scholarly journals Myelodysplastic Syndrome/Acute Myeloid Leukemia Arising in Idiopathic Erythrocytosis

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Eibhlin Conneally ◽  
Catherine M. Flynn
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
Molecular Abnormalities ◽  
Serum Erythropoietin Level ◽  
Exon 9 ◽  
Next Generation Sequencing Ngs ◽  
Idiopathic Erythrocytosis ◽  
Acute Myeloid

The term “idiopathic erythrocytosis (IE)” is applied to those cases where a causal clinical or pathological event cannot be elucidated and likely reflects a spectrum of underlying medical and molecular abnormalities. The clinical course of a patient with IE is described manifesting as a persistent erythrocytosis with a low serum erythropoietin level, mild eosinophilia, and with evidence of a thrombotic event. The patient subsequently developed a myelodysplasic syndrome (MDS) and acute myeloid leukemia (AML), an event not observed in erythrocytosis patients other than those with polycythemia vera (PV). Application of a next-generation sequencing (NGS) approach targeted for myeloid malignancies confirmed wild-type JAK2 exons 12–15 and identified a common SH2B3 W262R single-nucleotide polymorphism associated with the development of hematological features of myeloproliferative neoplasms (MPNs). Further NGS analysis detected a CBL L380P mutated clone expanding in parallel with the development of MDS and subsequent AML. Despite the absence of JAK2, MPL exon 10, or CALR exon 9 mutations, a similarity with the disease course of PV/MPN was evident. A clonal link between the erythrocytosis and AML could be neither confirmed nor excluded. Future molecular identification of the mechanisms underlying IE is likely to provide a more refined therapeutic approach.

How I treat acute myeloid leukemia

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3147-3156 ◽  
Author(s):  
Jacob M. Rowe ◽  
Martin S. Tallman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Transplantation ◽  
Malignant Cell ◽  
Current Approach ◽  
Molecular Abnormalities ◽  
The Past ◽  
Survival Pathways ◽  
Large Populations ◽  
Acute Myeloid

AbstractMore than one quarter of a million adults throughout the world are diagnosed annually with acute myeloid leukemia (AML). Despite considerable progress during the past 3 decades in the therapy of AML, two-thirds of young adults and 90% of older adults still die of their disease. The reported median age has increased over the past few decades, mostly because of a greater willingness of physicians to diagnose and treat older patients, and now is 72 years. The greatest challenge is in this age group. However, much improvement in therapy is needed for all adults with AML. Recent advances in allogeneic transplantation, a better understanding of prognostic factors, and development of targeted agents have only modestly improved overall outcome when large populations of patients are considered. Although an explosion in knowledge about the molecular pathogenesis of AML has outpaced treatment advances, such insights hold promise for the development of new therapies directed at specific molecular abnormalities that perturb malignant cell survival pathways. The current approach in 2010 to the management of this disease is presented through a discussion of illustrative cases.

scholarly journals MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3183-3189 ◽  
Author(s):  
Ramiro Garzon ◽  
Stefano Volinia ◽  
Chang-Gong Liu ◽  
Cecilia Fernandez-Cymering ◽  
Tiziana Palumbo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mirna Expression ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Independent Set ◽  
Microarray Platform ◽  
Small Subset ◽  
Trisomy 8 ◽  
Molecular Abnormalities ◽  
Acute Myeloid

Abstract MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are negative regulators of gene expression. To determine whether miRNAs are associated with cytogenetic abnormalities and clinical features in acute myeloid leukemia (AML), we evaluated the miRNA expression of CD34+ cells and 122 untreated adult AML cases using a microarray platform. After background subtraction and normalization using a set of housekeeping genes, data were analyzed using Significance Analysis of Microarrays. An independent set of 60 untreated AML patients was used to validate the outcome signatures using real-time polymerase chain reaction. We identified several miRNAs differentially expressed between CD34+ normal cells and the AML samples. miRNA expression was also closely associated with selected cytogenetic and molecular abnormalities, such as t(11q23), isolated trisomy 8, and FLT3-ITD mutations. Furthermore, patients with high expression of miR-191 and miR-199a had significantly worse overall and event-free survival than AML patients with low expression (overall survival: miR-191, P = .03; and miR-199a, P = .001, Cox regression). In conclusion, miRNA expression in AML is closely associated with cytogenetics and FLT3-ITD mutations. A small subset of miRNAs is correlated with survival.

