scholarly journals Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Blood ◽  
2016 ◽  
Vol 127 (1) ◽  
pp. 29-41 ◽  
Author(s):  
David Grimwade ◽  
Adam Ivey ◽  
Brian J. P. Huntly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Molecular Abnormalities ◽  
Disease Entities ◽  
Molecular Landscape ◽  
Individualization Of Therapy ◽  
Acute Myeloid

Abstract Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.

scholarly journals Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

2020 ◽  
Vol 22 (6) ◽  
Author(s):  
Ludovica Marando ◽  
Brian J. P. Huntly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Influence Strategies ◽  
Prognostic Information ◽  
Therapeutic Implications ◽  
Genomic Landscape ◽  
Genetic Landscape ◽  
Molecular Landscape ◽  
Acute Myeloid

Abstract Purpose of Review The field of acute myeloid leukemia (AML) has been revolutionized in recent years by the advent of high-throughput techniques, such as next-generation sequencing. In this review, we will discuss some of the recently identified mutations that have defined a new molecular landscape in this disease, as well as their prognostic, predictive, and therapeutic implications. Recent Findings Recent studies have shown how many cases of AML evolve from a premalignant period of latency characterized by the accumulation of several mutations and the emergence of one or multiple dominant clones. The pattern of co-occurring mutations and cytogenetic abnormalities at diagnosis defines risk and can determine therapeutic approaches to induce remission. Besides the genetic landscape at diagnosis, the continued presence of particular gene mutations during or after treatment carries prognostic information that should further influence strategies to maintain remission in the long term. Summary The recent progress made in AML research is a seminal example of how basic science can translate into improving clinical practice. Our ability to characterize the genomic landscape of individual patients has not only improved our ability to diagnose and prognosticate but is also bringing the promise of precision medicine to fruition in the field.

Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”?

Blood ◽  
2014 ◽  
Vol 124 (23) ◽  
pp. 3345-3355 ◽  
Author(s):  
David Grimwade ◽  
Sylvie D. Freeman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Reliable Determination ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.

scholarly journals Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”?

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 222-233 ◽  
Author(s):  
David Grimwade ◽  
Sylvie D. Freeman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Reliable Determination ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.

Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”?

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 222-233 ◽  
Author(s):  
David Grimwade ◽  
Sylvie D. Freeman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Reliable Determination ◽  
Minimal Residual ◽  
Acute Myeloid

The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.

scholarly journals Comprehensive molecular landscape in patients older than 80 years old diagnosed with acute myeloid leukemia: A study of the French Hauts-de-France AML observatory

2018 ◽  
Vol 94 (1) ◽  
pp. E24-E27 ◽  
Author(s):  
Loïc Renaud ◽  
Olivier Nibourel ◽  
Alice Marceau-Renaut ◽  
Bérengère Gruson ◽  
Nathalie Cambier ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Landscape ◽  
Acute Myeloid

scholarly journals Acute Myeloid Leukemia: Advanced Practice Management From Presentation to Cure

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Meredith Beaton, RN, MSN, AG-ACNP ◽  
Glen J. Peterson, RN, DNP, ACNP ◽  
Kelly O'Brien, RN, MSN, ANP-C, ACNP-BC
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Treatment Options ◽  
Signs And Symptoms ◽  
The Elderly ◽  
Poor Performance Status ◽  
Curative Therapy ◽  
Initial Symptoms ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, diagnosed in approximately 21,450 individuals annually in the US with nearly 11,000 deaths attributable to this disease (National Cancer Institute, 2020). Acute myeloid leukemia is a disease of the elderly, with the average age of diagnosis being 68 years old (Kouchkovsky & Abdul-Hay, 2016). It is a heterogeneous disease with widely varying presentations but universally carries a poor prognosis in the majority of those affected. Unfortunately, the 5-year overall survival rate remains poor, at less than 5% in patients over 65 years of age (Thein, Ershler, Jemal, Yates, & Baer, 2013). The landscape of AML is beginning to change, however, as new and improved treatments are emerging. Advanced practitioners (APs) are often involved in the care of these complex patients from the time of initial symptoms through diagnosis, treatment, and potentially curative therapy. It is vitally important for APs to understand and be aware of the various presentations, initial management strategies, diagnostic workup, and treatment options for patients with AML, especially in the elderly population, which until recently had few treatment options. This Grand Rounds article highlights the common presenting signs and symptoms of patients with AML in the hospital, including a discussion of the upfront clinical stability issues, oncologic emergencies, diagnostic evaluation, and current treatment options for elderly patients and those with poor performance status.

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 Blood counts at time of complete remission provide additional independent prognostic information in acute myeloid leukemia

2008 ◽  
Vol 32 (10) ◽  
pp. 1505-1509 ◽  
Author(s):  
Masamitsu Yanada ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Prognostic Information ◽  
Acute Myeloid

scholarly journals Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

2019 ◽  
Vol 3 (3) ◽  
pp. 242-255 ◽  
Author(s):  
Shaneice R. Mitchell ◽  
Karilyn Larkin ◽  
Nicole R. Grieselhuber ◽  
Tzung-Huei Lai ◽  
Matthew Cannon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Tumor Development ◽  
Xenograft Model ◽  
Nicotinamide Phosphoribosyltransferase ◽  
P21 Activated Kinase ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

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