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

2008 ◽  
Vol 26 (29) ◽  
pp. 4791-4797 ◽  
Author(s):  
Dimitri A. Breems ◽  
Wim L.J. Van Putten ◽  
Georgine E. De Greef ◽  
Shama L. Van Zelderen-Bhola ◽  
Klasien B.J. Gerssen-Schoorl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Single Chromosome ◽  
Cytogenetic Abnormalities ◽  
Poor Outcome ◽  
Monosomal Karyotype ◽  
Acute Myeloid

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%).

The Influence of Monosomal Karyotype On Survival in Patients with Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Survey On Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 158-158 ◽  
Author(s):  
Angelique V.M. Brands-Nijenhuis ◽  
Myriam Labopin ◽  
Harry C. Schouten ◽  
Liisa Volin ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 158 Introduction: Monosomal karyotype (MK) has been shown to be associated with a very poor prognosis in AML patients (Breems, 2008). Whether allogeneic hematopoietic stem cell transplantation (alloHSCT) performed in an early phase can overcome the adverse prognosis in this cytogenetic patient category is currently unknown. To address this issue we performed a retrospective analysis on data from the registry of the EBMT among patients with primary AML who underwent alloHSCT in CR1. Patients and methods: A total of 4119 patients with primary AML and known cytogenetic abnormalities at diagnosis that underwent alloHSCT in CR1 were included in the analysis. Survival curves were calculated with Kaplan-Meier method. Log rank test and Cox regression analysis were used to determine statistical significance. Results: Median follow-up was 24 months (range 2–374). Overall, 171 patients (4.2%) fulfilled criteria for MK and 297 patients (7.2%) for complex karyotype (CK), with 115 patients fulfilling both conditions (MK and CK). Both the presence of a MK (2-yr OS: 35.5% versus 63.2%, p<0.0001) and CK (2-yr OS: 48.8% versus 61.9%, p<0.0001) were associated with a poorer outcome when compared with the remaining cytogenetics subtypes. Given the significant overlap between both categories, we further analyzed their prognostic impact after defining four subgroups of patients: MK but not CK (56 patients; MK+CK-), no MK but CK (180 patients; MK-CK+), MK and CK (115 patients; MK+CK+), and patients without either MK or CK (MK-CK-). Outcome of the MK-CK- subgroup did not differ according to cytogenetics. Patients harboring a MK, regardless concomitant presence of a CK, presented with a poorer OS after alloHSCT (2-yr OS: 31.7–43.0% versus 61.1%, p<0.0001). On the contrary patients with a CK but not MK showed a similar outcome than MK-CK- (2-yr OS: 61.1% versus 63.3%, p=0.170). Moreover, multivariate analysis confirmed the independent negative impact of MK (HR:1.90, range 1.5–2.4; p<0.0001) together with age, interval diagnosis-transplant, AML subtype, WBC at diagnosis, T-cell depletion, number of induction cycles and use of TBI during conditioning, whereas the presence of a CK did not retain its negative prognostic value. Conclusion: These results indicate that MK is a better indicator for poor outcome than CK after alloHSCT in patients with primary AML in CR1. Nonetheless, the potential curative role of alloHSCT for a subset of patients with MK should be further investigated. Reference: DA Breems, WLJ van Putten, GE de Greef, SL van Zelderen-Bhola, KBJ Gerssen-Schoorl, CHM Mellink, A Nieuwint et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008;26(29):4791–7. Disclosures: No relevant conflicts of interest to declare.

Prognostic Value of Monosomal Karyotype in Patients with Primary Acute Myeloid Leukemia On Behalf of Spanish CETLAM Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1003-1003 ◽  
Author(s):  
Isabel Granada ◽  
Salut Brunet ◽  
Montserrat Hoyos ◽  
Dolors Costa ◽  
Anna Aventín ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 1003 Poster Board I-25 Introduction: Recently, the cooperative group HOVON-SAKK has refined the prognostic impact of cytogenetic abnormalities in acute myeloid leukemia (AML) by introducing the concept of monosomal karyotype (MK). This consists of ≥ 2 autosomal monosomies or one autosomal monosomy in addition to a structural alteration. In their experience, MK would explain the poor prognosis of AML with a complex karyotype. Objective: To investigate the prognostic impact of MK in patients with primary (de novo) AML enrolled in the Spanish CETLAM group protocols (AML 94/99/03). Also, to determine whether considering MK added predictive value to the cytogenetic classification of the Medical Research Council (MRC). Methods: Retrospective analysis of data from 1149 AML patients. Chromosomal formula was centrally reviewed with karyotypes being classified by the presence of MK and allocated into the MRC risk categories. Complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were calculated. Results: The karyotype was assessable in 904 (79%) of the 1149 cases. In 145 of the 904 cases (16%), abnormalities involving CBF gene were detected and in 437 (48%) the karyotype was normal (NK). In 253 (28%) additional patients the karyotype was not monosomal; of them, 61 (24%) belonged to the unfavorable MRC with 17 cases harboring a complex karyotype ≥ 5 abnormalities, 7 cases with rearrangements 3q, 13 cases with -7, 9 cases with 5q abnormalities and 16 cases with t(6;9)). The remaining 69 (7.7%) patients had a MK; of them, 59 (85.5%) were from the unfavorable MRC category and included 43 cases with complex karyotype ≥ 5 abnormalities, 6 cases with rearrangements 3q, 5 cases with -7, 5 cases with alterations of 5q). The following table summarizes the results in terms of CR rate, DFS and OS: Conclusions: The addition of MK to the MRC cytogenetic classification refines the prognostic prediction. In our series, the dismal outcome of patients with MK is confirmed; these patients had worse prognosis than those with adverse cytogenetics without MK. Alternative treatment strategies are mandatory for MK+ patients. Supported in part by grants: GR1-01075, ECO07/90065, PI080672 and RD06/0020/0101. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 551-558 ◽  
Author(s):  
Sabine Kayser ◽  
Manuela Zucknick ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
World Health ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Allogeneic Hsct ◽  
Monosomal Karyotype ◽  
Acute Myeloid