Monocytic Maturation Induced by FLT3 Inhibitor Therapy of Acute Myeloid Leukemia: Morphologic and Immunophenotypic Characteristics

2019 ◽  
Vol 51 (5) ◽  
pp. 478-483
Author(s):  
Cade D Arries ◽  
Sophia L Yohe
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Population ◽  
Myeloid Leukemia ◽  
Inhibitor Therapy ◽  
Molecular Abnormalities ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract Background FMS-like tyrosine kinase-3 (FLT3-ITD) mutations are some of the most common mutations in acute myeloid leukemia (AML), and patient outcomes have improved since the advent of tyrosine kinase inhibitors. First, granulocytic differentiation was described in FLT3-positive AML treated with FLT3 inhibitors, and more recently, monocytic differentiation was reported. Methods Two patients with myelomonocytic cells in their bone marrow were identified during routine follow-up after AML treatment that included FLT3 inhibitors. The bone marrow study was done as standard of care. Results Both patients had FLT3-ITD+ AML and showed an atypical maturing monocytic cell population and a decrease in the leukemic blast cell population after FLT3 inhibitor therapy. Concurrent genetic testing revealed persistent genetic abnormalities. Conclusions These cases illustrate monocytic maturation in FLT3+ AML after FLT3 inhibitor treatment. It is critical for pathologists and clinicians to be aware of the differentiation phenomenon, as these patients have persistent molecular abnormalities despite response to treatment and normalization of blast counts.

GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High-Resolution Molecular Cytogenetic Studies

2017 ◽  
Vol 152 (1) ◽  
pp. 33-37
Author(s):  
Roberto R. Capela de Matos ◽  
Daniela R. Ney Garcia ◽  
Elaine Cifoni ◽  
Moneeb A.K. Othman ◽  
Mariana Tavares de Souza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Resolution ◽  
Myeloid Leukemia ◽  
Molecular Cytogenetic ◽  
Severe Diarrhea ◽  
Molecular Abnormalities ◽  
Cytogenetic Studies ◽  
Novel Complex ◽  
Ploidy Changes ◽  
Acute Myeloid

Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases. Here, we describe a 7- month-old girl with a history of fever and severe diarrhea, and a physical examination remarkable for pallor and hepatosplenomegaly. A novel complex hyperdiploid karyotype 53,XX,+X,+6,t(9;11)(p21.3;q23.3),+der(9)t(9;11)(p21.3;q23.3),dup(13)(q31q34),+14,+19,+21,+22 was characterized by high-resolution molecular cytogenetic approaches. Fluorescence in situ hybridization, multiplex-FISH, and multicolor chromosome banding were applied, revealing 2 reverse MLLT3-KMT2A fusions and a duplication of the GAS6 oncogene. Our work suggests that molecular cytogenetic studies are crucial for the planning of a proper strategy for risk therapy in AML infants with hyperdiploid karyotypes.

Treatment for Primary Acute Myeloid Leukemia: Results of Two Consecutive Trials From the Spanish CETLAM Group Showing Improvement with the Use of G-CSF Priming and Precise Risk-Adapted Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1066-1066
Author(s):  
Jorge Sierra ◽  
Montserrat Hoyos ◽  
Josep F. Nomdedeu ◽  
Jordi Esteve ◽  
Rafael F. Duarte ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
High Dose ◽  
Phase Ii Trials ◽  
Molecular Abnormalities ◽  
Factors Influencing ◽  
Leukocyte Counts ◽  
Postremission Therapy ◽  
Acute Myeloid

