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Mutation Patterns of 16 Genes in Primary and Secondary Acute Myeloid Leukemia (AML) with Normal Cytogenetics  [PDF]
Marta Fernandez-Mercado, Bon Ham Yip, Andrea Pellagatti, Carwyn Davies, María José Larrayoz, Toshinori Kondo, Cristina Pérez, Sally Killick, Emma-Jane McDonald, María Dolores Odero, Xabier Agirre, Felipe Prósper, María José Calasanz, James S. Wainscoat, Jacqueline Boultwood
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042334
Abstract: Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.
Cryptic PML-RARα positive acute promyelocytic leukemia with unusual morphology and cytogenetics  [cached]
Goyal Manu,Dattatreya Palinki,Goud Irawathy,Murthy Sudha
Indian Journal of Pathology and Microbiology , 2010,
Abstract: Acute Promyelocytic Leukemia (APL) is different from other forms of acute myeloid leukemia (AML), to the reason being the potential devastating coagulopathy and the sensitivity to all-trans retinoic acid (ATRA) and arsenic trioxide (As 2 O 3 ). We hereby present a case of APL, morphologically distinct from the hypergranular APL; however, the flow cytometry revealed a characteristic phenotype showing dim CD45, bright CD13, bright CD33 and dim CD117 positivity. These were negative for CD34, HLA-DR, B-lymphoid and T-lymphoid lineage markers. Conventional cytogenetics revealed a distinct karyotype of a male with translocation t(4;15)(q34.2:q26.3). However, interphase florescence-in-situ hybridization (FISH) revealed PML/RARA fusion signal on chromosome 15 in 90% cells. The cryptic translocations may be missed on conventional cytogenetics, however, need to be picked by other techniques as FISH.
Optimization of the indications for allogeneic stem cell transplantation in Acute Myeloid Leukemia based on interactive diagnostic strategies
Hartwig M,Zander AR,Haferlach T,Fehse B
Cellular Therapy and Transplantation , 2008,
Abstract: The indications for allogeneic stem cell transplantation (SCT) in Acute Myeloid Leukemia (AML) represent a real challenge due to the clinical and genetic heterogeneity of the disorder. Therefore, an optimized indication for SCT in AML first requires the determination of the individual relapse risk based on diverse chromosomal and molecular prognosis-defining aberrations. A broad panel of diagnostic methods is needed to allow such subclassification and prognostic stratification: cytomorphology, cytogenetics, molecular genetics, and immunophenotyping by multiparameter flow cytometry. These methods should not be seen as isolated techniques but as parts of an integral network with hierarchies and interactions. Examples for a poor risk constellation as a clear indication for allogeneic SCT are provided by anomalies of chromosome 7, complex aberrations, or FLT3-length mutations. In contrast, the favorable reciprocal translocations such as the t(15;17)/PML-RARA or t(8;21)/AML1-ETO are not indications for SCT in first remission due to the rather good prognosis after standard therapy. Further, the indication for SCT should include the results of minimal residual disease (MRD) diagnostics by polymerase chain reaction (PCR) or flow cytometry. New aspects for a safe and fast risk stratification as basis for an optimized indication for SCT in AML might be provided by novel technologies such as microarray-based gene expression profiling.
Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide
Yuka Sugimoto, Mikkael A Sekeres, Hideki Makishima, Fabiola Traina, Valeria Visconte, Anna Jankowska, Andres Jerez, Hadrian Szpurka, Christine L O'Keefe, Kathryn Guinta, Manuel Afable, Ramon Tiu, Kathy L McGraw, Alan F List, Jaroslaw Maciejewski
Journal of Hematology & Oncology , 2012, DOI: 10.1186/1756-8722-5-4
Abstract: We have studied clinical, molecular and cytogenetic features of 42 patients with MDS, myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes and secondary acute myeloid leukemia (sAML) without del[5q] by metaphase cytogenetics (MC) who underwent therapy with LEN.Fluorescence in situ hybridization (FISH) or single nucleotide polymorphism array (SNP-A)-based karyotyping marginally increased the diagnostic yield over MC, detecting 2/42 (4.8%) additional cases with del[5q], one of whom were responded to LEN. Responses were more often observed in patients with a normal karyotype by MC (60% vs abnormal MC; 17%, p = .08) and those with gain of chromosome 8 material by either of all 3 karyotyping methods (83% vs all other chromosomal abnormalities; 44% p = .11). However, 5 out of those 6 patients received combined LEN/AZA therapy and it may also suggest those with gain of chromosome 8 material respond well to AZA. The addition of FISH or SNP-A did