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)

Byrd, John C.; Mrózek, Krzysztof; Dodge, Richard K.; Carroll, Andrew J.; Edwards, Colin G.; Arthur, Diane C.; Pettenati, Mark J.; Patil, Shivanand R.; Rao, Kathleen W.; Watson, Michael S.; Koduru, Prasad; Moore, Joseph O.; Stone, Richard; Mayer, Robert J.; Feldman, Eric J.; Davey, Frederick R.; Schiffer, Charles A.; Larson, Richard A.; Bloomfield, Clara D.

doi:10.1182/blood-2002-03-0772

Cited by 1,415 publications

(1,136 citation statements)

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“…Among these are certain secondary cytogenetic aberrations, leukocytosis, CD56 expression and extramedullary manifestations. Review of the literature found that some suggested indicators, most notably CD56 9 and extramedullary involvement, 10 were identified in a single or relatively small studies; others were based on the patients treated with different protocols [11][12][13][14] or included secondary leukemia, 15 rendering it difficult to compare and draw consistent conclusions. This is particularly true regarding implications of additional cytogenetic aberrations.…”

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confidence: 99%

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Lin¹,

Chen

Luthra³

et al. 2008

Modern Pathology

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Acute myeloid leukemia with t(8;21)(q22;q22) is a distinct type of leukemia considered to have a favorable prognosis. However, some patients rapidly succumb to disease despite chemotherapy. We studied 56 patients with acute myeloid leukemia associated with t(8;21) and correlated clinicopathologic, cytogenetic and molecular findings with outcome to identify markers of prognosis. In a subset of patients, we also assessed the status of the c-KIT, FLT3 and RAS genes. There were 31 men and 25 women, with a median age of 38 years (range 4-76). The follow-up period ranged from 17 to 104 months (median 52). At the last follow-up, 29 patients had died, 25 patients were in complete remission and two patients were alive with disease. The median survial was 38 months. The 5-year overall survival rate of newly diagnosed patients was 56%. Most patients (39/56, 70%) had chromosomal aberrations in addition to t(8;21), with loss of a sex chromosome (39%) being most common followed by del(9q)(q21-22) (11%) and trisomy 8 (7%). These aberrations, however, did not predict survival. C-KIT (D816V or D816Y), FLT3 (ITD or D835) and RAS mutations were detected in 26, 10 and 7%, respectively, of cases assessed. The 5-year overall survival rate of patients with mutated leukemia was 20%. No mutations were observed in three patients who died within 7 months of diagnosis. Leukocytosis or CD56 expression did not correlate with a poor survival nor did the levels of CD19 expression predict c-KIT mutation status. We conclude that acute myeloid leukemia associated with t(8;21) is a heterogeneous disease with poor survival in a subset of patients unrelated to common secondary cytogenetic aberrations. Keywords: t(8;21); cytogenetics; c-KIT mutation The t(8;21)(q22;q22) is the most common cytogenetic abnormality in acute myeloid leukemia (AML), occurring in up to 12% of patients. 1 As a result of t(8;21), the ETO (MTG8) gene on chromosome 8 is fused to the AML1 (RUNX1) gene on chromosome 21, producing a novel chimeric gene, AML1-ETO. The AML1 gene encodes the alpha subunit of core-binding factor (CBF) that is essential for normal hematopoiesis. AML1-ETO fusion gene disrupts the CBF transcription complex, thus initiating the first step of leukemogenesis. 2 The AML1-ETO fusion protein is a multifunctional cellular protein that affects cell differentiation, proliferation, apoptosis and self-renewal. 3 Evidence suggests that additional cytogenetic aberrations may act synergistically with AML-ETO in leukemogenesis. 3 AML with t(8;21), similar to AML with inv(16) or t(15;17), is generally considered a disease with an overall favorable prognosis characterized by a higher response rate and longer median survival compared with other types of AML. This concept is adopted in the current World Health Organization Classification. 4 Of the two references cited by the WHO classification, both published in 1998, 5,6 one was a British study of 1612 AML patients in which 122 patients had AML with t(8;21). The 5-year overall survival (OS) rate of patients with t(8;21) ...