Abstract Abstract 1066 Different approaches have been investigated to improve the prognosis of adult patients with primary acute myeloid leukemia. In two consecutive phase II trials our group has explored the use of intermediate-dose cytarabine in induction associated with idarubicin and etoposide, the addition of G-CSF priming to the previous combination, and risk-adapted postremission therapy. Objective: To compare the results of two consecutive trials for primary AML and to analyze the factors influencing the outcome. Patients and methods: Adult patients between 17 and 60 years of age with de novo AML, diagnosed between 1999 and 2009, were included in the CETLAM AML-99 and AML-03 trials. Induction chemotherapy (CT) included one or two courses of idarubicin 12 mg/m2 IV days 1,3,5, cytarabine 500 mg/m2/12h over 2h IV days 1,3,5,7 and etoposide 100 mg/m2 IV days 1,2,3. This was followed by one consolidation with mitoxantrone 12 mg/m2 IV from day 4 to 6, and cytarabine 500 mg/m2/12h IV from day 1–6. In the AML 03 trial, patients also received G-CSF priming, 150 mg/m2 subcutaneously (SC) from day 0 to the last day of induction and consolidation CT. Postremission therapy consisted of high-dose cytarabine (CBF AML), autologous or allogeneic hematopoietic transplantation depending on cytogenetics, courses to complete remission (CR), and in the AML-03 protocol also based on molecular abnormalities involving FLT3 or MLL genes and/or the persistence of minimal residual disease after consolidation. Results: Overall, 788 patients were included, 353 in the AML-99 trial and 435 in the AML-03. Median age of the patients was 46 years (range 17–60). There were no differences between patients included in the two protocols regarding age, gender, leukocyte counts, cytogenetics and proportion of favourable and unfavourable molecular cases in the group with intermediate-risk karyotype. The main results achieved appear in the table. Multivariate analysis confirmed the favourable impact of AML-03 protocol on outcome. Other significant factors influencing survival were age, leukocyte counts and cytogenetics. Conclusion: G-CSF priming improved the CR rate of adult patients with primary AML and favourable or unfavourable cytogenetics. This fact and a more precise risk-adapted therapy taking into account genetic data and MRD studies translated into improved overall survival. Disclosures: No relevant conflicts of interest to declare.

Most Risk-Stratification Molecular Markers in Acute Myeloid Leukemia (AML) Are Rarely Found in Early Childhood AML in the Middle Eastern Population

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5239-5239
Author(s):  
Hala Abalkhail ◽  
Hassan El-Solh ◽  
Amal Alseraihy ◽  
Asim F Belgaumi ◽  
Abdullah Al-Jefri ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Early Childhood ◽  
Myeloid Leukemia ◽  
Pediatric Patients ◽  
Adult Patients ◽  
Intensive Chemotherapy ◽  
Adult Group ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Abstract 5239 Background: Acute myeloid leukemia (AML) is biologically heterogeneous with significant molecular and clinical variation. Most of the recent studies suggest that AML in pediatric population differs significantly clinically and biologically from adult AML. Numerous newly described molecular abnormalities in AML have been described in adult patients, but except for rare publications, a little is known about the molecular abnormalities and their clinical relevance in pediatric AML, especially in early childhood and when the patients are treated with intensive chemotherapy followed by hematopoietic stem cell transplant (HSCT). The Saudi Arabian population is known to be genetically homogenous due to high consanguinity. Higher incidence of inherited diseases including certain types of cancer has been reported in Saudi Arabia. We attempted to compare the molecular abnormalities and their clinical relevance in pediatric AML patients from Saudi Arabia with adult AML from the same population. Methods: Samples from 87 adult patients with AML and samples from 40 pediatric AML patients were analyzed for FLT3-ITD and FLT3-D835, IDH1, IDH2, NPM1, and DNMT3A mutations by direct sequencing and by fragment length analysis (FLT3 and NPM1). The prevalence of mutations was compared between the adult and pediatric groups. They included patients with intermediate-risk cytogenetics (N=66 adults, N=26 pediatrics) and adverse cytogenetics (N=21 adults, N=14 pediatrics). The median age of the pediatric patients is 7 years, with a range from less than one year to 14 years. All patients were treated with intensive chemotherapy, followed by HSCT in first remission. Results: FLT3-ITD mutation was detected in 18 patients (21%) of the adult group, but detected only in 3 patients of the pediatric group (7.5%). Two of the 3 patients in the pediatric group carrying the FLT3 mutation died within the first year after the transplant. The FLT3-D835 mutation was detected in 6 patients (7%) of the adult group, while none of the pediatric patients showed this mutation. In addition, the pediatric patients showed no mutations in IDH1 or IDH2, while the adult patients showed IDH1 and IDH2 mutations in 6 (7%) and 7 (8%), respectively. Mutations in the DNMT3A gene were detected in three patients (3%) in the adult group, but were not detected in any of the pediatric AML. NPM1 mutations were detected in 9 (10%) of the adult AML patients, but none of the pediatric patients showed NPM1 mutation. Conclusion: This data suggests that the biology of AML in pediatric patients is significantly different from that in the adult patients. Mutations in FLT3, IDH1, IDH2, NPM1, and DNMT3A genes are very rare in pediatric patients. However, our data involves early childhood (90% younger than 13 years of age) and there is a possibility that older children may have higher incidence of mutations. Most of the currently used molecular markers in risk-stratifying adult AML patients are difficult to use in stratifying pediatric AML patients. Disclosures: No relevant conflicts of interest to declare.

