Variant allele frequencies do not correlate well with myeloblast counts in a clinically validated gene sequencing panel for routine acute myeloid leukemia workup

Toth, Laura N.; Green, Donald P.; Peterson, Julie; Deharvengt, Sophie J.; Abreu, Francine B. de; Loo, Eric Y.

doi:10.1080/10428194.2019.1587757

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…The absence of correlation between the blast frequency in BM and VAF% for NPM1 contrasts to a study by Toth et al who found a moderate correlation for NPM1, but not for FLT3, KRAS, NRAS and NPM1 analyzed together [42]. Assuming a heterozygous NPM1 mutation, without copy-number aberrations and with presence exclusively in leukemic blasts, VAF% should equal half of the blast count percentages.…”

Section: Discussioncontrasting

confidence: 67%

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Pettersson

Holmgren

Juliusson

et al. 2021

Leukemia & Lymphoma

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AML with mutated NPM1 occurs in all age groups. Yet, the mutational pattern is not extensively studied in the very old, which may hamper appropriate risk assessment. Herein we examined 22 cases of NPM1-mutated de novo AML in patients older than 75, with a median age of 84. All diagnostic samples were sequenced aiming for coverage of the most relevant AML-associated mutations. For comparison with younger patients, we used already published data on several cohorts. A total of 76 mutations including 50 different variants were identified in 16 recurrently mutated AML genes. Compared with younger patients, a significant enrichment of TET2 and SRSF2 was observed, together with a reduced frequency of DNMT3A mutations. Our results indicate that the mutational pattern may be different in the very old as compared to younger patients with NPM1-mutated AML. HIGHLIGHTS The mutational spectrum of NPM1-mutated AML in patients above 75 years displays distinct features. A significant enrichment of TET2 and SRSF2 mutations together with a reduced frequency of DNMT3A mutations was observed in the elderly. NPM1 mutation is a secondary event in the development of AML in the very old.

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Section: Discussioncontrasting

confidence: 67%

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Pettersson

Holmgren

Juliusson

et al. 2021

Leukemia & Lymphoma

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“…Chen et al 35 also reported that the distribution of variant allele frequencies (VAFs) of individually mutated genes did not differ between MDS-EB and AML-MRC/t-AML, despite the difference in blast percentages between these entities. Toth et al 36 reported similar results.…”

Section: Biologic Datamentioning

confidence: 61%

Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal

Estey

Hasserjian

Döhner

2022

Blood

108

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Patients with acute myeloid leukemia (AML) have conventionally received more "intense" therapy than patients with myelodysplastic syndromes (MDS). Although less intense therapies are being used more often in AML, the AML-MDS dichotomy remains, with the presence of ≥ 20% myeloblasts in marrow or peripheral blood generally regarded as defining AML. Consequently, patients with 19% blasts are typically ineligible for AML studies, with patients with 21% blasts ineligible for MDS studies. Here we cite biologic and clinical data to question this practice. Biologically, abnormalities in chromosome 3q26,and mutations in NPM1, and FLT3, regarded as AML-associated, also occur in MDS. The genetic signatures of MDS, particularly cases with 10-19% blasts (MDS-EB2), resemble those of AML following a preceding MDS ("secondary AML"). Mutationally, secondary AML appears at least as similar to MDS-EB2 as to de novo AML. Patients presenting with de novo AML but with secondary-type AML mutations, appear to have the same poor prognoses associated with clinically defined secondary AML. Seattle data indicate that after accounting for European LeukemiaNet (ELN) 2017 risk, age, performance status, clinically secondary AML, and treatment including allogeneic transplant, patients with WHO-defined AML (n=769) have similar rates of OS, EFS and CR/CRi as patients with MDS-EB2 (n=202). We suggest defining patients with 10-30% blasts ("AML/MDS") as eligible for either AML or MDS studies. This would permit empirical testing of the independent effect of blast percentage on outcome, allow patients access to more therapies, and potentially simplify the regulatory approval process.

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“…MDS cases with 10% to 19% blasts are now diagnosed as MDS/AML, as described above, reflecting the diagnostic continuum between AML and MDS and clinical and genetic heterogeneity among individual patients with these lower blast counts. 126,[204][205][206][207] Cases of MDS/AML are subclassified as MDS/AML with mutated TP53, MDS/AML with myelodysplasia-related gene mutations, MDS/AML with myelodysplasia-related cytogenetic abnormalities, or MDS/ AML, NOS.…”

Section: Germline Predispositionmentioning

confidence: 99%

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

Arber

Orazi

Hasserjian

et al. 2022

Blood

1,399

778

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The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CAC) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

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Variant allele frequencies do not correlate well with myeloblast counts in a clinically validated gene sequencing panel for routine acute myeloid leukemia workup

Cited by 5 publications

References 24 publications

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years

Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal

International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data

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