Originally published as JCO Early Release 10.1200/JCO.2008.16.0259 on August 11 2008

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Breems, D. A. Articles by Löwenberg, B. Search for Related Content PubMed PubMed Citation Articles by Breems, D. A. Articles by Löwenberg, B. Social Bookmarking                            What's this?

Monosomal Karyotype in Acute Myeloid Leukemia: A Better Indicator of Poor Prognosis Than a Complex Karyotype

Dimitri A. Breems, Wim L.J. Van Putten, Georgine E. De Greef, Shama L. Van Zelderen-Bhola, Klasien B.J. Gerssen-Schoorl, Clemens H.M. Mellink, Aggie Nieuwint, Martine Jotterand, Anne Hagemeijer, H. Berna Beverloo, Bob Löwenberg

From the Department of Hematology, Hospital Network Antwerp, Campus Stuivenberg, Antwerp; Center for Human Genetics, University of Leuven, Leuven, Belgium; Dutch-Belgian Hemato-Oncology Cooperative Group Data Center; Departments of Trials and Statistics, Hematology, and Clinical Genetics, Erasmus University Medical Center, Rotterdam; Department of Clinical Genetics, Free University Medical Center; Department of Clinical Genetics, Institute for Human Genetics, Academic Medical Center, Amsterdam; Department of Genetics, University Medical Center, Groningen, the Netherlands; and Unit of Cancer Cytogenetics, Department of Medical Genetics, University Hospital Center Vaudois, Lausanne, Switzerland

Corresponding author: Bob Löwenberg, MD, PhD, Department of Hematology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, the Netherlands; e-mail: b.lowenberg{at}erasmusmc.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML).

Patients and Methods Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years.

Results Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy –7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome.

Conclusion MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% ± 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% ± 1%).

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Adult acute myeloid leukemia (AML) is a remarkably heterogeneous disease with regard to clinical features and diversity of acquired genetic alterations. Using diagnostic cytogenetics, generally different prognostic subgroups are defined for patients with AML who are age 60 years or younger.^1-4 Although precise risk group assignments of various cytogenetic findings vary among clinical study groups, AML with multiple cytogenetic abnormalities, often designated as complex karyotype, is universally considered as unfavorable.^5,6 Some define AML with complex karyotype as the "presence of a clone with at least five unrelated cytogenetic abnormalities,"¹ whereas others apply a criterion of at least three abnormalities^3,4,7,8 or presence of a clone with more than three cytogenetic abnormalities.⁹ One study did not show a difference between the prognostic values of karyotypes with three versus four versus five or more cytogenetic abnormalities.⁴ The aforementioned studies did not resolve the predictive significance of the types of cytogenetic abnormalities among complex karyotype.

Because AML with complex karyotype is currently widely used in the clinical decision algorithm of risk-adapted treatment as well as in the results evaluation of clinical trials, we set out to evaluate the prognostic contribution of various cytogenetic abnormalities among complex karyotypes and optimize distinction between poor risk AML and very poor risk AML with multiple cytogenetic abnormalities. In the analysis presented here, we considered any cytogenetic abnormality, including numerical aberrations, structural abnormalities, marker chromosomes, and ring chromosomes, irrespective of individual contributing chromosomes or types of abnormalities involved.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Patients
A total of 1,975 AML patients with available cytogenetic data at diagnosis were enrolled during the period from 1987 to 2004 in four successive Dutch-Belgian Haemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research phase III trials (AML4, AML4a, AML29, and AML42).^10-12 Patients without cytogenetic analysis (n = 52) or with a failure of cytogenetic analysis (n = 128) were not included in this study. The studies were open to patients with newly diagnosed AML age 15 to 60 years, with exception of acute promyelocytic leukemia patients. The studies had been approved by ethics committees of participating institutions and conducted in accordance with the Declaration of Helsinki. All participants had given informed consent.

