Patient-specific analysis of FLT3 internal tandem duplications for the prognostication and monitoring of acute myeloid leukemia

Abstract Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315). Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

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Acute Myeloid Leukemia Stem Cells: The Challenges of Phenotypic Heterogeneity

Cancers ◽

10.3390/cancers12123742 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3742

Author(s):

Marlon Arnone ◽

Martina Konantz ◽

Pauline Hanns ◽

Anna M. Paczulla Stanger ◽

Sarah Bertels ◽

...

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Current Knowledge ◽

Phenotypic Variability ◽

Cellular Level ◽

Patient Specific ◽

Heterogeneous Landscape ◽

Cells Of Origin ◽

Acute Myeloid

Patients suffering from acute myeloid leukemia (AML) show highly heterogeneous clinical outcomes. Next to variabilities in patient-specific parameters influencing treatment decisions and outcome, this is due to differences in AML biology. In fact, different genetic drivers may transform variable cells of origin and co-exist with additional genetic lesions (e.g., as observed in clonal hematopoiesis) in a variety of leukemic (sub)clones. Moreover, AML cells are hierarchically organized and contain subpopulations of more immature cells called leukemic stem cells (LSC), which on the cellular level constitute the driver of the disease and may evolve during therapy. This genetic and hierarchical complexity results in a pronounced phenotypic variability, which is observed among AML cells of different patients as well as among the leukemic blasts of individual patients, at diagnosis and during the course of the disease. Here, we review the current knowledge on the heterogeneous landscape of AML surface markers with particular focus on those identifying LSC, and discuss why identification and targeting of this important cellular subpopulation in AML remains challenging.

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Expression of pSTAT5 predicts FLT3 internal tandem duplications in acute myeloid leukemia

Annals of Hematology ◽

10.1007/s00277-009-0890-8 ◽

2010 ◽

Vol 89 (7) ◽

pp. 663-669 ◽

Cited By ~ 11

Author(s):

Ellen Christina Obermann ◽

Caroline Arber ◽

Martine Jotterand ◽

Andre Tichelli ◽

Petra Hirschmann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tandem Duplications ◽

Acute Myeloid

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Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults

Hematology ◽

10.1182/asheducation-2014.1.21 ◽

2014 ◽

Vol 2014 (1) ◽

pp. 21-33 ◽

Cited By ~ 21

Author(s):

Mohamed L. Sorror ◽

Elihu Estey

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Cell Transplantation ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Hematopoietic Cell ◽

Assessment Tools ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Patient Specific ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is primarily a disease of the elderly and the numbers of these patients are increasing. Patients ≥60 years of age continue to have poor prognosis. Preliminary results suggest benefit from reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in selected patients 60-80 years of age. However, although patients in this age range comprise >50% of those with AML, they currently constitute only 17% of those offered HCT. In the absence of prospective randomized studies comparing HCT and chemotherapy, the decision to recommend HCT rests on retrospective analyses of the risks of relapse and nonrelapse mortality after each approach. There is strong evidence that pre-HCT comorbidities can predict HCT-related morbidity and mortality. Age alone does not appear predictive and, particularly if the risk of relapse with chemotherapy is high, should not be the sole basis for deciding against HCT. Use of geriatric assessment tools, inflammatory biomarkers, and genetic polymorphism data may further aid in predicting nonrelapse mortality after HCT. Disease status and pretreatment cytogenetics with FLT3-TID, NPM-1, and CEBP-α status are the main factors predicting relapse and these are likely to be supplemented by incorporation of other molecular markers and the level of minimal residual disease after chemotherapy. HLA-matched related and unrelated donor grafts seem preferable to those from other donor sources. Donor age is of no clear significance. Models combining comorbidities with AML risk factors are useful in risk assessment before HCT. In this chapter, we integrated information on AML-specific, HCT-specific, and patient-specific risk factors into a risk-adapted approach to guide decisions about HCT versus no HCT.

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Detection of NPM1 exon 12 mutations and FLT3 – internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia

Journal of Hematology & Oncology ◽

10.1186/1756-8722-1-10 ◽

2008 ◽

Vol 1 (1) ◽

pp. 10 ◽

Cited By ~ 28

Author(s):

Angela YC Tan ◽

David A Westerman ◽

Dennis A Carney ◽

John F Seymour ◽

Surender Juneja ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Resolution ◽

Myeloid Leukemia ◽

High Resolution Melting ◽

Normal Karyotype ◽

High Resolution Melting Analysis ◽

Melting Analysis ◽

Tandem Duplications ◽

Acute Myeloid

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Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy

Leukemia ◽

10.1038/sj.leu.2402246 ◽

2001 ◽

Vol 15 (12) ◽

pp. 1848-1851 ◽

Cited By ~ 30

Author(s):

