstein, R. T. Peterson, and D. A. Sweetser
Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival
Blood, April 15, 2008; 111(8): 4338 - 4347.
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U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger
Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients
Blood, March 1, 2008; 111(5): 2527 - 2537.
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BloodHome page
H. Wandt, U. Schakel, F. Kroschinsky, G. Prange-Krex, B. Mohr, C. Thiede, U. Pascheberg, S. Soucek, M. Schaich, and G. Ehninger
MLD according to the WHO classification in AML has no correlation with age and no independent prognostic relevance as analyzed in 1766 patients
Blood, February 15, 2008; 111(4): 1855 - 1861.
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Clin. Cancer Res.Home page
A.-M. Tsimberidou, H. M. Kantarjian, S. Wen, S. O'Brien, J. Cortes, W. G. Wierda, C. Koller, S. Pierce, M. Brandt, E. J. Freireich, et al.
The Prognostic Significance of Serum {beta}2 Microglobulin Levels in Acute Myeloid Leukemia and Prognostic Scores Predicting Survival: Analysis of 1,180 Patients
Clin. Cancer Res., February 1, 2008; 14(3): 721 - 730.
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Clin. Cancer Res.Home page
H. J.M. de Jonge, A. C. Weidenaar, A. ter Elst, H. M. Boezen, F. J.G. Scherpen, J. C.A. Bouma-ter Steege, G. J.L. Kaspers, B. F. Goemans, U. Creutzig, M. Zimmermann, et al.
Endogenous Vascular Endothelial Growth Factor-C Expression Is Associated with Decreased Drug Responsiveness in Childhood Acute Myeloid Leukemia
Clin. Cancer Res., February 1, 2008; 14(3): 924 - 930.
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ASH Education BookHome page
T. Haferlach
Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid Leukemia
Hematology, January 1, 2008; 2008(1): 400 - 411.
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Am Soc Clin Oncol Ed BookHome page
R. M. Stone
Genetically Defined Prognostic Factors and Novel Therapeutics for AML
ASCO Educational Book, January 1, 2008; 2008(1): 280 - 284.
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BloodHome page
D. Haase, U. Germing, J. Schanz, M. Pfeilstocker, T. Nosslinger, B. Hildebrandt, A. Kundgen, M. Lubbert, R. Kunzmann, A. A. N. Giagounidis, et al.
New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients
Blood, December 15, 2007; 110(13): 4385 - 4395.
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BloodHome page
M. L. Sorror, S. Giralt, B. M. Sandmaier, M. De Lima, M. Shahjahan, D. G. Maloney, H. J. Deeg, F. R. Appelbaum, B. Storer, and R. Storb
Hematopoietic cell transplantation specific comorbidity index as an outcome predictor for patients with acute myeloid leukemia in first remission: combined FHCRC and MDACC experiences
Blood, December 15, 2007; 110(13): 4606 - 4613.
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BloodHome page
M. A. Elliott, M. R. Litzow, L. L. Letendre, R. C. Wolf, C. A. Hanson, A. Tefferi, and M. S. Tallman
Early peripheral blood blast clearance during induction chemotherapy for acute myeloid leukemia predicts superior relapse-free survival
Blood, December 15, 2007; 110(13): 4172 - 4174.
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Clin. Cancer Res.Home page
C. H. Seedhouse, M. Grundy, P. White, Y. Li, J. Fisher, D. Yakunina, A. V. Moorman, T. Hoy, N. Russell, A. Burnett, et al.
Sequential Influences of Leukemia-Specific and Genetic Factors on P-Glycoprotein Expression in Blasts from 817 Patients Entered into the National Cancer Research Network Acute Myeloid Leukemia 14 and 15 Trials
Clin. Cancer Res., December 1, 2007; 13(23): 7059 - 7066.
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haematolHome page
G. J.L. Kaspers and C. M. Zwaan
Pediatric acute myeloid leukemia: towards high-quality cure of all patients
Haematologica, November 1, 2007; 92(11): 1519 - 1532.
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The OncologistHome page
M. E. King and J. M. Rowe
Recent Developments in Acute Myelogenous Leukemia Therapy
Oncologist, October 1, 2007; 12(suppl_2): 14 - 21.
