scholarly journals A National Multicenter Evaluation of the Clinical Utility of Optical Genome Mapping for Assessment of Genomic Aberrations in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Brynn Levy ◽  
Linda B. Baughn ◽  
Scott Chartrand ◽  
Brandon LaBarge ◽  
David Claxton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genome Mapping ◽  
Genomic Structure ◽  
World Health ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Accurate Identification ◽  
Genomic Aberrations ◽  
Acute Myeloid

AbstractDetection of hallmark genomic aberrations in acute myeloid leukemia (AML) is essential for prognosis and patient management. Clinical practice guidelines for identifying such structural variants (SVs), established by the World Health Organization (WHO), European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN), rely substantially on cytogenetic/cytogenomic techniques such as karyotyping, fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA). However, these techniques are limited by the need for skilled personnel as well as significant time and labor, making them cost-prohibitive for some patients. Optical genome mapping (OGM) addresses these limitations and allows for the accurate identification of clinically significant SVs using a novel, high throughput, inexpensive methodology. In a single assay, OGM offers a significantly higher resolution than karyotyping with comprehensive genome-wide analysis comparable to CMA and the added unique ability to detect balanced SVs that are missed by microarray. Here, we report the performance of OGM in a cohort of 100 AML cases, which were previously characterized by karyotype alone or karyotype and FISH. CMA was performed as an additional test in some cases. OGM identified all the clinically relevant SVs and CNVs reported by these standard cytogenetic methods. Moreover, OGM identified clinically relevant SVs in 11% of cases that had been missed by the routine methods. In 24% of cases, OGM refined the underlying genomic structure reported by traditional cytogenomic testing (13%), identified additional clinically relevant variants (7%) or both (4%). Three of 48 (6.25%) cases reported with normal karyotypes were shown to have cryptic translocations involving gene fusions. Two of these cases included fusion between NSD1-NUP98. Based on the comprehensive genomic profiling of the AML patients in this multi-institutional study, we recommend that OGM be considered as a first-line test for detection and identification of clinically relevant SVs.

Optical genome mapping for assessment of genomic aberrations in acute myeloid leukemia: a multicenter evaluation

2021 ◽  
Vol 132 ◽  
pp. S218
Author(s):  
Brynn Levy ◽  
Linda Baughn ◽  
Scott Chartrand ◽  
Brandon LaBarge ◽  
David Claxton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genome Mapping ◽  
Genomic Aberrations ◽  
Acute Myeloid

Comprehensive Genomic Analysis of Noonan Syndrome and Acute Myeloid Leukemia in Adults: A Review and Future Directions

2020 ◽  
Vol 143 (6) ◽  
pp. 583-593
Author(s):  
Muhned S. Alhumaid ◽  
Majed J. Dasouki ◽  
Syed O. Ahmed ◽  
Halah AbalKhail ◽  
Samya Hagos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Noonan Syndrome ◽  
Myeloid Leukemia ◽  
Genomic Analysis ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Young Adult Patient ◽  
Acute Myeloid

Acute myeloid leukemia (AML) in the setting of Noonan syndrome (NS) has been reported before without clear guidelines for treatment or prognosis in these subgroups of patients, most likely due to its rarity and incomplete understanding of the pathogenesis of both diseases. In the current era of next-generation sequencing-based genomic analysis, we can better identify patients with NS with more accurate AML-related prognostic markers. Germline mutations in <i>PTPN11</i> are the most common cause of NS. Somatic mutations in <i>NPM1</i> occur frequently in AML. Here, we describe a young adult patient with a novel combined germline <i>PTPN11</i> and somatic <i>NPM1</i>, <i>IDH1</i>,<i></i>and<i> BCL6</i> mutations who presented with fatal AML. In addition, a 50.5-Mb interstitial deletion of 7q21.11-q33 in tumor DNA was detected by chromosomal microarray analysis. While mutations in the transcriptional repressor <i>BCL6</i> are known to contribute to the pathogenesis of diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL), its novel identification in this patient suggests an expanded role in aggressive AML. The identification of key molecular aberrations including the overexpression of SHP2, which drives leukemogenesis and tumorigenesis, has led to the development of novel investigational targeted SHP2 inhibitors.