Treatment Protocols
Treatment in the AML4/4a, AML29, and AML42 studies has been described previously and involved two remission induction cycles including a first cycle of daunorubicin or idarubicin in combination with cytarabine and a second cycle of amsacrine combined with intermediate-dose cytarabine.^10-12 In case of complete remission, patients were consolidated according to the different protocols with a third cycle of mitoxantrone and etoposide chemotherapy or autologous or allogeneic stem-cell transplantation.

Cytogenetic and Statistical Analysis
At diagnosis, samples of bone marrow and blood were examined for cytogenetic abnormalities using standard banding techniques and karyotyped according to the International System for Human Cytogenetic Nomenclature.¹³ An abnormality was considered clonal and therefore mentioned in the karyotype when at least two metaphases had the same aberration in case of a structural abnormality or an extra chromosome. If there was a monosomy, it had to be present in at least three metaphases. The Dutch Working Party on Cancer Genetics and Cytogenetics performed review of the cytogenetic results. The karyotype analysis was based on 20 or more metaphases in 73% of patients. In 22% of the patients, 10 to 19 metaphases were examined, whereas in 5% of the patients, the karyotype resulted from analysis of less than 10 metaphases. There were no apparent differences in outcome between the latter three groups. Regarding normal karyotype AMLs, cytogenetically normal karyotypes were established after analysis of 20 or more metaphases in 80% of patients, after analysis of 10 to 19 metaphases in 15% of patients, and after analysis of less than 10 metaphases in 5% of patients, without observing differences in overall survival (OS) between these three normal karyotype subgroups. Subsequently, the different abnormalities in the karyotype were extracted with a computer program and described with a large number of indicator variables indicating which chromosome and chromosome arm were involved in the abnormality and the nature of the abnormality. The following abnormalities were scored for each chromosome: loss of a chromosome (monosomy), extra copy of a chromosome (trisomy or tetrasomy), structural cytogenetic abnormalities (deletion of part of a chromosome, inversion within a chromosome, translocation between chromosomes, or addition of chromosomal material), marker chromosomes, ring chromosomes, and the frequencies of each of the individual abnormalities. Only indicator variables describing abnormalities that occurred in at least four patients were analyzed. In considering these frequencies, it was ignored whether such clonal abnormalities were present in the same or in different (sub)clones. OS was used as the end point for evaluation. Statistical analysis was limited to subgroups of at least 10 patients. Kaplan-Meier estimates of the mean OS at 4 years in the different subgroups were calculated. Cox regression analysis and the likelihood ratio test were used to test for a difference between subgroups and to test for trend. A sequential approach was used to identify the indicator variable with the strongest association with OS.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Cytogenetic Analysis of AML Patients
Karyotype and OS were determined in 1,975 newly diagnosed AML patients between 15 to 60 years of age. A normal karyotype was found in 988 patients with a 4-year OS rate of 41% (standard error, ± 2%). There were 987 AML patients with an abnormal karyotype. Of these, 254 patients had presented with a core binding factor (CBF) AML, including 134 patients with t(8;21) (4-year OS, 63% ± 4%) and 120 patients with inv(16) or t(16;16) (4-year OS, 70% ± 4%). The 733 remaining patients presenting with a variety of cytogenetic abnormalities and a relatively poor prognosis (4-year OS, 21% ± 2%) are the main subject of analysis of the current study.

Effect of Autosomal Monosomies on OS
The karyotypes of patients with cytogenetic abnormalities could be described by a total of 613 indicator variables as defined in Patients and Methods, each describing a subgroup containing at least four patients. For each of these 613 subcategories of abnormalities, the 4-year OS was assessed and compared with the 4-year OS estimate of patients without that particular abnormality. The notable initial observation was that loss of an autosomal chromosome expressed the strongest correlation with poor prognosis. Subsequently, we set out to study in detail which of the different components of a karyotype contribute to poor prognosis.