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of −5/5q−, −7, 7q−, abnl(12p), abnl(17p), −18/18q−, −20/20q−, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK+. Response to induction therapy and overall survival in MK+ patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

scholarly journals Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2224-2228 ◽  
Author(s):  
Bruno C. Medeiros ◽  
Megan Othus ◽  
Min Fang ◽  
Diane Roulston ◽  
Frederick R. Appelbaum
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Remission Rate ◽  
Risk Category ◽  
Prognostic Impact ◽  
Oncology Group ◽  
Southwest Oncology Group ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.

Validation of Monosomal Karyotype Based Model In the Risk Stratification of Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2745-2745
Author(s):  
Murtadha K. Al-Khabori ◽  
Karen Yee ◽  
Vikas Gupta ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Structural Abnormality ◽  
Complex Karyotype ◽  
Poor Risk ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 2745 Background: The influence of cytogenetic abnormalities on the prognosis of acute myeloid leukemia (AML) has been well-documented; however, the relative impact of certain miscellaneous abnormalities remains controversial. Recently, monosomal karyotype-based risk stratification has been shown to further discriminate the prognosis within the poor-risk karyotype group (Breems et al. JCO 2008), but this finding requires further validation. Methods: We retrospectively reviewed 779 consecutive adult AML patients treated with standard induction chemotherapy, consisting of daunorubicin plus cytarabine (3+7), at our institution from 1998–2008. After excluding patients with favourable risk, normal, missing or failed karyotype, 290 patients remained and were included in the analysis. Results: The baseline characteristics of these 290 patients were as follows: median age 59 y (range 18–81), male 181, prior malignancy 110, median white cell count (WBC) 7.6 × 10^9/L (range 0–246). The karyotypic features included single monosomy in 42, 2 or more monosomies in 51, and non-monosomy structural and numerical abnormalities in 197 patients. Of the 290, 116 (40 %) had three or more abnormalities (complex karyotype, CK). A total of 141 patients (49 %) achieved complete remission (CR) with 3+7 induction chemotherapy. Sixty-four patients received allogeneic stem cell transplantation in CR. The median overall survival (OS) for all patients was 12 months (95% CI: 10–14 months). The median OS was 10 (95% CI: 6–18), 7 (95% CI: 6–10) and 14 months (95% CI: 12–16) in the single monosomy, 2+ monosomy and non-monosomy groups, respectively (p < 0.0001 by log-rank test comparing the three groups). Among the patients containing at least one monosomy, the OS was not significantly different between the CK and non-CK groups (p = 0.08 by log rank). Similarly, in the non-monosomy structural abnormality group, the OS was not significantly different between the CK and non-CK groups (p = 0.2). Conclusions: Our results provide validation for the monosomal karyotype-based risk stratification for AML, indicating that patients with at least one monosomy have an inferior OS compared to other poor-risk non-monosomy groups. Within each of the monosomy and non-monosomy groups, the presence of a complex karyotype does not significantly influence the OS. Disclosures: No relevant conflicts of interest to declare.