Genomic structure and nucleotide sequence of AML1-ETO fusion genes in children with acute myeloid leukemia

2004 ◽  
Vol 216 (03) ◽  
Author(s):  
C Gall ◽  
T Langer ◽  
M Metzler ◽  
S Viehmann ◽  
J Harbott ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nucleotide Sequence ◽  
Myeloid Leukemia ◽  
Genomic Structure ◽  
Fusion Genes ◽  
Acute Myeloid

scholarly journals Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation

2021 ◽  
Author(s):  
Aleksandra Wysocka-Słowik ◽  
Lidia Gil ◽  
Zuzanna Ślebioda ◽  
Agnieszka Kręgielczak ◽  
Barbara Dorocka-Bobkowska
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Oral Mucositis ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
World Health ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractThis study was designed to investigate the frequency and severity of oral mucositis in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups based on the conditioning regimen used before transplantation. The intensity of oral inflammatory lesions induced by chemotherapy (oral mucositis) was evaluated according to a 5-point scale recommended by World Health Organization. Oral mucosa was investigated in all patients before the transplantation and during two subsequent stages of the post-transplantation procedure in relation to the conditioning regimen used. Mucositis in the oral cavity was observed in the majority of patients (66%) in the first week after transplantation, whereas the largest percentage of patients suffering oral lesions (74%) occurred in the second week after transplantation. A significantly higher percentage of patients with mucositis was observed in the group which underwent myeloablation therapy (74% of MAC and 50% of RIC patients in the first week; 83% of MAC and 53% of RIC patients in the second examination).The severity of mucositis after transplantation was higher in the MAC patients compared to the RIC patients. The highest mean value of the mucositis index was recorded in the second week in the MAC group (1.59). In AML sufferers receiving allo-HSCT, oral mucositis is a significant complication of the transplantation. This condition is more frequent and more severe in patients after treatment with myeloablation therapy.

scholarly journals Myelodysplastic Syndrome with Excess Blasts and Secondary Acute Myeloid Leukemia: Same Disease with Different Blast Count

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2692-2692
Author(s):  
Xueyan Chen ◽  
Megan Othus ◽  
Brent L Wood ◽  
Roland B. Walter ◽  
Pamela S. Becker ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Mutational Analysis ◽  
World Health ◽  
Secondary Aml ◽  
Data Safety ◽  
Monitoring Committee ◽  
Mutational Hotspots ◽  
Acute Myeloid

