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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1312-1320

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial

David Grimwade, Helen Walker, Georgina Harrison, Fiona Oliver, Stephen Chatters, Christine J. Harrison, Keith Wheatley, Alan K. Burnett, and Anthony H. Goldstone on behalf of the Medical Research Council Adult Leukaemia Working Party

From the Department of Haematology, University College London Hospitals and Medical School, London; the Department of Haematology, University of Wales College of Medicine, Cardiff; the Division of Medical and Molecular Genetics, Guy's, King's and St Thomas' School of Medicine, London; the Clinical Trial Service Unit, Radcliffe Infirmary, Oxford; the Cytogenetics Laboratory, Royal Free and University College Medical School, London; and the University of Birmingham Clinical Trials Unit, United Kingdom.

Acute myeloid leukemia (AML) in older adults carries a poor prognosis, and the optimum treatment remains to be determined. In younger patients, treatment stratification is frequently based upon diagnostic karyotype, which was the most important prognostic factor in the UK Medical Research Council (MRC) AML10 trial. Considered here is whether karyotype is also predictive in older adults; this is done by studying 1065 cases from MRC AML11 (median age, 66 years). Three prognostic groups were distinguished on the basis of response to induction therapy and overall survival (OS). Those with t(15;17), t(8;21), or inv(16) composed the favorable risk group. Overall, these abnormalities predicted a superior complete remission (CR) rate (72%), reflecting relatively low levels of resistant disease (RD) (8%), and lower relapse risk (RR) (56%) associated with superior OS (34% at 5 years). Normal karyotype (CR, 63%; RD, 17%; RR, 78%; OS, 15%) and other noncomplex abnormalities (CR, 53%; RD, 32%; RR, 85%; OS, 10%) composed the intermediate group; while complex karyotype predicted an extremely poor prognosis (CR, 26%; RD, 56%; RR, 91%; OS, 2%). Combining MRC AML10 and AML11 (n = 2677) revealed that the most favorable changes were rarer in older patients (younger than 55 years, 24%; 55 years or older, 7%), while complex abnormalities were more common (6% vs 13%). This study suggests that hierarchical cytogenetic classification identifies biologically distinct subsets of AML that are represented in all age groups. Furthermore, it highlights the importance of karyotype as a critical independent determinant of outcome in older patients with AML, providing a potential framework for stratified treatment approaches.

© 2001 by The American Society of Hematology.
 

