Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia

PURPOSE Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood. METHODS Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50). RESULTS In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration–approved drugs. CONCLUSION This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions.

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Ex-vivo sensitivity profiling to guide clinical decision making in acute myeloid leukemia: A pilot study

Leukemia Research ◽

10.1016/j.leukres.2017.11.008 ◽

2018 ◽

Vol 64 ◽

pp. 34-41 ◽

Cited By ~ 21

Author(s):

Ronan T. Swords ◽

Diana Azzam ◽

Hassan Al-Ali ◽

Ines Lohse ◽

Claude-Henry Volmar ◽

...

Keyword(s):

Decision Making ◽

Acute Myeloid Leukemia ◽

Pilot Study ◽

Myeloid Leukemia ◽

Clinical Decision Making ◽

Ex Vivo ◽

Clinical Decision ◽

Acute Myeloid

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A Clinical Laboratory-Developed LSC17 Stemness Score Assay for Rapid Risk Assessment of Acute Myeloid Leukemia Patients

Blood Advances ◽

10.1182/bloodadvances.2021005741 ◽

2021 ◽

Author(s):

Stanley WK Ng ◽

Tracy Murphy ◽

Ian King ◽

Tong Zhang ◽

Michelle Mah ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Clinical Decision Making ◽

Clinical Laboratory ◽

Clinical Decision ◽

Response To Therapy ◽

Molecular Diagnostic ◽

Synthetic Control ◽

Technical Performance ◽

Acute Myeloid

Leukemia stem cells (LSC) are linked to relapse in acute myeloid leukemia (AML). The LSC17 gene expression score robustly captures LSC stemness properties in AML and can be used to predict survival outcomes and response to therapy, enabling risk-adapted upfront treatment approaches. The LSC17 score was developed and validated in a research setting. To enable wide use of the LSC17 score in clinical decision-making, we established a Laboratory Developed Test (LDT) for the LSC17 score that can be deployed broadly in clinical molecular diagnostic laboratories. We extensively validated the LSC17 LDT in a College of American Pathologists/Clinical Laboratory Improvements Act (CAP/CLIA)-certified laboratory, determining specimen requirements, a synthetic control, and performance parameters for the assay. Importantly, we correlated values from the LSC17 LDT to clinical outcome for a reference cohort of AML patients, establishing a median assay value that can be used for clinical risk stratification of individual patients with newly-diagnosed AML. The assay was established in a second independent CAP/CLIA-certified laboratory and its technical performance validated using an independent cohort of AML patient samples, demonstrating that the LSC17 LDT can be readily implemented in other settings. This study enables the clinical use of the LSC17 score for upfront risk-adapted management of AML patients.

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Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia

Personalized Medicine ◽

10.2217/pme-2018-0077 ◽

2019 ◽

Vol 16 (6) ◽

pp. 479-490

Author(s):

Zohreh Sharifi ◽

Mohammad Faranoush ◽

Alireza Mohseni ◽

Shahrbano Rostami ◽

Mani Ramzi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Nucleotide Excision Repair ◽

Induction Therapy ◽

Genetic Variants ◽

Myeloid Leukemia ◽

Excision Repair ◽

Response To Therapy ◽

Response To Chemotherapy ◽

Nucleotide Excision ◽

Acute Myeloid

Aim: Acute myeloid leukemia (AML) is a heterogeneous disease in pathogenesis and response to therapy. Nucleotide excision repair (NER) pathway has a major role in the elimination of genotoxic effects of chemotherapeutic agents. We aimed to clarify the effects of selected variants of XPD, XPC, ERCC5 and ERCC1 genes on the outcomes of induction therapy. Materials & methods: The prevalence of NER genetic variants was evaluated in 67 subjects with AML and their effects on clinical outcomes were analyzed by χ2 test. Results: The XPD 751 Lys variant was associated with improved response to chemotherapy compared with XPD 751 Gln and Lys/Gln variants (p = 0.023; odds ratio: 4.5; 95% CI: 1.14–17.73). There were no associations between other genotypes and any outcomes. Conclusion: Current findings suggest that XPD Lys751Gln variant could be considered as a prognostic factor in AML.

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NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2021.0002 ◽

2021 ◽

Vol 19 (1) ◽

pp. 16-27

Author(s):

Daniel A. Pollyea ◽

Dale Bixby ◽

Alexander Perl ◽

Vijaya Raj Bhatt ◽

Jessica K. Altman ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Clinical Decision Making ◽

Treatment Strategies ◽

Clinical Decision ◽

Genetic Alterations ◽

Nccn Guidelines ◽

New Information ◽

Prognostic Importance ◽

Acute Myeloid

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

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High expression of AK1 predicts inferior prognosis in acute myeloid leukemia patients undergoing chemotherapy

Bioscience Reports ◽

10.1042/bsr20200097 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 1

Author(s):

Tong Qin ◽

Hongmian Zhao ◽

Yunli Shao ◽

Ning Hu ◽

Jinlong Shi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Clinical Decision Making ◽