Introduction: The World Health Organization (WHO) diagnoses acute myeloid leukemia (AML) if ≥20% myeloid blasts are present in peripheral blood or bone marrow. Consequently a patient with even 19% blasts is often ineligible for an "AML study". A less arbitrary means to define "AML" and myelodysplastic syndromes ("MDS") emphasizes biologic features. Here, focusing on patients with WHO-defined MDS with excess (5-19%) blasts (MDS-EB) or AML with myelodysplasia-related changes (AML-MRC) or therapy-related (t-AML) (WHO defined secondary AML), we compared morphologic blast percentage (MBP) with the frequency of mutations in genes belonging to different functional groups, and with the variant allele frequency (VAF) for individually mutated genes. Methods: 328 adults with WHO-defined AML (de novo and secondary; n=149) or MDS (n=179) and with mutational analysis by next-generation sequencing (NGS) performed at the University of Washington Hematopathology Laboratory between 2015-2017 were included. Of these, 86 had MDS-EB and 49 had secondary AML. Mutational analysis was performed using a customized, amplicon-based assay, TruSeq Custom Amplicon (Illumina, San Diego, CA). Custom oligonucleotide probes targeted specific mutational hotspots in ASXL1, CBL, CEBPA, CSF3R, EZH2, FBXW7, FGFR1, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KMT2A, KRAS, MAP2K1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, RB1, RUNX1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, and ZRSR2. VAF ≥5% was required to identify point mutations. Spearman's correlation coefficient was used to examine the relation between VAF of individually mutated genes and MBP. The Mann Whitney test served to compare the distribution of VAF in AML (≥20% blasts) vs. MDS (<20% blasts), before and after exclusion of subgroups as described below. Fisher's exact test was used to compare incidence of mutations. Results: 96% of cases had ≥one mutation in the 36 genes tested using NGS. Considering all 328 patients, mutations in tumor suppressor and cohesin complex genes were similarly frequent in MDS and AML, whereas spliceosomal genes, in particular SF3B1 and SRSF2, were more frequently mutated in MDS than in AML (46% vs. 26%, p<0.001). Mutations in epigenetic modifiers were more common in AML than MDS (54% vs. 42%, p= 0.035) as were transcription factor mutations (52% vs. 28%, p<0.001). However comparisons limited to MDS-EB vs. AML-MRC/t-AML, indicated the differences observed when comparing all MDS and all AML were less apparent, both statistically and more perhaps importantly with respect to observed frequencies. For example, spliceosomal gene mutations were found in 35% in MDS-EB and 27% in AML-MRC/t-AML (p=0.34) vs. 46% and 26% in all MDS and all AML. NPM1 mutations were detected in only 8% of AML-MRC/t-AML vs. 3% in MDS-EB but 29% for all AML. Results were analogous with FLT3 ITD, FLT3 TKD, and JAK2 mutations. Examining 20 individually mutated genes detected in ≥ 10 patients only with SRSF2 (p=0.04), did distribution of VAF differ statistically according to whether blast percentage was <20% versus ≥20%. Conclusions: The similar prevalence of mutations in different functional categories in MDS-EB and AML-MRC/t-AML suggests these entities are two manifestations of the same disease. We believe it appropriate to combine these WHO entities allowing patients in each to be eligible for both AML and MDS trials. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Walter:Amgen: Consultancy; Boston Biomedical: Consultancy; Agios: Consultancy; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

The Value of CD64 Expression in Distinguishing Acute Myeloid Leukemia With Monocytic Differentiation From Other Subtypes of Acute Myeloid Leukemia: A Flow Cytometric Analysis of 64 Cases

2007 ◽  
Vol 131 (5) ◽  
pp. 748-754
Author(s):  
Cherie H. Dunphy ◽  
Wohzan Tang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Flow Cytometric Analysis ◽  
World Health ◽  
Monocytic Differentiation ◽  
Flow Cytometric Immunophenotyping ◽  
Cd64 Expression ◽  
Flow Cytometric ◽  
Health Organization ◽  
Acute Myeloid

Abstract Context.—Flow cytometric immunophenotyping is a useful ancillary tool in the diagnosis and subclassification of acute myeloid leukemias (AMLs). A recent study concluded that CD64 is sensitive and specific for distinguishing AMLs with a monocytic component (ie, AML M4 and AML M5) from other AML subtypes. However, in that study, the intensity of CD64 was not well defined and the number of non-M4/non-M5 AMLs was small. Objective.—To evaluate the usefulness of CD64 by flow cytometric immunophenotyping in distinguishing AMLs with monocytic differentiation from other AML subtypes. Design.—Sixty-four AMLs subclassified based on the French-American-British and World Health Organization classifications on pretreatment bone marrows were retrieved from our files (7 M0s, 11 M1s, 17 M2s, 7 M3s, 9 M4s, 7 M5s, 4 M6s, and 2 M7s). A standard panel of markers, including CD2, CD3, CD5, CD7, CD10, CD11b, CD13, CD14, CD15, CD19, CD20, CD33, CD34, CD45, CD56, CD64, CD117, and HLA-DR, were analyzed by flow cytometric immunophenotyping in all AMLs (52 bone marrow samples; 12 peripheral blood samples). Results.—CD64 was expressed in AML subtypes M0 to M5 in varying intensities: heterogeneously expressed in 1 of 7 M0s; dimly expressed in 3 of 11 M1s; dimly and moderately expressed in 6 and 2 of 17 M2s, respectively; dimly and moderately expressed in 5 and 1 of 7 M3s, respectively; dimly expressed in 4 of 9 M4s; and heterogeneously, moderately, and strongly expressed in 1, 3, and 3 of 7 M5s, respectively. Conclusions.—Strong CD64 expression distinguishes AML M5; however, heterogeneous, dim, or moderate expression in itself does not distinguish M0 through M4 subtypes from M5 with dim to moderate CD64 expression. However, any CD64 expression associated with strong CD15 expression distinguishes AML M4 or M5, from other AML subtypes.