Among the 733 patients with AML with non-CBF cytogenetic abnormalities, loss of one or more autosomal chromosomes was apparent in 225 patients. In addition, 39 other patients presented with sex chromosomal monosomies –X or –Y. Because of the apparent lack of a negative prognostic effect of the latter aberrations (4-year OS, 50%), the 14 patients with AML with losses of chromosomes X or Y but with no other abnormality were considered together with cytogenetically normal AML patients in the subsequent analysis. In contrast, autosomal chromosomal monosomies showed strong negative prognostic impact on OS (Table 1). A single autosomal monosomy was found in 109 patients with an estimated 4-year OS of 12%. The 116 patients with two or more autosomal monosomies had a 4-year OS of 3%. For comparison, the 494 AML patients with non-CBF cytogenetic abnormalities but without any autosomal monosomies had an estimated 4-year OS of 27% (P < .001; Fig 1A). The single most prevalent single monosomy was –7, which was observed in 63 patients. There was no apparent difference in outcome between AML patients with a single monosomy –7 and AML patients with any other type of single autosomal monosomy (4-year OS: 13% v 11%, respectively), indicating that the type of autosomal chromosome loss did not matter with regard to prognosis. Among the 116 patients with AML with multiple autosomal monosomies, in 49 patients, the karyotype included various other autosomal monosomies besides monosomy –7 (4-year OS, 0%), whereas 67 patients presented with various autosomal monosomies but no monosomy –7 (4-year OS, 6%). Apparently, there is no difference regarding the notably adverse prognostic value between an autosomal monosomy in general and the specific –7 monosomy.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival of patients with acute myeloid leukemia (AML) and non–core binding factor chromosomal abnormalities. (A) Survival in relation to number of autosomal chromosomal monosomies (ms; none, one, or two). (B) Survival in relation to monosomal karyotype (MK) as defined in this article and/or complex karyotype (CK) with three cytogenetic clonal abnormalities.

Prognostic Effect of Number of Other Cytogenetic Abnormalities in Presence of Autosomal Monosomy
Subsequently, the effect of the number of chromosomal abnormalities was analyzed in the context of presence of autosomal monosomies. Three categories were considered based on the number of different autosomal monosomies (Table 2). In category A (ie, AML with just one autosomal monosomy; n = 109), the supplemental presence of one or more extra chromosomes or marker or ring chromosomes did not add any significant prognostic value. Only coexistence of one or more additional structural cytogenetic abnormalities with a single monosomy contributed an additional negative effect on OS. The dismal outcome of AML patients in category B (ie, AML with two or more autosomal monosomies; n = 116) was not further modified by the absence or presence of other chromosomal aberrations. Finally, in category C (ie, AML without any autosomal monosomies; n = 494), the presence of one or more extra chromosomes, marker or ring chromosomes, or structural abnormalities exhibited no significant prognostic effect. As a result, a very poor prognostic subgroup of 184 AML patients (4-year OS, 4%) could be recognized based on the following simple criteria: at least two autosomal monosomies or one single autosomal monosomy in combination with at least one structural abnormality. We use the term monosomal karyotype (MK) for karyotypes that fall in this category.

All 44 patients with a monosomy –5 from Table 1 were MK positive (ie, had another autosomal monosomy, most frequently –7, or an additional structural abnormality). Twenty-five patients had a monosomy –5 without a monosomy –7 (Table 3). The other 19 patients had a monosomy –5 without monosomy –7, but with one or more other autosomal monosomies and/or additional structural abnormalities. Also, most of the patients with monosomy –7 were MK positive and had the associated poor prognosis. However, there were 27 AML patients with monosomy –7 without other autosomal monosomies or structural abnormalities, and they had a better prognosis that was not different from cytogenetically abnormal AML patients without MK (4-year OS, 22%). The 74 AML patients with MK but without monosomies –5 and –7 had a very poor prognosis with a 4-year OS rate of 7%, indicating that the very poor prognosis of patients with MK did not specifically depend on the presence of monosomy –5 or –7 (Table 3).