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A. van Rhenen, N. Feller, A. Kelder, A. H. Westra, E. Rombouts, S. Zweegman, M. A. van der Pol, Q. Waisfisz, G. J. Ossenkoppele, and G. J. Schuurhuis
High Stem Cell Frequency in Acute Myeloid Leukemia at Diagnosis Predicts High Minimal Residual Disease and Poor Survival
Clin. Cancer Res., September 15, 2005; 11(18): 6520 - 6527.
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JCOHome page
S. Frohling, C. Scholl, D. G. Gilliland, and R. L. Levine
Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications
J. Clin. Oncol., September 10, 2005; 23(26): 6285 - 6295.
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JCOHome page
L. Bullinger and P. J.M. Valk
Gene Expression Profiling in Acute Myeloid Leukemia
J. Clin. Oncol., September 10, 2005; 23(26): 6296 - 6305.
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BloodHome page
T. Haferlach, A. Kohlmann, S. Schnittger, M. Dugas, W. Hiddemann, W. Kern, and C. Schoch
Global approach to the diagnosis of leukemia using gene expression profiling
Blood, August 15, 2005; 106(4): 1189 - 1198.
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Ann OncolHome page
C.-C. Chen, C.-F. Yang, M.-H. Yang, K.-D. Lee, W.-K. Kwang, J.-Y. You, Y.-B. Yu, C.-H. Ho, C.-H. Tzeng, W.-K. Chau, et al.
Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia
Ann. Onc., August 1, 2005; 16(8): 1366 - 1373.
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BloodHome page
S. Amadori, S. Suciu, U. Jehn, R. Stasi, X. Thomas, J.-P. Marie, P. Muus, F. Lefrere, Z. Berneman, G. Fillet, et al.
Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: final results of AML-13, a randomized phase-3 study
Blood, July 1, 2005; 106(1): 27 - 34.
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Ann OncolHome page
L. Pagano, A. Pulsoni, M. Vignetti, M. E. Tosti, P. Falcucci, P. Fazi, L. Fianchi, A. Levis, A. Bosi, E. Angelucci, et al.
Secondary acute myeloid leukaemia: results of conventional treatments. Experience of GIMEMA trials
Ann. Onc., February 1, 2005; 16(2): 228 - 233.
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BloodHome page
J. M. Allan, A. G. Smith, K. Wheatley, R. K. Hills, L. B. Travis, D. A. Hill, D. M. Swirsky, G. J. Morgan, and C. P. Wild
Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy
Blood, December 15, 2004; 104(13): 3872 - 3877.
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W. Kern, D. Voskova, C. Schoch, W. Hiddemann, S. Schnittger, and T. Haferlach
Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia
Blood, November 15, 2004; 104(10): 3078 - 3085.
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Clin. Cancer Res.Home page
G. F. V. Woude, G. J. Kelloff, R. W. Ruddon, H.-M. Koo, C. C. Sigman, J. C. Barrett, R. W. Day, A. P. Dicker, R. S. Kerbel, D. R. Parkinson, et al.
Reanalysis of Cancer Drugs: Old Drugs, New Tricks
Clin. Cancer Res., June 1, 2004; 10(11): 3897 - 3907.
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NEJMHome page
P. J.M. Valk, R. G.W. Verhaak, M. A. Beijen, C. A.J. Erpelinck, S. B. v. W. van Doorn-Khosrovani, J. M. Boer, H. B. Beverloo, M. J. Moorhouse, P. J. van der Spek, B. Lowenberg, et al.
Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia
N. Engl. J. Med., April 15, 2004; 350(16): 1617 - 1628.
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G. J. Ossenkoppele, W. J. Graveland, P. Sonneveld, S. M. G. J. Daenen, D. H. Biesma, L. F. Verdonck, M. R. Schaafsma, P. H. M. Westveer, G. J. Peters, P. Noordhuis, et al.
The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients
Blood, April 15, 2004; 103(8): 2908 - 2913.
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J. Virol.Home page
S. J. Erkeland, M. Valkhof, C. Heijmans-Antonissen, A. van Hoven-Beijen, R. Delwel, M. H. A. Hermans, and I. P. Touw
Large-Scale Identification of Disease Genes Involved in Acute Myeloid Leukemia
J. Virol., February 15, 2004; 78(4): 1971 - 1980.
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J. M. Rowe, D. Neuberg, W. Friedenberg, J. M. Bennett, E. Paietta, A. Z. Makary, J. L. Liesveld, C. N. Abboud, G. Dewald, F. A. Hayes, et al.
A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group
Blood, January 15, 2004; 103(2): 479 - 485.
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ASH Education BookHome page
R. M. Stone, M. R. O'Donnell, and M. A. Sekeres
Acute Myeloid Leukemia
Hematology, January 1, 2004; 2004(1): 98 - 117.
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S. Schnittger, M. Weisser, C. Schoch, W. Hiddemann, T. Haferlach, and W. Kern
New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts
Blood, October 15, 2003; 102(8): 2746 - 2755.
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C. Schoch, S. Schnittger, M. Klaus, W. Kern, W. Hiddemann, and T. Haferlach
AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases
Blood, October 1, 2003; 102(7): 2395 - 2402.
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BloodHome page
C. D. Baldus, S. M. Tanner, A. S. Ruppert, S. P. Whitman, K. J. Archer, G. Marcucci, M. A. Caligiuri, A. J. Carroll, J. W. Vardiman, B. L. Powell, et al.
BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study
Blood, September 1, 2003; 102(5): 1613 - 1618.
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Clin. Cancer Res.Home page
J. E. Karp, D. D. Ross, W. Yang, M. L. Tidwell, Y. Wei, J. Greer, D. L. Mann, T. Nakanishi, J. J. Wright, and A. D. Colevas
Timed Sequential Therapy of Acute Leukemia with Flavopiridol: In Vitro Model for a Phase I Clinical Trial
Clin. Cancer Res., January 1, 2003; 9(1): 307 - 315.
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BloodHome page
J. C. Byrd, K. Mrozek, R. K. Dodge, A. J. Carroll, C. G. Edwards, D. C. Arthur, M. J. Pettenati, S. R. Patil, K. W. Rao, M. S. Watson, et al.
Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461)
Blood, December 15, 2002; 100(13): 4325 - 4336.
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CA Cancer J ClinHome page
R. M. Stone
The Difficult Problem of Acute Myeloid Leukemia in the Older Adult
CA Cancer J Clin, November 1, 2002; 52(6): 363 - 371.
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BloodHome page
N. Dastugue, M. Lafage-Pochitaloff, M.-P. Pages, I. Radford, C. Bastard, P. Talmant, M. J. Mozziconacci, C. Leonard, C. Bilhou-Nabera, C. Cabrol, et al.
Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH)
Blood, June 28, 2002; 100(2): 618 - 626.
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian
Acute Myeloid Leukemia
Hematology, January 1, 2002; 2002(1): 73 - 110.
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BloodHome page
A. H. Goldstone, A. K. Burnett, K. Wheatley, A. G. Smith, R. M. Hutchinson, and R. E. Clark
Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial
Blood, September 1, 2001; 98(5): 1302 - 1311.
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