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confidence: 99%

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Lin¹,

Chen

Luthra³

et al. 2008

Modern Pathology

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“…Currently, cytogenetic findings provide the most important prognostic information and are used to guide risk-adapted treatment strategies [2]. Cytogenetically normal AML (CN-AML) represents 40-50 % of all AML cases and currently is considered separate entity in WHO classification [3].…”

Section: Introductionmentioning

confidence: 99%

Prevalence and Prognostic Impact of CEBPA Gene Mutation (Simplified Assay Technique) in Egyptian Acute Myeloid Leukemia Patients with Normal Cytogenetics

Said

El‐Masry

Salem

et al. 2015

Indian J Hematol Blood Transfus

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Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), especially in those with a normal cytogenetics. However, few studies were done on Egyptian AML patients and none of them look for easier and less expensive method for CEBPA mutation screening. This study is aimed to investigate the prevalence of CEBPA mutations and its clinical and prognostic impact in Egyptian patients with cytogenetically normal AML (CN-AML). This was done using fragment analysis to assess this method as a cheaper and less laborious screening method compared to sequencing. Fluorescent PCR was done to amplify CEBPA gene in DNA extracted from 40 CN-AML patients. This was followed by fragment analysis of post-PCR products using GeneMapper software for detection of CEBPA mutations. CEBPA gene mutations were found in 7/40 CN-AML patients (17.5 %) and it was significantly associated with lower LDH levels (p = 0.039). All patients with CEBPA mutations achieved clinical remission and none of them showed refractoriness, relapsed, or died by the end of the 2 years study period. Furthermore, those patients demonstrate significantly longer overall and disease free survival than those with wild type CEBPA gene (p = 0.001 and 0.004 respectively). CEBPA mutation has a favorable prognostic impact in CN-AML. Fragment analysis is a good, lees laborious and cheaper method that can be used for CEBPA mutation screening in patients with CN-AML.

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“…Prognostically bad karyotypic abnormalities, also present in B15% of patients, include deletion of chromosome 7, deletion of chromosome 5q and more than three chromosomal abnormalities. 4,5 Other karyotypic abnormalities that have an unclear effect on prognosis have been observed, including trisomy 8 and trisomy 21d. These abnormalities are generally considered to be in the intermediate-risk prognosis category along with normal karyotype.…”

Section: Introductionmentioning

confidence: 99%

“…These abnormalities are generally considered to be in the intermediate-risk prognosis category along with normal karyotype. The identification of these markers led to the development of cytogenetic risk classification systems by several cooperative groups internationally, including the Cancer and Leukemia Group B, 5 Eastern Cooperative Oncology and Southwest Oncology Groups, 6 the UK Medical Research Council 2 and Frö hling et al 4 in Germany.…”

Section: Introductionmentioning

confidence: 99%

“…Five-year survival rates are B55%, 24% and 5% in patients with favorable-, intermediate-and poor-risk cytogenetics, respectively. 5 Even among patients with normal karyotype AML, however, clinical outcomes are heterogenous. Among other patient-related factors, mutations in key genes involved in AML pathogenesis lead to large interpatient variability in prognostic risk (Table 2).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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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)

Abstract: We analyzed prospectively 1213 adults with de novo acute myeloid leukemia (AML) to ascertain the prognostic impact of cytogenetic abnormalities on complete remission (CR) rate, 5-year cumulative incidence of relapse (CIR), and 5-year overall survival (OS

Cited by 1,415 publications

References 48 publications

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

Prevalence and Prognostic Impact of CEBPA Gene Mutation (Simplified Assay Technique) in Egyptian Acute Myeloid Leukemia Patients with Normal Cytogenetics

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

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