Clinical Decision ◽

The Cancer Genome Atlas ◽

Hematopoietic Stem ◽

Expression Levels ◽

Cancer Genome Atlas ◽

Adenylate Kinase 1 ◽

Acute Myeloid

Abstract The purpose of the present study was to investigate whether expression levels of adenylate kinase 1 (AK1) were associated with prognosis of acute myeloid leukemia (AML) in patients treated with chemotherapy or allogeneic hematopoietic stem cell transplantation (allo-HSCT). 85 AML patients with AK1 expression report who received chemotherapy-alone and 71 who underwent allo-HSCT from The Cancer Genome Atlas database were identified and grouped into either AK1high or AK1low based on their AK1 expression level relative to the median. Then, overall survival (OS) and event-free survival (EFS) were compared between patients with high vs. low AK1 expression. In the chemotherapy group, high AK1 expression was favorable for both EFS (P=0.016) and OS (P=0.014). In the allo-HSCT group, there was no association for AK1 expression levels and clinical outcomes. Further analyses suggested that in the high AK1 expression group, EFS and OS were longer in patients treated with allo-HSCT compared with those treated with chemotherapy (P=0.0011; P<0.0001, respectively), whereas no significant differences were observed in the low AK1 expression group. In summary, we reported AK1 as an independent unfavorable prognostic factor of AML patients undergoing chemotherapy, and its use could also facilitate clinical decision-making in selecting treatment for AML patients. Patients with high AK1 expression may be recommended for early allo-HSCT.

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Advances in Acute Myeloid Leukemia Genomics, where do we stand in 2018?

Acta Medica Academica ◽

10.5644/ama2006-124.240 ◽

2019 ◽

Vol 48 (1) ◽

pp. 35

Author(s):

Yazan F. Madanat ◽

Matt E. Kalaycio ◽

Aziz Nazha

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Complex Disease ◽

Clinical Decision Making ◽

Standard Of Care ◽

Clinical Decision ◽

World Health ◽

Disease Evolution ◽

Disease Biology ◽

Acute Myeloid

The aim of this review is to summarize the data on commonly mutated genes and genomic pathways in acute myeloid leukemia (AML) with a focus on recently approved targeted therapies. AML is a heterogeneous disease with recurrent cytogenetic and genomic abnormalities that define the disease biology and pathogenesis. Classification of the disease categories and their prognostication was updated in the past 2 years to reflect the most recent advances in understanding the complex disease biology of AML. This review highlights major updates in the World Health Organization classification, including cytogenetic re-classifications, provisional entities, and updates to the European Leukemia Net (ELN) AML risk group stratification. An overview of pivotal studies that used novel sequencing techniques to define the mutational landscape of AML is also provided. In these studies, mutations are classified into subgroups based on functional pathways and are used to understand various interactions and mutual exclusivity of some mutations, suggesting important roles in disease evolution and AML pathogenesis. The complex interactions between mutations can dictate outcomes as well as possibly predict disease phenotypes after correcting for clinical variables.Conclusion. Genomic testing in AML using next generation sequencing has become widely available and a new standard of care for all patients. Therefore, it is vital to use novel methods to incorporate these data in clinical decision making.

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Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia

Hematology ◽

10.1182/asheducation-2013.1.324 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 324-330 ◽

Cited By ~ 27

Author(s):

Richard F. Schlenk ◽

Hartmut Döhner

Keyword(s):

Acute Myeloid Leukemia ◽

Treatment Strategy ◽

Myeloid Leukemia ◽

Prognostic Value ◽

Clinical Decision Making ◽

Experimental Treatment ◽

Clinical Decision ◽

Genetic Profile ◽

Patient Counseling ◽

Acute Myeloid

Abstract In recent years, research in genomics has resulted in the rapid uncovering of the molecular pathogenesis of acute myeloid leukemia (AML). The identification of the genetic determinants of response to standard—but also to experimental—treatment is increasingly used for patient counseling, to guide clinical decision making, and for resource-efficient care provision at diagnosis, during consolidation treatment and follow-up, and after relapse. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges in evaluating the prognostic value of a specific mutation in the concert of the various concurrent mutations and determining the relative prognostic value of the genetic profile during the disease course. In particular, changes in the genetic profile in relapse compared with that at diagnosis will increasingly affect the treatment strategy at relapse, but also will give us the possibility of learning which treatment strategy during frontline therapy is best to prevent them.

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Genomics of Acute Myeloid Leukemia Diagnosis and Pathways

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.2208 ◽

2017 ◽

Vol 35 (9) ◽

pp. 934-946 ◽

Cited By ~ 160

Author(s):

Lars Bullinger ◽

Konstanze Döhner ◽

Hartmut Döhner

Keyword(s):

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Myeloid Leukemia ◽

Clinical Care ◽

Clonal Expansion ◽

Disease Classification ◽

Disease Evolution ◽

Myeloid Neoplasms ◽

Increased Risk ◽

Acute Myeloid

In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. The same genes are frequently found to be mutated in elderly individuals along with clonal expansion of hematopoiesis that confers an increased risk for the development of hematologic cancers. Furthermore, such mutations may persist after therapy, lead to clonal expansion during hematologic remission, and eventually lead to relapsed disease. In contrast, mutations involving NPM1 or signaling molecules (eg, FLT3, RAS) typically are secondary events that occur later during leukemogenesis. Genetic data are now being used to inform disease classification, risk stratification, and clinical care of patients. Two new provisional entities, AML with mutated RUNX1 and AML with BCR- ABL1, have been included in the current update of the WHO classification of myeloid neoplasms and AML, and mutations in three genes— RUNX1, ASXL1, and TP53—have been added in the risk stratification of the 2017 European LeukemiaNet recommendations for AML. Integrated evaluation of baseline genetics and assessment of minimal residual disease are expected to further improve risk stratification and selection of postremission therapy. Finally, the identification of disease alleles will guide the development and use of novel molecularly targeted therapies.

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