scholarly journals TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2114-2121 ◽  
Author(s):  
Frank G. Rücker ◽  
Richard F. Schlenk ◽  
Lars Bullinger ◽  
Sabine Kayser ◽  
Veronica Teleanu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Multivariable Analysis ◽  
Complex Karyotype ◽  
Copy Number Alterations ◽  
Genomic Complexity ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as −5/5q−, −7/7q−, −16/16q−, −18/18q−, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, 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 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.

scholarly journals Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation

Blood ◽  
2011 ◽  
Vol 118 (6) ◽  
pp. 1490-1494 ◽  
Author(s):  
Min Fang ◽  
Barry Storer ◽  
Elihu Estey ◽  
Megan Othus ◽  
Lisa Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Hazard Ratio ◽  
Hematopoietic Cell ◽  
Complex Karyotype ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Monosomal karyotype (MK), defined as ≥ 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK+ patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK+. The 4-year overall survival of patients after HCT was 25% for MK+ AML and 56% for MK− AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK+ patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK+ patients remains worse than that for MK− patients in the transplantation setting, HCT appears to improve the overall outcome of MK+ patients, especially patients without a complex karyotype. However, the 28% of MK+ patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients.

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.

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.

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.

scholarly journals Survival Outcome of Patients with Acute Myeloid Leukemia Transformed from Myeloproliferative Neoplasms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1940-1940 ◽  
Author(s):  
Dai Chihara ◽  
Hagop M. Kantarjian ◽  
Kate J Newberry ◽  
Farhad Ravandi ◽  
Naval G. Daver ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Treatment Strategies ◽  
Survival Outcome ◽  
Hazard Ratio ◽  
Complex Karyotype ◽  
Acute Myeloid

Abstract Purpose: Progression to acute myeloid leukemia (AML) from myeloproliferative neoplasms (MPNs) is almost always fatal. To explore the best treatment strategies for this serious complication, we analyzed the survival outcome of patients with MPNs who progressed to AML based on treatment received at our institution. Patients and Methods: A total of 273 patients who were diagnosed with AML secondary to MPNs between 1989 and 2016 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were calculated. Results: The patients progressed to AML from essential thrombocythemia (ET, N=60), polycythemia vera (PV, N=49), primary myelofibrosis (PMF, N=105), post-ET/PV MF (N=37), and MPN-unclassifiable (N=22). The median age of the patients was 67 (range: 28-92). The median time to AML transformation from MPN diagnosis was 64.5 months (range: 0.9-477.7 months). Complex karyotype was seen in 99 patients at the time of transformation (38%). With a median follow up of 16.5 months (range: 2.7-115.7 months), 247 patients had died (88% from AML, 6% from treatment-related mortality, 6% with other cause including infection and GVHD). Ninety-nine patients received hypomethylating including agent (HMA), 71 a high-dose cytarabine regimen, 52 a low-dose cytarabine regimen, 28 other treatments, and 24 patients did not receive any treatment due deterioration of the patientfs condition or patientfs decision. The median PFS and OS after progression to AML were 2.6 months and 7.0 months, respectively. There was no significant improvement in PFS and OS by date of diagnosis (1989 to 2016). Also, complete response (CR) rate and survival outcome were not significantly different by type of treatment (Figure A) or prior MPN subtype. Overall, 46 patients (27 in CR, 14 not in CR, 4 unknown due to the transplant outside) proceeded to allogeneic transplant (allo-SCT), and the median overall survival after transplant was 15.3 months (6.1-29.4 months). Although it was not statistically significant, patients who achieved a CR before allo-SCT had longer OS than those who received allo-SCT without achieving a CR (35.1 vs 8.9 months; Figure B). Complex karyotype was associated with both shorter PFS (Hazard ratio: 2.2, 95%CI: 1.6-2.9) and OS (Hazard ratio: 2.0, 95%CI: 1.5-2.6). Summary: Survival outcome for AML secondary to MPN remains very poor, and there has been no improvement in survival outcome since 1989. Further studies are urgently needed to test new treatment strategies and to detect residual disease post allo-SCT. Considering dismal outcome after transformation, studies are also needed to explore strategies to prevent this fatal complication. Disclosures DiNardo: Daiichi Sankyo: Research Funding; Abbvie: Research Funding; Agios: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract 2451: Genomic wide microarray analysis identifies novel copy number alterations in adult acute myeloid leukemia

2017 ◽  
Author(s):  
Maria Chiara Fontana ◽  
Giovanni Marconi ◽  
Cristina Papayannidis ◽  
Eugenio Fonzi ◽  
Giorgia Simonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Microarray Analysis ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Copy Number Alterations ◽  
Acute Myeloid
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