not improve the predictive value of normal cytogenetics by MC. Mutational analysis of TET2, UTX, CBL, EZH2, ASXL1, TP53, RAS, IDH1/2, and DNMT-3A was performed on 21 of 41 patients, and revealed 13 mutations in 11 patients, but did not show any molecular markers of responsiveness to LEN.Normal karyotype and gain of chromosome 8 material was predictive of response to LEN in non-del[5q] patients with myeloid malignancies.Lenalidomide (LEN) is particularly effective in patients with myelodysplastic syndromes (MDS) and the del[5q] cytogenetic abnormality [1-3]. In MDS-003, the phase II registration trial of 148 lower-risk MDS patients with del[5q] with or without other karyotypic abnormalities, 67% achieved transfusion independence with a complete and partial cytogenetic response rate of 45% and 28%, respectively [2]. There was no significant association between karyotypic complexity and the frequency of a cytogenetic response. LEN also has activity in a proportion of MDS without del[5q] [4] and [5]. Transfusion-dependent MDS p
Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics
Tara K Gregory, David Wald, Yichu Chen, Johanna M Vermaat, Yin Xiong, William Tse
Journal of Hematology & Oncology , 2009, DOI: 10.1186/1756-8722-2-23
Abstract: Acute Myeloid Leukemia (AML) is a broad range of disorders that are all characterized by an arrest of maturation along with uncontrollable proliferation of hematopoietic progenitor cells. The French-American-British classification is still widely used in clinical setting that groups AML into 8 subgroups (M0-M7) based on its degree of differentiation and morphology. Due to the heterogenous nature of AML even within specific FAB subtypes, there is a highly variable prognosis among AML patients. The overall 5-year survival rate for AML is still less than 50% in adults and significantly lower in the elderly [1]. The median survival in patients over the age of 65 is less than one year and only 20% of these patients survive two years [2]. Treatment for all subtypes of AML, except the M3 subtype, involves combination chemotherapy and a possible hematopoietic stem cell transplant as part of consolidation therapy. Acute Promyelocytic Leukemia (APL, M3 subtype) is treated with a combination of the differentiation-inducing agent all-trans retinoic acid and chemotherapy resulting in the presumed cure of 75–85% of patients [3]. In general, the prognosis of patients with AML is currently based upon the presence or absence of cytogenetic abnormalities and is divided into favorable, intermediate and unfavorable subgroups (see table 1) [4]. There is heterogeneity within these subgroups, especially the intermediate subgroup, and the age of the patient is also an important prognostic factor. One study estimated the 5 year overall survival (OS) of the favorable subgroup at 55%, the intermediate subgroup at 38% and the unfavorable subgroup at 11% [5]. Patients who have the following cytogenetic abnormalities: inv(16), t(15;17) (the translocation found in APL), or t(8;21) have a favorable prognosis while patients with several other cytogenetic abnormalities including monosomy 5, monosomy 7, 11q23, and complex cytogenetics may have a poor prognosis. However, approximately 40% of AML patie
Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission  [PDF]
Rada M. Grubovikj,Asif Alavi,Ahrin Koppel,Mary Territo,Gary J. Schiller
Cancers , 2012, DOI: 10.3390/cancers4020601
Abstract: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS.
Immunophenotypes of Acute Myeloid Leukemia From Flow Cytometry Data Using Templates  [PDF]
Ariful Azad,Bartek Rajwa,Alex Pothen
Computer Science , 2014,
Abstract: Motivation: We investigate whether a template-based classification pipeline could be used to identify immunophenotypes in (and thereby classify) a heterogeneous disease with many subtypes. The disease we consider here is Acute Myeloid Leukemia, which is heterogeneous at the morphologic, cytogenetic and molecular levels, with several known subtypes. The prognosis and treatment for AML depends on the subtype. Results: We apply flowMatch, an algorithmic pipeline for flow cytometry data created in earlier work, to compute templates succinctly summarizing classes of AML and healthy samples. We develop a scoring function that accounts for features of the AML data such as heterogeneity to identify immunophenotypes corresponding to various AML subtypes, including APL. All of the AML samples in the test set are classified correctly with high confidence. Availability: flowMatch is available at www.bioconductor.org/packages/devel/bioc/html/flowMatch.html; programs specific to immunophenotyping AML are at www.cs.purdue.edu/homes/aazad/software.html.