Approximately half of AML patients with inv(3)/t(3;3) belonged to the MK-positive group and had a 4-year OS rate of 0%. The other patients without MK showed a distinctly better outcome (4-year OS, 31%), indicating the prognostic significance of MK regarding the subset of AML patients with inv(3)/t(3;3) (Table 3). The majority of the del(5q) patients were MK positive with low OS. But del(5q) patients without MK showed a 4-year OS rate of 23%, which was not different from other cytogenetically abnormal AML patients (Table 3). AML del(7q) patients without MK showed a clearly better 4-year OS rate (42%) than patients with MK (Table 3). AML patients with t(6;9), t(9;22), abn11q23, or abn(17p) showed insufficient diversity to allow for detailed comparisons (Table 3). AML patients with inv(3)/t(3;3), t(6;9), t(6;11), t(11;19), –5, –7, or del(5q) abnormalities were combined in one unfavorable risk group according to Mrózek and Bloomfield⁶; 148 of these patients were MK positive and had a low 4-year OS rate of 2% compared with the remaining 101 patients who were MK negative who had a 4-year OS rate of 21% (Table 3). Thus, MK also conferred a very poor outcome among AML patients with various previously established individual adverse cytogenetic markers.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The prognostic value of pretreatment cytogenetic analysis of AML patients is generally accepted in clinical practice.⁶ The coexistence of multiple clonal cytogenetic abnormalities, often referred to as complex karyotypes, has been proposed to confer poor outcome of disease. Commonly applied definitions of this poor prognostic subgroup of AML patients with complex cytogenetic abnormalities do not account for type of abnormalities, and in addition, definitions vary in different studies.^1-4,7-9 However, they usually are based on the counts of numerical and structural abnormalities. In the present study, we addressed the contribution of the different components of the complex cytogenetic abnormalities (ie, loss of one or more chromosomes, extra copy of one or more chromosomes, and structural cytogenetic abnormalities) as determinants of poor prognosis. A diverse series of indicator variables, each describing a specific type or class of abnormalities for individual chromosomes, was evaluated for their relationship with outcome. Presence of autosomal chromosomal monosomies strongly predicted for an adverse prognosis.

Negative prognostic impact of autosomal monosomies in AML has been described for monosomies of chromosomes 5 and 7.^1,3,4 The present study shows, in multiple comparisons, that any type of monosomy in AML is associated with a dismal outcome. For example, direct comparison between 63 AML patients with a single monosomy 7 and other variable single autosomal monosomies reveals identically poor OS. Even more profound is the influence of multiple (ie, two or more) autosomal monosomies or one autosomal monosomy in combination with at least one structural chromosomal abnormality in AML, which results in extremely poor outcome (4-year OS, 4%). In direct comparisons, extra copies of one or more chromosomes did not seem to exert any clearly additive negative effect on prognosis in AML. Data in the literature concerning the prognostic value of trisomies in AML are somewhat controversial. One study has reported adverse prognosis for AML patients with isolated trisomies of chromosomes +8, +11, +13, and +21,¹⁴ whereas several others have reported intermediate prognosis for AML patients with trisomies +6, +8, +11, +21, and +22,^1,3,4 with one exception of a suggested adverse prognosis for AML patients with trisomy +8.⁴ Finally, we show that ring or marker chromosomes and structural chromosomal aberrations in the absence of autosomal monosomies have minimal prognostic impact.

The findings reported here lead to a proposal of a score for prognostically unfavorable AML with multiple cytogenetic abnormalities. The new MK index defines AML with very poor prognosis as non-CBF leukemias with a karyotype with at least two autosomal monosomies or one single autosomal monosomy in the presence of one or more structural cytogenetic abnormalities. The MK index is a simplification, and it furnishes superior predictability of very unfavorable risk AML compared with the traditionally defined complex karyotypes regardless of whether complexity is defined by three or five clonal cytogenetic abnormalities.