Acute Leukemia

2016 ◽  
Author(s):  
Richard A. Larson ◽  
Roland B Walter
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Lymphoblastic Leukemia ◽  
World Health ◽  
Acute Leukemias ◽  
Acute Myeloid

The acute leukemias are malignant clonal disorders characterized by aberrant differentiation and proliferation of transformed hematopoietic progenitor cells. These cells accumulate within the bone marrow and lead to suppression of the production of normal blood cells, with resulting symptoms from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration into tissues. They are currently classified by their presumed cell of origin, although the field is moving rapidly to genetic subclassification. This review covers epidemiology; etiology; classification of leukemia by morphology, immunophenotyping, and cytogenetic/molecular abnormalities; cytogenetics of acute leukemia; general principles of therapy; acute myeloid leukemia; acute lymphoblastic leukemia; and future possibilities. The figure shows the incidence of acute leukemias in the United States. Tables list World Health Organization (WHO) classification of acute myeloid leukemia and related neoplasms, expression of cell surface and cytoplasmic markers for the diagnosis of acute myeloid leukemia and mixed-phenotype acute leukemia, WHO classification of acute lymphoblastic leukemia, WHO classification of acute leukemias of ambiguous lineage, WHO classification of myelodysplastic syndromes, European LeukemiaNet cytogenetic and molecular genetic subsets in acute myeloid leukemia with prognostic importance, cytogenetic and molecular subtypes of acute lymphoblastic leukemia, terminology used in leukemia treatment, and treatment outcome for adults with acute leukemia. This review contains 1 highly rendered figure, 9 tables, and 117 references.

Clinico-pathologic characteristics and outcomes of the World Health Organization (WHO) provisional entity de novo acute myeloid leukemia with mutated RUNX1

2020 ◽  
Vol 33 (9) ◽  
pp. 1678-1689
Author(s):  
Andrés E. Quesada ◽  
Guillermo Montalban-Bravo ◽  
Rajyalakshmi Luthra ◽  
Keyur P. Patel ◽  
Koji Sasaki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
World Health Organization ◽  
Myeloid Leukemia ◽  
De Novo ◽  
World Health ◽  
The World ◽  
Health Organization ◽  
Acute Myeloid

The Size of the Dendritic Cell Population At Diagnosis Worsens Prognosis in Acute Myeloid Leukemia – Bigger Is Not Better

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4870-4870
Author(s):  
Marta I Pereira ◽  
Ana I Espadana ◽  
Emília Cortesão ◽  
Gilberto P Marques ◽  
Catarina Geraldes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
World Health ◽  
Biological Behavior ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
De Novo Aml ◽  
Dc Component ◽  
Acute Myeloid