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JCOHome page
M. L. Sorror, B. M. Sandmaier, B. E. Storer, M. B. Maris, F. Baron, D. G. Maloney, B. L. Scott, H. J. Deeg, F. R. Appelbaum, and R. Storb
Comorbidity and Disease Status Based Risk Stratification of Outcomes Among Patients With Acute Myeloid Leukemia or Myelodysplasia Receiving Allogeneic Hematopoietic Cell Transplantation
J. Clin. Oncol., September 20, 2007; 25(27): 4246 - 4254.
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JCOHome page
N. P. Mayor, B. E. Shaw, D. A. Hughes, H. Maldonado-Torres, J. A. Madrigal, S. Keshav, and S. G.E. Marsh
Single Nucleotide Polymorphisms in the NOD2/CARD15 Gene Are Associated With an Increased Risk of Relapse and Death for Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation With Unrelated Donors
J. Clin. Oncol., September 20, 2007; 25(27): 4262 - 4269.
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F. Forghieri, M. Luppi, M. Morselli, L. Potenza, F. Volzone, G. Riva, A. Imovilli, E. Rivolti, and G. Torelli
Cytarabine-related lung infiltrates on high resolution computerized tomography: a possible complication with benign outcome in leukemic patients
Haematologica, September 1, 2007; 92(9): e85 - e90.
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Clin. Cancer Res.Home page
G. Strathdee, T. L. Holyoake, A. Sim, A. Parker, D. G. Oscier, J. V. Melo, S. Meyer, T. Eden, A. M. Dickinson, J. C. Mountford, et al.
Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis
Clin. Cancer Res., September 1, 2007; 13(17): 5048 - 5055.
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BloodHome page
D. C. Link, G. Kunter, Y. Kasai, Y. Zhao, T. Miner, M. D. McLellan, R. E. Ries, D. Kapur, R. Nagarajan, D. C. Dale, et al.
Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia
Blood, September 1, 2007; 110(5): 1648 - 1655.
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Clin. Cancer Res.Home page
C. W. Ross, P. D. Ouillette, C. M. Saddler, K. A. Shedden, and S. N. Malek
Comprehensive Analysis of Copy Number and Allele Status Identifies Multiple Chromosome Defects Underlying Follicular Lymphoma Pathogenesis
Clin. Cancer Res., August 15, 2007; 13(16): 4777 - 4785.
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BloodHome page
L. Bullinger, F. G. Rucker, S. Kurz, J. Du, C. Scholl, S. Sander, A. Corbacioglu, C. Lottaz, J. Krauter, S. Frohling, et al.
Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia
Blood, August 15, 2007; 110(4): 1291 - 1300.
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P. Brown, E. McIntyre, R. Rau, S. Meshinchi, N. Lacayo, G. Dahl, T. A. Alonzo, M. Chang, R. J. Arceci, and D. Small
The incidence and clinical significance of nucleophosmin mutations in childhood AML
Blood, August 1, 2007; 110(3): 979 - 985.
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M. S. Tallman, G. W. Dewald, S. Gandham, B. R. Logan, A. Keating, H. M. Lazarus, M. R. Litzow, J. Mehta, T. Pedersen, W. S. Perez, et al.
Impact of cytogenetics on outcome of matched unrelated donor hematopoietic stem cell transplantation for acute myeloid leukemia in first or second complete remission
Blood, July 1, 2007; 110(1): 409 - 417.
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M. Schaich, R. F. Schlenk, H. K. Al-Ali, H. Dohner, A. Ganser, G. Heil, T. Illmer, R. Krahl, J. Krauter, C. Sauerland, et al.
Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup
Haematologica, June 1, 2007; 92(6): 763 - 770.
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H. Hasle, T. A. Alonzo, A. Auvrignon, C. Behar, M. Chang, U. Creutzig, A. Fischer, E. Forestier, A. Fynn, O. A. Haas, et al.
Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study
Blood, June 1, 2007; 109(11): 4641 - 4647.
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C. Agueli, R. Basirico, F. Fabbiano, V. Rizzo, L. Cascio, G. Cammarata, A. Marfia, M. La Rosa, S. Mirto, and A. Santoro
Loss of heterozygosity in acute leukemia: evidence of frequent submicroscopic deletions
Haematologica, May 1, 2007; 92(5): 678 - 681.
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BloodHome page
A. V. Moorman, C. J. Harrison, G. A. N. Buck, S. M. Richards, L. M. Secker-Walker, M. Martineau, G. H. Vance, A. M. Cherry, R. R. Higgins, A. K. Fielding, et al.
Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial
Blood, April 15, 2007; 109(8): 3189 - 3197.