There are many different specific cytogenetic abnormalities that have been implicated to express poor prognosis in AML. For most of these abnormalities, this study also shows a poor prognosis, but only when the patients carry an MK. The subgroups of AML without MK but with distinct inv(3)/t,(3;3), del(5q), del(7q), or monosomy –7 only or the prognostic category of AML defined according a combination of unfavorable cytogenetic abnormalities all show a notably better 4-year OS than their MK-positive counterparts. Thus, the negative prognostic significance of MK holds up in the context of various cytogenetic abnormalities implicated to confer a poor prognosis. Also, no specific prognostic effect could be attributed to monosomy –7 or –5 compared with other autosomal deletions.

Using the standardized definition of MK, four clearly distinctive prognostic cytogenetic subgroups of AML can be derived that might be used in risk-adapted treatment schedules (Fig 2 and Table 4). A relatively favorable prognosis is observed in CBF AML (ie, AML with inv[16], t[16;16], or t[8;21]). In addition, AML with a normal karyotype or with –X or –Y as the sole abnormality predicts for intermediate risk. Subsequently, there is the third group with various cytogenetic abnormalities but who are MK negative. This relatively large group of 535 patients was associated with poor risk (4-year OS, 26% ± 2%), and this subgroup deserves further analysis because this category contains AML patients with a diverse range of cytogenetic abnormalities, without the strong negative prognostic influence of MK. The fourth excessively poor prognostic subgroup of AML consists of MK-positive patients. As shown in Table 4, the poor OS (4-year OS, 4% ± 1%) of the MK-positive group is explained by an excessively low proportion of patients attaining complete remission (48%) and a high relapse rate of 41%.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival of the following four prognostic subcategories of acute myeloid leukemia (AML) aggregated according to cytogenetics: core binding factor (CBF) abnormalities; normal karyotype (CN); non-CBF abnormalities but monosomal karyotype (MK) negative (MK–); and non-CBF abnormalities but MK positive (MK+). MK refers to two autosomal monosomies or one autosomal monosomy with at least one structural abnormality.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Dimitri A. Breems, Wim L.J. Van Putten, Georgine E. De Greef, H. Berna Beverloo, Bob Löwenberg

Collection and assembly of data: Dimitri A. Breems, Wim L.J. Van Putten, Georgine E. De Greef, Shama L. Van Zelderen-Bhola, Klasien B.J. Gerssen-Schoorl, Clemens H.M. Mellink, Aggie Nieuwint, Martine Jotterand, Anne Hagemeijer, H. Berna Beverloo, Bob Löwenberg

Data analysis and interpretation: Dimitri A. Breems, Wim L.J. Van Putten, H. Berna Beverloo, Bob Löwenberg

Manuscript writing: Dimitri A. Breems, Wim L.J. Van Putten, H. Berna Beverloo, Bob Löwenberg

Final approval of manuscript: Dimitri A. Breems, Wim L.J. Van Putten, Georgine E. De Greef, Shama L. Van Zelderen-Bhola, Klasien B.J. Gerssen-Schoorl, Clemens H.M. Mellink, Aggie Nieuwint, Martine Jotterand, Anne Hagemeijer, H. Berna Beverloo, Bob Löwenberg