TP53 Alterations in Acute Myeloid Leukemia with Complex Karyotype Correlate with Specific Copy Number Alterations, Monosomal Karyotype, and Dismal Outcome,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3558-3558 ◽  
Author(s):  
Frank G. Rücker ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Sabine Kayser ◽  
Veronica Teleanu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Complex Karyotype ◽  
Copy Number Alterations ◽  
Free Survival ◽  
Genomic Complexity ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 3558 Acute myeloid leukemia with complex karyotype (CK-AML, CK+) is defined as ≥3 acquired chromosome abnormalities in the absence of recurrent genetic abnormalities (WHO 2008). CK-AML account for 10–15% of all AML and are characterized by a dismal outcome. To delineate prognostic markers in this unfavorable subgroup, we performed integrative analysis using genomic profiling (array-comparative genomic hybridization [CGH] and/or single-nucleotide polymorphism [SNP] analysis), as well as TP53 mutation screening in 234 CK-AML. TP53 mutations were found in 141/234 (60%) CK-AML comprising 130 missense, 21 insertion/deletion, nine nonsense, and eight splice site mutations; genomic losses of TP53 were identified in 94/234 (40%). Combining these data, TP53 alterations were detected in 70% of patients, and at least 66% of these exhibited biallelic alterations. TP53 alterations (loss and/or mutation in TP53) were characterized by a higher degree of genomic complexity, as measured by total number of copy number alterations per case (mean±SD 14.30±9.41 versus 6.16±5.53, P <.0001), and by the association with specific genomic alterations, that is, monosomy 3 or losses of 3q (-3/3q-) (P=.002), -5/5q- (P<.0001), -7/7q- (P=.001), -16/16q- (P<.0001), -18/18q- (P=.001), and -20/20q- (P=.004); gains of chromosome 1 or 1p (+1/+1p) (P=.001), +11/+11q (P=.0002), +13/+13q (P =.02), and +19/+19p (P =.04); and amplifications in 11q13∼25 [amp(11)(q13∼25)]. The recently described cytogenetic category “monosomal karyotype” (MK), defined as two or more autosomal monosomies or one single autosomal monosomy in the presence of structural abnormalities, for which a prognostic impact could be demonstrated even in CK-AML, was correlated with TP53 alterations (P <.0001). Clinically, TP53altered CK-AML patients were older (median age, 61 versus 54 years, P =.002), had lower bone marrow (BM) blast counts (median 65% versus 78%, P=. 04), and had lower complete remission (CR) rates (28% versus 50%, P =.01). For multivariable analysis, a conditional model was used with an age cut point at 60 years to address the different treatment intensities applied in the different age cohorts. In this model the only significant factors for CR achievement were TP53altered (OR, 0.55; 95%-CI, 0.30 to 1.00; P =.05) and age (OR for a 10 years difference, 0.67; 95%-CI, 0.52 to 0.87; P =.003). TP53 altered predicted for inferior survival; the 3-year estimated survival rates for CK+/TP53altered and CK+/TP53unaltered patients were as follows: event-free survival (EFS), 1% versus 13% (log-rank, P =.0007); relapse-free survival (RFS), 7% versus 30% (P =.01); and overall survival (OS), 3% versus 28% (P <.0001), respectively. Other variables predicting for inferior OS in univariable analyses were age and MK. Among the cohort of CK+/MK+ AML, TP53altered patients had a significantly worse OS (P =.0004). Multivariable analysis (stratified for age at cut point of 60 years) revealed TP53altered (HR, 2.43; 95%-CI, 1.56 to 3.77; P =.0001), logarithm of WBC (HR, 1.62; 95%-CI 1.17 to 2.26; P =.004), and age (HR for 10 years difference, 1.26; 95%-CI, 1.01 to 1.56, P =.04), but not MK as significant variables for OS. In addition, explorative subset analysis suggested that allogeneic hematopoietic stem-cell transplantation in first CR which was performed in 30 CK-AML did not impact outcome in TP53altered CK-AML. In summary, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category. TP53 mutational status should be assessed in clinical trials investigating novel agents in order to identify compounds that may be effective in this subset of patients. Disclosures: No relevant conflicts of interest to declare.

Patients with Monosomal Karyotype in Acute Myeloid Leukemia Is Prognostically Worse Than with Complex Karyotype

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4735-4735
Author(s):  
Liu Xiaoli ◽  
Xu Na ◽  
DU Qingfeng ◽  
Xu Dan ◽  
Meng Fanyi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Confidence Interval ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Disease Free Survival ◽  
Structural Abnormality ◽  
Complex Karyotype ◽  
Significant Difference ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 4735 Purpose: Monosomal karyotype (MK) refers to the presence of two or more distinct autosomal monosomies or a single monosomy associated with a structural abnormality. To analyze the prognosis of cytogenetic components of a complex karyotype or Monosomal Karyotype in acute myeloid leukemia (AML) except acute promyelocytic leukemia(APL). Patients and Methods:Cytogenetics and overall survival (OS), Disease free survival(DFS) were analyzed in 551 AML patients age 14 to 60 years in our center.Results: There ware 235 patiets with cytogenetic abnormalities, 25 cases with inv(16)(p13.1q22) or t(16;16)(p13.1;q22),and 63 cases with t(8;21); 31 cases (13.2%)met the criteria for MK and 39 cases (16.6%) had a complex karyotype without monosomies. OS was significantly inferior in patients with MK compared with those with a complex karyotype without monosomies (P<0.01;HR 1.85,95% confidence interval(95%CI),0.95-2.81). There was no difference between MK cases with complex karyotype cases in DFS (P>0.05□GHR 3.42,95% confidence interval(95%CI),2.96-6.70). There was significant difference in regardless of whether OS or DFS between MK+ patients with MK− patients (P<0.01). Conclusion: MK was one of independent risk factor in AML patients. Disclosures: No relevant conflicts of interest to declare.

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