Abstract Abstract 4870 Background: Dendritic cells (DC) are a heterogeneous population of lineage-negative antigen-presenting cells derived from CD34+ hematopoietic progenitors, present in tissue, blood and bone marrow (BM), where plasmacytoid DC (pDC) are a normal finding, representing 0.2 ± 0.1% of cell populations (Matarraz et al, 2010). DC neoplasms include solid tumors (such as DC sarcomas) and an entity classified by the World Health Organization (2008) as an acute myeloid leukemia (AML)-related precursor neoplasm: blastic pDC neoplasm/leukemia, an aggressive disease with poor prognosis, with no clinical trials to orient consensus regarding the most effective treatment; it is usually chemo-resistant, although some cases respond to AML-like regimens and allogeneic hematopoietic stem cell transplant. It is not clear if the presence of an increased DC population in non-DC AML confers pDC neoplasm-like biological characteristics to the former. Aims: This study aims to evaluate whether an increase in the size of DC populations in newly-diagnosed non-DC AML affects the latter's biological behavior, as represented by the overall survival (OS) of patients with the disease. Methods: We reviewed all AML diagnosed in our Hospital between January 1st 2008 and December 31st 2010, identifying 146 patients. We excluded 9 patients who had no flow cytometry immunophenotyping (IP) performed, and 7 whose first IP was performed after treatment was instituted. In that time frame, we also diagnosed 4 pDC neoplasms. Of the 130 patients included, 91 had their presenting IP performed on BM aspirate, while the remaining 39 were phenotyped on blood samples. The size of the DC populations and blastic DC maturation were determined on these samples. Patients were classified into 2 groups according to the size of the DC component; one (the Non-DC Group) had a DC component of up to 0.3% (in practice, the highest value in this group was 0.2%); the other (DC Group) had a percentage over this limit (the lowest value being 1.0%). OS data was determined for both groups; special consideration was given to age strata, separating patients under 65 years of age (Under-65) from those 65 or older (Over-65) and etiology (distinguishing de novo AML from AML secondary to therapy, myelodysplasia or myeloproliferative diseases). The percentage of DC identified by IP did not influence nor alter the type of treatment instituted. Results: We found that the presence of a DC component above the normal BM interval (as determined by Matarraz et al) was associated with a significantly decreased OS, with patients with DC components over 0.3% presenting with a median OS of 2.4 months (mean: 6.4 ± 1.6) and those with a component under 0.3% with a median OS of 8.6 months (mean: 17.0 ± 1.9) (p = 0.033). In our series, patients Over-65 had a median OS of 2.9 months (mean = 6.9 ± 1.0) and those Under-65 a median of 21.3 months (mean = 22.5 ± 2.5), p < 0.001. The differences in OS according to DC component were attenuated in patients Over-65 (median = 1.8 vs. 3.9 months, p = NS), whereas in patients Under-65 the median survival was 2.7 months (mean: 8.7 ± 2.9) for the DC Group and 24.4 months (mean: 24.3 ± 2.7) for the non-DC Group (p = 0.035). The differences in OS were also significant for de novo AML (median = 2.4 vs. 16.0 months, mean = 4.7 ± 1.9 vs. 20.5 ± 2.6, p = 0.017), but not statistically relevant for secondary AML (median = 4.4 vs. 5.5 months, mean = 8.4 vs. 10.8, p = NS). Discussion: In this study, we found that an increase in the size of the DC component as determined by IP at diagnosis on newly-diagnosed AML had a negative impact on prognosis, with a significant decrease in median and mean OS in patients with a percentage of DC over the upper limit of the normal interval. We also determined that the decreased survival was primarily attributed to the better-prognosis groups (patients under 65 and with de novo AML), whereas the effect of the worsened prognosis was attenuated in those patients with a bad prognosis at the outset (patients over 65 and with secondary AML). If data from DC neoplasms could be extrapolated, we could suggest that AML with increased DC components are less chemo-sensitive, which would explain the OS differences found in the Under-65 group, as well as the no-difference found in the Over-65 Group, which is frequently undertreated due to comorbidities. Conclusion: Our study suggests that the size of the DC component at diagnosis as determined by IP is a new prognostic marker predictive of decreased survival. Disclosures: No relevant conflicts of interest to declare.

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