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

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.

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

2021 ◽  
pp. 191-203
Author(s):  
Erica K. Barnell ◽  
Kenneth F. Newcomer ◽  
Zachary L. Skidmore ◽  
Kilannin Krysiak ◽  
Sydney R. Anderson ◽  
...  
Keyword(s):  
Decision Making ◽  
Acute Myeloid Leukemia ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Clinical Decision Making ◽  
Clinical Care ◽  
Clinical Decision ◽  
Hematologic Malignancies ◽  
Response To Therapy ◽  
Acute Myeloid

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.

scholarly journals NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021

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.

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

2020 ◽  
Vol 40 (6) ◽  
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.

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

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

<p>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.</p><p><strong>Conclusion. </strong>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.</p>

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

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 324-330 ◽  
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.

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

2018 ◽  
Vol 64 ◽  
pp. 34-41 ◽  
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

Detection of the JAK2V617F Mutation in Myeloproliferative Disorders by Melting Curve Analysis Using the LightCycler System

2006 ◽  
Vol 130 (7) ◽  
pp. 997-1003
Author(s):  
Randall J. Olsen ◽  
Zhouwen Tang ◽  
Daniel H. Farkas ◽  
David W. Bernard ◽  
Youli Zu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Clinical Laboratory ◽  
Melting Curve ◽  
Myeloproliferative Disorder ◽  
Curve Analysis ◽  
Melting Curve Analysis ◽  
Wild Type ◽  
Acute Myeloid

Abstract Context.—A specific mutation, JAK2V617F, was recently recognized as having diagnostic value for myeloproliferative disorders. No practical assay is currently available for routine use in a clinical laboratory. Objective.—We report the development of a real-time polymerase chain reaction melting curve analysis assay that is appropriate for molecular diagnostics testing. Design.—Specific primers and fluorescence resonance energy transfer probes were designed, and patients with a previously diagnosed myeloproliferative disorder, de novo acute myeloid leukemia, or reactive condition were selected. The DNA was extracted from fresh and archived peripheral blood and bone marrow specimens, and real-time polymerase chain reaction melting curve analysis was performed on the LightCycler platform (Roche Applied Science, Indianapolis, Ind). Results.—The JAK2 region was successfully amplified, and wild-type amplicons were reproducibly discriminated from JAK2V617F amplicons. Titration studies using homozygous wild-type and mutant cell lines showed the relative areas under a melting curve were proportional to allele proportion, and the assay reliably detected one mutant in 20 total cells. JAK2V617F was identified in patients previously diagnosed with a myeloproliferative disorder or acute myeloid leukemia transformed from myeloproliferative disorder, whereas a wild-type genotype was identified in patients with reactive conditions or de novo acute myeloid leukemia. Conclusions.—These findings demonstrate the suitability of this assay for identifying JAK2V617F in a clinical laboratory setting. Furthermore, the semiquantitative detection of JAK2V617F in archived specimens provides a new tool for studying the prognostic significance of this mutation.

scholarly journals Highly Sensitive Detection of IDH2 Mutations in Acute Myeloid Leukemia

2020 ◽  
Vol 9 (1) ◽  
pp. 271 ◽  
Author(s):  
Jessica Petiti ◽  
Valentina Rosso ◽  
Eleonora Croce ◽  
Vanessa Franceschi ◽  
Giacomo Andreani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Limit Of Detection ◽  
Digital Pcr ◽  
Allelic Frequency ◽  
Response To Therapy ◽  
Molecular Alterations ◽  
Disease Marker ◽  
Acute Myeloid

Background: Acute myeloid leukemia is a heterogeneous hematological disease, characterized by karyotypic and molecular alterations. Mutations in IDH2 have a role in diagnosis and as a minimal residue disease marker. Often the variant allele frequency during follow up is less than 20%, which represents the limit of detection of Sanger sequencing. Therefore, the development of sensitive methodologies to identify IDH2 mutations might help to monitor patients’ response to therapy. We compared three different methods to identify and monitor IDH2 mutations in patients’ specimens. Methods: Performances of PNA-PCR clamping, droplet digital PCR and Sanger for IDH2 status identification were evaluated and compared in 96 DNA patients’ specimens. Results: In contrast with Sanger sequencing, our results highlighted the concordance between PNA clamping and digital PCR. Furthermore, PNA-PCR clamping was able to detect more mutated DNA with respect to Sanger sequencing that showed several false negatives independently from the allelic frequency. Conclusions: We found that PNA-PCR clamping and digital PCR identified IDH2 mutations in DNA samples with comparable results in a percentage significantly higher compared to Sanger sequencing. PNA-PCR clamping can be used even in laboratories not equipped for sophisticated analyses, decreasing cost and time for IDH2 characterization.

scholarly journals Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4532-4538 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Kristiina Heinonen ◽  
David Lawrence ◽  
Andrew J. Carroll ◽  
Prasad R.K. Koduru ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Response To Therapy ◽  
High Dose ◽  
Postremission Therapy ◽  
De Novo Aml ◽  
Group B ◽  
Acute Myeloid

Abstract Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

scholarly journals From Bench to Bedside and Beyond: Therapeutic Scenario in Acute Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 357 ◽  
Author(s):  
Carmelo Gurnari ◽  
Maria Teresa Voso ◽  
Jaroslaw P. Maciejewski ◽  
Valeria Visconte
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response To Therapy ◽  
New Drugs ◽  
Survival Outcomes ◽  
Variable Response ◽  
Therapeutic Approaches ◽  
Long Term Survivors ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatment. A specific focus will be given to molecularly targeted therapies for AML as a representation of possible agents for precision medicine. We will discuss experimental and preclinical data for FLT3, IDH1, BCL-2, Hedgehog pathway inhibitors, and epitherapy.

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