Neutropenic enterocolitis in acute myeloid leukemia  [PDF]
?olovi? Nata?a,Raji? Zoran,Sretenovi? Mirjana,Stojkovi? Mirjana
Acta Chirurgica Iugoslavica , 2004, DOI: 10.2298/aci0402127c
Abstract: In this report we focus on the importance of an accurate diagnosis of gastrointestinal complications during chemotherapy for acute myeloid leukemia. The leukemic infiltrtion of the digestive system may cause mucosal ulcers which can lead to bleeding or perforation. The immune system deficiency in this cohort of patients may result in necrotic enterocolitis (leukemic typhlitis), perianal inflammation, abscesses, and peritonitis. We describe a 37-year old male who presented in June 2004 with 2- month history of fever, weakness and sore throat, treated with antibiotic therapy. Physical examination demonstrated palor. The peripheral blood count at admittance was as follow: Hemoglobin 87 g/l, WBC 63 x109/l, and platelets 56 x109/l. The peripheral blood differential count showed: myeloblasts 4%, polymorphonuclear neutrophils (PMN) 20%, monocytes 60%, lymphocytes 16%. The diagnosis of acute myeloid leukemia (AML) was confirmed by bone marrow aspirate, which presented an almost total infiltration by monocytoid blasts, AML type M5 according to FAB classification. Immunophenotypic evaluation by flow cytometry showed that the blast cells reacted with antibodies to CD33, CD13, CD14, CD64, CD15, cytogenetics showed normal karyotype. Induction treatment consisting of cytarabine 2 x 200 mg intravenously in push on days 1-8, vepeside 200 mg i.v. on days 1-5, adriblastine 90 mgon days 1,3 and 5. On day 15 of chemotherapy the patient got fever 38.5oC, abdominal pain and diarrhea (10 stools daily). Broad-spectrum antibiotic therapy with ceftriaxone and amikacin was promptly instituted but condition worsened, abdominal pain extended to all abdomen while the fever and diarrhea persisted. Ultrasonography on day 18 documented bowel wall thickness of colic tract, part of duodenum and jejunum. Owing to suspicion of neutropenic enterocolitis, antibiotic therapy intensified with teicoplanin, fluconazole, metronidazole and pipril. Patient was neutropenic and thrombocytopenic, although daily platelet transfusion from a single donor were given. We started with granulocyte colony stimulating factor (G-CSF) 5 g/kg, which was adiminstered for 7 days. After 7 days neutrophil value reached 1x x109/l, but fever persisted, abdominal distension and diarrhea progressively improved. The fever peristed and central venous catheter was removed on day 30. After removal of the catheter the patient was getting better: the fever disappeared. The blood count showed Hb 91 g/l, WBC 3,4 x109/l, platelet 114 x109/l and normal leukocyte differential count. We emphesize the importance of collaboration betw
A novel dic (17;18) (p13.1;q11.2) with loss of TP53 and BCR/ABL rearrangement in an Imatinib resistant chronic myeloid leukemia  [cached]
Al-achkar Walid,Wafa Abdulsamad,Moassass Faten,Othman Moneeb Abdullah
Molecular Cytogenetics , 2012, DOI: 10.1186/1755-8166-5-36
Abstract: Background The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) cases. It results in juxtaposition of the 5′ part of the BCR gene on chromosome 22 to the 3′ part of the ABL gene on chromosome 9. Since the majority of CML cases are currently treated with Imatinib, variant rearrangements in general have no specific prognostic significance, although the mechanisms involved in resistance to therapy have yet to be investigated. The T315I mutation within the abl-gene is the most frequent one associated with resistance to tyrosine kinase inhibitors. Results This study evaluated a Ph chromosome positive CML case resistant to imatinib mesylate. A dic(17;18), loss of TP53 gene, co-expression of b2a2 and b3a2 fusions transcript and a T315I mutation were found. Conclusions We reported here a novel case of a Ph chromosome positive CML with a secondary abnormality [dic(17;18)], resulting to Glivec resistance but good response to nilotinib. The dic(17;18) might be a marker for poor prognosis in CML. Our finding indicated for an aggressive progression of the disease. The patient died under the treatment due to unknown reasons.
Molecular and cytogenetic abnormalities in acute myeloid leukemia: review and case studies
Elvira Deolinda Rodrigues Pereira Velloso,Carlos Henrique Ares Silveira da Motta,Juliana Braga Furtado,Nydia Strachman Bacal
Einstein (S?o Paulo) , 2011,
Abstract: Objective: To study the frequency of mutations that maylead to a good or bad prognosis, as well as their relation withthe karyotype and immunophenotype in patients with acutemyeloid leukemia. Methods: Thirty samples of patients withacute myeloid leukemia were studied, in which FLT3-ITD, FLT3-TKD and NPM1 mutations were investigated. All samples weresubmitted to immunophenotyping and 25 to karyotyping. Results:An occurrence of 33.3% NPM1 mutation and an equal numberof FLT3-ITD mutation were observed. When only the cases withnormal karyotype were studied, this figures increased to 50 and40%, respectively. Eight percent of cases with normal karyotypeand genotype NPM1+/FLT3- were included in the group of acutemyeloid leukemia with good prognosis. The typical phenotypeof acute myeloid leukemia with normal karyotype and mutatedNPM1 (HLA-DR and CD34 negative) was not observed in thissmall series. Conclusion: Good prognosis cases were identifiedin this series, emphasizing the need to include new geneticmarkers in the diagnostic routine for the correct classification ofacute myeloid leukemia, to more properly estimate prognosis anddetermine treatment.
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