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The following investigators from Belgium (B), Germany (D), Switzerland (S), and the Netherlands (NL) have participated in the clinical studies: P. Zachée and D.A. Breems, Hospital Stuivenberg, Antwerp (B); A. Ferrant, Hôpital St Luc, Brussels (B); P. Mineur, Hôpital St Joseph, Gilly (B); A. Delannoy, Hôpital St Paul Jolimont, Haine (B); J. Maertens, G. Verhoef, and M. Boogaerts, Ziekenhuis Gasthuisberg, Leuven (B); H. Demuynck, Ziekenhuis Heilig Hart, Roeselare (B); A. Bosly, Hôpital Mont Godinne Yvoir (B); E. Jaeger, Hospital Nordwest, Frankfurt am Main (D); T. Fischer and M. Theobald, Hospital Gutenberg, Mainz (D); M. Bargetzi and M. Wernli, Kantonsspital, Aarau (S); A. Gratwohl, Kantonsspital, Basel (S); G. Marini and L. Leoncini-Franscini, Hospital San Giovanni, Bellinzona (S); M.F. Fey and T. Pabst, Inselspital, Bern (S); B. Chapuis, Cantonal University, Geneva (S); A. Herr and T. Kovascovics, Centre Hospitalier Universitaire Vaudois, Lausanne (S); W.A. Wuillemin, Kantonsspital, Luzern (S); B. Zimmerli and D. Piguet, Hôpital Cadolles, Neuchatel (S); U. Hess, Kantonsspital, St Gallen (S); T. Kroner, Kantonsspittal, Winterthur (S); E. Jacky and A. Knuth, University Hospital, Zürich (S); J. Gmür, Hospital Im Park, Zurich (S); S. Wittebol, Meander Medisch Centrum, Amersfoort (NL); J. Van Der Lelie and J. Baars, Academic Medical Center, Amsterdam (NL); B. de Valk, Onze Lieve Vrouwen Gasthuis, Amsterdam (NL); P.C. Huijgens and G. Ossenkoppele, Free University Medical Center, Amsterdam (NL); H.P. Muller, Hospital Gooi Noord, Bussum (NL); E. Maartense, Hospital Reinier De Graaf, Delft (NL); P.W. Wijermans, Hospital Leyenburg, Den Haag (NL); W.G. Peters, Catharina Hospital, Eindhoven (NL); M.R. Schaafsma, Medisch Spectrum Twente, Enschede (NL); S.M.G.J. Daenen and E. Vellenga, University Medical Center Groningen (NL); P.J. Voogt, Hospital Atrium, Heerlen (NL); P. Joosten, Medisch Centrum Leeuwarden (NL); H.C. Schouten University Hospital, Maastricht (NL); H. de Korte, Diaconessen Ziekenhuis, Meppel (NL); D.H. Biesma, Antonius Ziekenhuis, Nieuwegein (NL); P. Sonneveld, G.E. De Greef, and B. Löwenberg, Erasmus Medical Center, Rotterdam (NL); H.C.T. van Zaanen, St Franciscus Hospital, Rotterdam (NL); L.F. Verdonck and M. Theobald, Universitair Medisch Centrum Utrecht, Utrecht (NL); and M. Van Marwijk Kooy, Sophia Hospital, Zwolle (NL).

The following colleagues performed the cytogenetic analysis: H. Antoine-Poirel and L. Michaux, Génétique Médicale, Brussels (B); K. Rack and C. Fourneaux, Institut de Pathologie et de Génétique, Gosselies (B); A. Hagemeijer, Gasthuisberg, Leuven (B); A. Eberhard, Dortmund (D); V. Beyer, Gutenberg, Mainz (D); R. Kircheisen and A. Friedrich-Freksa, Klin Genetik, Mainz (D); M. Jotterand and S. Porter, Centre Hospitalier Universitaire Vaudois, Lausanne (S); C.H. Mellink, Academic Medical Center, Amsterdam (NL); A. Nieuwint, Free University Medical Center, Amsterdam (NL); D. Olde Weghuis, Medisch Centrum Twente, Enschede (NL); E. Van Den Berg, University Medical Center, Groningen (NL); W.G. Kroes, Klinisch Genetisch Centrum Leiden, Leiden (NL); J. Janssen, University Hospital, Maastricht (NL); M. Stevens-Kroef, Radboud University Hospital, Nijmegen (NL); H.B. Beverloo, Erasmus University Medical Center, Rotterdam (NL); A. Buijs, University Medical Center, Utrecht (NL); and M. Van der Blij-Philipsen, Veldhoven (NL).