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BloodHome page
G.-B. Zhou, H. Kang, L. Wang, L. Gao, P. Liu, J. Xie, F.-X. Zhang, X.-Q. Weng, Z.-X. Shen, J. Chen, et al.
Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo
Blood, April 15, 2007; 109(8): 3441 - 3450.
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JCOHome page
C. J. Hess, J. Berkhof, F. Denkers, G. J. Ossenkoppele, J. P. Schouten, J. J. Oudejans, Q. Waisfisz, and G. J. Schuurhuis
Activated Intrinsic Apoptosis Pathway Is a Key Related Prognostic Parameter in Acute Myeloid Leukemia
J. Clin. Oncol., April 1, 2007; 25(10): 1209 - 1215.
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B. Falini, I. Nicoletti, N. Bolli, M. P. Martelli, A. Liso, P. Gorello, F. Mandelli, C. Mecucci, and M. F. Martelli
Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias
Haematologica, April 1, 2007; 92(4): 519 - 532.
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Ann OncolHome page
Y-B Yu, J-P Gau, J-Y You, H-H Chern, W-K Chau, C-H Tzeng, C-H Ho, and H-C Hsu
Cost-effectiveness of postremission intensive therapy in patients with acute leukemia
Ann. Onc., March 1, 2007; 18(3): 529 - 534.
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The OncologistHome page
S. Meshinchi and R. J. Arceci
Prognostic Factors and Risk-Based Therapy in Pediatric Acute Myeloid Leukemia
Oncologist, March 1, 2007; 12(3): 341 - 355.
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BloodHome page
B. Falini, I. Nicoletti, M. F. Martelli, and C. Mecucci
Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features
Blood, February 1, 2007; 109(3): 874 - 885.
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BloodHome page
A. G. Smith, L. J. Worrillow, and J. M. Allan
A common genetic variant in XPD associates with risk of 5q- and 7q-deleted acute myeloid leukemia
Blood, February 1, 2007; 109(3): 1233 - 1236.
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BloodHome page
A. C. Spoo, M. Lubbert, W. G. Wierda, and J. A. Burger
CXCR4 is a prognostic marker in acute myelogenous leukemia
Blood, January 15, 2007; 109(2): 786 - 791.
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JCOHome page
F. Giles, D. Rizzieri, J. Karp, N. Vey, F. Ravandi, S. Faderl, K. Dad Khan, G. Verhoef, P. Wijermans, A. Advani, et al.
Cloretazine (VNP40101M), a Novel Sulfonylhydrazine Alkylating Agent, in Patients Age 60 Years or Older With Previously Untreated Acute Myeloid Leukemia
J. Clin. Oncol., January 1, 2007; 25(1): 25 - 31.
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ASH Education BookHome page
J. Pedersen-Bjergaard, M. T. Andersen, and M. K. Andersen
Genetic Pathways in the Pathogenesis of Therapy-Related Myelodysplasia and Acute Myeloid Leukemia
Hematology, January 1, 2007; 2007(1): 392 - 397.
[Abstract] [Full Text] [PDF]


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ASH-SAPHome page
S. Jeha and F. J. Giles
Acute myeloid leukemia
ASH Self-Assessment Program, January 1, 2007; 2007(1): 243 - 252.
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Clin. Cancer Res.Home page
C. Marzac, I. Teyssandier, O. Calendini, J.-Y. Perrot, A.-M. Faussat, R. Tang, N. Casadevall, J.-P. Marie, and O. Legrand
Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia
Clin. Cancer Res., December 1, 2006; 12(23): 7018 - 7024.
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BloodHome page
D. Montagna, R. Maccario, F. Locatelli, E. Montini, S. Pagani, F. Bonetti, L. Daudt, I. Turin, D. Lisini, C. Garavaglia, et al.
Emergence of antitumor cytolytic T cells is associated with maintenance of hematologic remission in children with acute myeloid leukemia
Blood, December 1, 2006; 108(12): 3843 - 3850.
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M. Kalaycio, L. Rybicki, B. Pohlman, R. Dean, J. W. Sweetenham, S. Andresen, R. Sobecks, M. A. Sekeres, A. Advani, R. Davis, et al.
Lactate Dehydrogenase (LDH) Level Predicts the Outcome of Patients with Acute Myelogenous Leukemia (AML) Following HLA-Matched Sibling Bone Marrow Transplant (BMT).
Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 3013 - 3013.
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