DH Christiansen ◽

J Pedersen-Bjergaard

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Normal Karyotype ◽

Previous Therapy ◽

Tandem Duplications ◽

Acute Myeloid

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Prognostic Importance ofMN1Transcript Levels, and Biologic Insights FromMN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.6110 ◽

2009 ◽

Vol 27 (19) ◽

pp. 3198-3204 ◽

Cited By ~ 109

Author(s):

Christian Langer ◽

Guido Marcucci ◽

Kelsi B. Holland ◽

Michael D. Radmacher ◽

Kati Maharry ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Expression Profiles ◽

Microrna Expression ◽

Wild Type ◽

Prognostic Importance ◽

Group B ◽

Leukemia Group ◽

Tandem Duplications ◽

Acute Myeloid

PurposeTo determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene– and microRNA–expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML).Patients and MethodsMN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials.ResultsHigher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation.ConclusionMN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.

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Low Frequency and Poor Prognosis Of MLL-Partial Tandem Duplications In Pediatric Acute Myeloid Leukemia Using MLPA Method: The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 Trial

Blood ◽

10.1182/blood.v122.21.1374.1374 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1374-1374

Author(s):

Kentaro Ohki ◽

Myoung-ja Park ◽

Hitoshi Sano ◽

Yusuke Hara ◽

Norio Shiba ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Pediatric Patients ◽

Low Frequency ◽

Rt Pcr ◽

Mll Gene ◽

Pediatric Aml ◽

Tandem Duplications ◽

Acute Myeloid

Abstract Background Mixed-lineage leukemia (MLL)-partial tandem duplications (PTDs) are found in 3-5% of adult acute myeloid leukemia (AML), and are associated with poor prognosis. Report of the incidence and prognostic relevance of MLL-PTD in pediatric AML is limited and large differences in the frequency have been reported. In pediatric AML cases, a frequency of 10-13% for MLL-PTD was detected using mRNA RT-PCR, whereas a frequency of only 2.5% was detected using multiplex ligation-dependent probe amplification (MLPA). We studied the frequency and prognostic effect of MLL-PTD in pediatric patients with AML treated with JPLSG AML-05 trial (between 2006-2010). Methods MLL-PTD of 331 pediatric de novo AML in the AML-05 trial was analyzed from genomic DNA extracted from their diagnostic bone marrow samples using MLPA analysis. We designed a probe mix for MLPA analysis containing adjacent probes within exon 2-5 and exon 7-13 of the MLL gene for the detection of common and rare type MLL-PTD. Exon 17 of the MLL gene was used as an internal control. We also performed RT-PCR to detect MLL-PTD transcripts to allow comparison with the MLPA results. To assess whether MLL-PTD overlap with known gene abnormalities, such as FLT3, KIT, and NPM1 mutations, mutational analyses of these genes were also performed in patients in the AML-05 trial. Results MLL-PTD was detected in 9 (2.7%) of 331 patients by MLPA analysis. In 303/331 samples mRNA RT-PCR screening for MLL-PTD was performed, and MLL-PTD was detected in 38 (12.5%). In 9 cases, both MLPA and mRNA-RT-PCR were positive for MLL-PTD. The characteristics of the 9 patients with MLL-PTD using MLPA analysis were below. None of the patients harbouring an MLL-rearrangement, t(8;21) or inv(16) revealed a MLL-PTD. All MLL-PTD cases were found in patients with normal cytogenetics. FLT3-ITD was present in 4 of 9 patients with MLL-PTD, while none of KIT and NPM1 mutation was detected in MLL-PTD cases. There was a significantly higher frequency of FLT3-ITD in patients with an MLL-PTD than in those without MLL-PTD (p=0.016). Among these 9 patients, 5 patients were classified as FAB-M5a (p=0.0068), and other 4 patients were classified as FAB-M1, M2, M4 and M6a. The age of patients with MLL-PTD was higher than that of patients without MLL-PTD (median 11.8 years (range; 9-15) and 7.4 years (range; 0-17), respectively; p=0.004). Patients with MLL-PTD tend to have higher white blood cell counts (WBC) at initial diagnosis than those without MLL-PTD (median WBC 6.0×10*9/l (range; 1500-151000) versus 2.2×10*9/l (range; 617-985000a) respectively; p=0.18). All 9 patients with MLL-PTD had events. There was a significantly higher frequency of event including refractory disease, relapse and death in patients with an MLL-PTD than in those without MLL-PTD (p=0.001). Only one of 9 patients was achieved complete remission (CR) after induction therapy (p= 1.1×10-11). Six of 9 patients relapsed, and 5 patients died. Conclusion Using DNA-MLPA as a novel screenings technique, low frequency of MLL-PTD in pediatric AML was found. However, MLL-PTD is highly associated with a poor prognosis in pediatric AML. These data suggest that screening for MLL-PTD in pediatric patients with AML is critical not only for outcome prediction but also for risk-adapted therapy. Disclosures: No relevant conflicts of interest to declare.

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