The Dutch Working Party on Cancer Genetics and Cytogenetics performed cytogenetic review: A. Hagemeijer, Gasthuisberg, Leuven (B); C.H. Mellink, Academic Medical Center, Amsterdam (NL); A. Nieuwint and S.L. Van Zelderen-Bhola, Free University Medical Center, Amsterdam (NL); K.B.J. Gerssen-Schoorl, University Medical Center, Groningen (NL); and H.B. Beverloo, Erasmus University Medical Center, Rotterdam (NL).

	ACKNOWLEDGMENTS

 
This study was done within the collaborative framework of the Dutch-Belgian Hemato-Oncology Cooperative Group, Swiss Group for Clinical Cancer Research Cooperative Group, and Dutch Working Party on Cancer Genetics and Cytogenetics. We thank the local and central data managers for collecting the patient data. See Appendix for participating investigators.

	NOTES

 
published online ahead of print at www.jco.org on August 11, 2008

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
1. Grimwade D, Walker H, Oliver F, et al: The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1612 patients entered into the MRC AML 10 trial. Blood 92:2322-2333, 1998[Abstract/Free Full Text]

2. Wheatley K, Burnett AK, Goldstone AH, et al: A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived form the MRC AML 10 trial. Br J Haematol 107:69-79, 1999[CrossRef][Medline]

3. Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 96:4075-4083, 2000[Abstract/Free Full Text]

4. Byrd JC, Mrozek K, Dodge RK, 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 (CALBG 8461). Blood 100:4325-4336, 2002[Abstract/Free Full Text]

5. Mrózek K, Heerema NA, Bloomfield CD: Cytogenetics in acute leukemia. Blood Rev 18:115-136, 2004[CrossRef][Medline]

6. Mrózek K, Bloomfield CD: Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 169-177, 2006

7. Schoch C, Haferlach T, Haase D: Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: A study of 90 patients. Br J Haematol 112:118-126, 2001[CrossRef][Medline]

8. Löwenberg B: Prognostic factors in acute myeloid leukemia. Best Pract Res Clin Haematol 14:65-75, 2001[Medline]

9. Visani G, Bernasconi P, Boni M, et al: The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia: Analysis of 848 patients. Leukemia 15:903-909, 2001[CrossRef][Medline]

10. Löwenberg B, Boogaerts MA, Daenen SMGJ, et al: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15:3496-3506, 1997[Abstract/Free Full Text]

11. Löwenberg B, Van Putten W, Theobald M, et al: Effect of priming with granulocyte-colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 349:743-752, 2003[Abstract/Free Full Text]

12. Breems DA, Boogaerts MA, Dekker AW, et al: Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: A prospective randomized Dutch-Belgian Haemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol 128:59-65, 2005[CrossRef][Medline]

13. Mitelman F (ed): ICSN 1995: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 1995

14. Farag SS, Archer KJ, Mrozek K, et al: Isolated trisomy of chromosomes 8, 11, 13 and 21 is an adverse prognostic factor in adults with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B 8461. Int J Oncol 21:1041-1051, 2002[Medline]

Submitted January 3, 2008; accepted June 5, 2008.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				B. Lowenberg, G. J. Ossenkoppele, W. van Putten, H. C. Schouten, C. Graux, A. Ferrant, P. Sonneveld, J. Maertens, M. Jongen-Lavrencic, M. von Lilienfeld-Toal, et al. High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia N. Engl. J. Med., September 24, 2009; 361(13): 1235 - 1248. [Abstract] [Full Text] [PDF]

				E. H. Estey Treatment of acute myeloid leukemia Haematologica, January 1, 2009; 94(1): 10 - 16. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Breems, D. A. Articles by Löwenberg, B. Search for Related Content PubMed PubMed Citation Articles by Breems, D. A. Articles by Löwenberg, B. Social Bookmarking                            What's this?