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University of Navarra. Acute myeloid leukemia AML comprises a biologically and clinically heterogeneous group of aggressive disorders that occur as a consequence of a wide variety of genetic and epigenetic abnormalities in hematopoietic progenitors.

Despite significant advances in the understanding of the biology of AML, most patients will die from relapsed disease. Whole-genome studies have identified novel recurrent gene mutations with prognostic impact in AML; furthermore, it is likely that in the near future genome-wide sequencing will become a routine for newly diagnosed patients with AML. Therefore, future clinical trials should aim to identify genetically defined high-risk patients, and further research is necessary to identify effective agents and develop new individualized therapeutic strategies for the treatment of this deadly disease.

Key words: Acute myeloid leukemia. Genetic marker. Whole-genome sequencing. Palabras clave: Leucemia mieloide aguda. Despite significant advances in the understanding of the biology of AML, overall survival remains poor due chiefly to the high rate of relapse after achieving complete remission, as well as primary failure of induction chemotherapy 1. Since it is predominantly a disease of older people, the therapeutic strategy offered for AML is determined by assessment of the patient's age and general fitness level.

The standard of care for over 3 decades has been the combination of daunorubicin with cytarabine Ara-C. This represents a steady improvement over the past 40 years, although much of this can be attributed to improvements in supportive care, much of which has been learned from the transplantation experience 2.

A major challenge is the treatment of older patients, defined arbitrarily as over 60 years, who represent the majority of patients with this disease. In addition, there are a substantial number of patients who are not considered suitable for intensive chemotherapy, for whom a palliative approach is usually offered 2.

Continuing research into the pathogenesis and heterogeneity of AML has resulted in the development of several potentially useful therapeutic agents. Notably, acute promyelocytic leukemia APL has much better prognosis due to the implementation of sensitive molecular diagnostic tools, and to the introduction of all-trans retinoic acid ATRA in combination with anthracycline into clinical practice.

Other therapies targeting specific molecular defects are being developed, such as small molecule inhibitors of FLT3 kinase in patients harboring the FLT3-ITD mutation, and all-trans retinoic acid in patients with the NPM1 mutation.

However, despite some advances in the treatment of AML, the overall outcome is still dismal for most patients. Cytogenetic and molecular aberrations with prognostic relevance in AML. Several studies over the past decades have identified a large set of chromosome aberrations, mutations and overexpressed genes with prognostic relevance in AML, improving our understanding of AML pathogenesis and risk stratification.

AML patients can be classified into three different prognostic subgroups according to presence or absence of distinct cytogenetic abnormalities. At present, most patients can be categorized into clinicopathological subgroups based on the presence of genetic defects. Our increasing knowledge of AML biology led to the establishment of the World Health Organization classification, which considers morphologic features and recurrent cytogenetic and molecular abnormalities 6.

In addition, an international expert panel from the European LeukemiaNet ELN has also recently proposed new guidelines for the management and stratification of therapies based on the strongest prognostic factors identified to date such as cytogenetic or molecular defects 7.

However, a large number of AML patients lack any of these abnormalities and there remains significant heterogeneity in clinical outcome within currently classified prognostic groups.

These observations suggested that there may be additional biomarkers that can predict outcome in AML. Several of these newly identified genetic abnormalities have prognostic importance in AML.

Moreover, the identification of mutations at diagnosis has served as a tool for minimal residual disease measurement. Interestingly, a recent study has provided a large-scale insight into the genetics of relapsed AML by performing whole-genome sequencing of 8 patients with relapsed AML 8. In all patients there was a founding clone that was not ablated by chemotherapy and was still persistent at relapse; thus, prospective identification of this clone could be of great clinical utility. Molecular markers in normal karyotype acute myeloid leukemia.

Because FLT3 can crosstalk with a network of various signaling pathways, identifying and analyzing the interplay of constitutively active FLT3 with aberrant signaling pathways may lead to the identification of novel therapeutic targets for treatment of AML patients harboring constitutively active FLT3 In the subset of patients with FLT3-ITD-negative intermediate-risk AML, there are 3 distinct risk groups that are based on mutational status and have vastly different outcomes.

These results have important clinical implications, because patients with mutationally defined favorable risk have a better outcome with standard induction and consolidation than even patients with core binding factor-positive AML.

In contrast, patients with mutationally defined adverse-risk AML have an outcome similar to patients with adverse karyotypic risk, and standard therapies are not sufficient to offer curative intent to the majority of these patients 4, Clinical impact of genetic aberrations in acute myeloid leukemia. With the discovery of novel genes associated with AML pathogenesis continuing at a high speed, the challenge is to integrate this knowledge into the current clinical understanding of AML 4.

Nevertheless, in the clinical setting, most AML centers use cytogenetic abnormalities and a relatively small set of gene-based tests to assign risk in AML and to determine post-remission therapy. As Patel and Levine indicate, the relative paucity of clinically used biomarkers is due to several factors.

First, most biomarker studies focus on a specific genetic lesion and its prognostic relevance without considering the complete set of known mutations in parallel to determine which mutations predict outcome independently in AML. Thus, given the increasing number of genetic abnormalities that have been identified in AML patients, it has become important to determine the prognostic relevance of all known recurrent genetic abnormalities in a uniformly treated AML patient cohort 4. Recent advances in the research of AML, especially the identification of novel genetic mutations, have enabled us to stratify this heterogeneous disease entity into distinct subtypes beyond the scopes of cytomorphology and cytogenetics.