Low MDR1 and BAALC expression Identifies a New Subgroup of Adult Cytogenetically Normal Acute Myeloid Leukemia with a Favorable Outcome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4312-4312
Author(s):  
Xutao Guo ◽  
Feili Chen ◽  
Pengcheng Shi ◽  
Jie Zha ◽  
Bingshan Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Long Term Outcome ◽  
Molecular Abnormalities ◽  
Mdr1 Expression ◽  
Cytogenetically Normal Aml ◽  
Low Expression ◽  
Acute Myeloid

Abstract Abstract 4312 OBJECTIVE: Cytogenetically normal acute myeloid leukemia (AML) is a heterogeneous disease, in terms of genetic/molecular abnormalities resulting into marked differences in outcome. We demonstrated that MDR1, BAALC expression was of prognostic significance and high MDR1 expression correlated with a high BAALC expression (r=0.487, P<0.001) in cytogenetically normal AML in the prophase study then we hypothesized that MDR1 and BAALC expression together would better identify the patient's risk profile. METHODS: Pretreatment bone marrow samples from 92 cytogenetically normal AML patients were analyzed for MDR1 and BAALC mRNA expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into low MDR1 and BAALC expression group and combined group (high MDR1 and/or high BAALC expression) according to MDR1 and BAALC levels and were compared for clinical outcome. RESULTS: 73 cases of 92 cytogenetically normal AML patients got CR after the first block with a CR rate being 79.3%. However, 29 cases of the CR patients relapsed with the relapsed rate being 39.7%. In contrast, Patients with low expression of both MDR1 and BAALC had a higher CR rate (93.3%vs72.6%, P=0.021), lower relapse rate (7.1% vs. 42.5%, P=0.000), longer OS (50.3% vs 17.8%,P=0.001) than high MDR1 and/or high BAALC expression (combined group) in cytogenecally normal AML. Results showed no statistical difference in CR rate (93.3%vs85.7%, P=0.341),relapse rate (7.1% vs. 8.8%, P=0.000) and OS (50.3% vs 63.1%,P=0.431) for cytogenetically normal patients with both MDR1 and BAALC low expression comparing to those with low-risk cytogenetically abnormal. CONCLUSION: The combined assessment of BAALC and MDR1 expression can improve treatment stratification in adult cytogenetically normal AML. Low expression of both MDR1 and BAALC identifies cytogenetically normal AML patients with a favorable long-term outcome. Disclosures: No relevant conflicts of interest to declare.

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