Thus, there is a common trend to characterize better AML subtypes as soon as the diagnosis is made. This is exemplified by the subgroup of patients with the monosomal karyotype, who have a dismal outcome with standard treatment, including transplantation However, in the group of intermediate AML the identification of mutations with impact on outcome has clinical and biological importance, and molecular screenings help to refine the treatment strategies.

Therefore, it is important to determine specific mutations or combinations of mutations in this subgroup of patients, although the main goal of future mutational studies should be to inform and improve prognostic algorithms in AML.

Moreover, validation of these findings in other large, homogeneously treated patient cohorts is of utmost clinical importance 4. As discussed above, application of whole-genome sequencing to AML has already yielded important discoveries, including the identification of common gene mutations with prognostic impact in AML. In the near future, it is likely that whole genome sequencing will become a routine part of the diagnostic workup of patients with AML Therefore, future clinical trials should aim to identify genetically defined high-risk patients to offer them novel therapies early in their disease course, in an effort to reduce relapse and increase cure 4.

Finally, although hundreds of different genetic lesions have been described in AML, this disease shares common programs of self-renewal and transformation downstream of leukemia-associated oncogenes These findings argue for the presence of common mechanisms of leukemia cell survival, and suggest that mechanistically common therapeutic approaches to AML are likely to be possible Further research is thus necessary to identify effective agents and develop new individualized therapeutic strategies for the treatment of this deadly disease.

Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. Blood ; Burnett AK. Treatment of acute myeloid leukemia: are we making progress?

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia?

Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med ; The revision of the World Health Organization WHO classification of myeloid neoplasms and acute leukemia: rationale and important changes. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet.

Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature ; The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer ; 3: Drug Resist Updat ; Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.

Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

Estey E. High cytogenetic or molecular genetic risk acute myeloid leukemia. Genomics of AML: clinical applications of next-generation sequencing. Cancer Genome Atlas Research Network. Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias. Cancer Res ; Correspondence: M.

E-mail: modero unav. Servicios Personalizados Revista. Pippa and M. Introduction Acute myeloid leukemia AML comprises a biologically and clinically heterogeneous group of aggressive disorders that occur as a consequence of a wide variety of genetic and epigenetic abnormalities in hematopoietic progenitors. Cytogenetic and molecular aberrations with prognostic relevance in AML Several studies over the past decades have identified a large set of chromosome aberrations, mutations and overexpressed genes with prognostic relevance in AML, improving our understanding of AML pathogenesis and risk stratification.

Clinical impact of genetic aberrations in acute myeloid leukemia With the discovery of novel genes associated with AML pathogenesis continuing at a high speed, the challenge is to integrate this knowledge into the current clinical understanding of AML 4. Conclusions and future perspectives Recent advances in the research of AML, especially the identification of novel genetic mutations, have enabled us to stratify this heterogeneous disease entity into distinct subtypes beyond the scopes of cytomorphology and cytogenetics.

Bibliography 1.

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La leucemia mieloide aguda LMA es poco frecuente en la infancia, pero cuando se presenta suele revestir mayor gravedad que las formas linfoides. Acute myeloblastic leukemia MLA is an uncommon disease in childhood and its prognosis is worse than that of lymphoblastic leukemia. Severe hemorrhage, infections and perfusion disorders secondary to leukostasis are the main complications leading to its high mortality rate. Both patients were admitted to the pediatric intensive care unit with acute respiratory distress syndrome and intra-cranial hemorrhage respectively, secondary to leukostasis. The first patient showed favorable clinical course and underwent bone marrow transplantation four months later; in contrast, the second patient died a few hours after admission. The physiopathology of each case, the therapeutic approach and the use of leukopheresis as a therapeutic alternative in patients with hyperleukocytosis and leukostasis are discussed.

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Estadísticas importantes sobre la leucemia mieloide aguda (AML)

Medwave se preocupa por su privacidad y la seguridad de sus datos personales. En este estudio mostramos la experiencia de nuestro centro universitario en pacientes con leucemia mieloide aguda, no candidatos a tratamiento de alta intensidad, tratados con azacitidina o con tratamiento de soporte. Todos los pacientes o sus acudientes firmaron un documento de consentimiento informado de tratamiento. Tabla 1. Tabla 2. Respuesta al tratamiento con azacitidina. Toxicidad La toxicidad asociada al tratamiento con azacitidina se describe en la Tabla 3.

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University of Navarra. Acute myeloid leukemia AML comprises a biologically and clinically heterogeneous group of aggressive disorders that occur as a consequence of a wide variety of genetic and epigenetic abnormalities in hematopoietic progenitors. Despite significant advances in the understanding of the biology of AML, most patients will die from relapsed disease. Whole-genome studies have identified novel recurrent gene mutations with prognostic impact in AML; furthermore, it is likely that in the near future genome-wide sequencing will become a routine for newly diagnosed patients with AML. Therefore, future clinical trials should aim to identify genetically defined high-risk patients, and further research is necessary to identify effective agents and develop new individualized therapeutic strategies for the treatment of this deadly disease. Key words: Acute myeloid leukemia.

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