Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Langabeer, Stephen E.; Haslam, Karl; Kelly, Johanna; Quinn, John; Morrell, Ruth; Conneally, Eibhlin

doi:10.1007/s12094-017-1722-2

Cited by 16 publications

(31 citation statements)

References 24 publications

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“…Langabeer et al initially reported next generation sequencing (NGS) results from a modest but informative cohort of four CSF3R T618I‐mutated CNL patients, identifying additional mutations in all subjects as follows: SRSF2 (n = 4/4), SETBP1 (n = 3/4), NRAS (n = 1), and CBL (n = 1) . Zhang et al very recently published pivotal results of comprehensive genomic and transcriptomic profiling of 158 cases of neutrophilic leukemias of ambiguous diagnosis, including 39 patients with CNL (the remainder consisting of aCML, MPN‐unclassified, MDS/MPN, and ambiguous diagnosis) .…”

Section: Molecular Pathogenesissupporting

confidence: 89%

“…Other reports have evaluated clonal evolution in CNL . Langabeer et alʼs NGS study identified clonal evolution in all patients at blast transformation documented by increasing CSF3R T618I allele frequency or gain/loss of mutations . Karyotypic aberrations in the form of acquisition of monosomy 5 and 7 were noted in a case of CNL with blast transformation .…”

Section: Molecular Pathogenesismentioning

confidence: 99%

“…Altogether, this data supports a linear vs branching mutation acquisition pattern in CNL. Other reports have evaluated clonal evolution in CNL . Langabeer et alʼs NGS study identified clonal evolution in all patients at blast transformation documented by increasing CSF3R T618I allele frequency or gain/loss of mutations .…”

Section: Molecular Pathogenesismentioning

confidence: 99%

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Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

2019

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Disease overview: Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL in 2013 anchored a new scientific framework, deepening our understanding of its molecular pathogenesis, providing a diagnostic biomarker, and rationalizing the use of pharmacological targeting. Diagnostic criteria: In 2016, the World Health Organization (WHO) included the presence of activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.Disease updates: Increasingly comprehensive genetic profiling of CNL has disclosed a complex genomic landscape and additional prognostically relevant mutational combinations. Though prognostic determination and therapeutic decision-making remain challenging, emerging data on prognostic markers and the use of newer therapeutic agents, such as JAK inhibitors, are helping to define state-of-the-art management in CNL.

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Section: Molecular Pathogenesissupporting

confidence: 89%

Section: Molecular Pathogenesismentioning

confidence: 99%

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Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

2019

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“…This has changed with the discovery of oncogenic mutations in the colony‐stimulating factor 3 receptor gene ( CSF3R ) in the majority of patients with CNL reported in a landmark study by Maxson et al in 2013 . This observation was subsequently validated in multiple other case series of WHO‐defined CNL . The knowledge of the molecular pathways involved in disease pathogenesis allows for the development of molecularly targeted therapy, the potential of which has since confirmed through in vitro , animal models and anecdotal clinical evidence and leading to the first multicenter clinical trial for CNL which is currently enrolling (http://clinicaltrials.gov‐study ID = 02092324) …”

Section: Disease Overview and Diagnosismentioning

confidence: 78%

“…In that data set of WHO‐defined CNL, the median age at diagnosis was 66 years (range: 15 – 86) and 56% were male . With the discovery of CSFR3 mutations in CNL, comes the opportunity for greater accuracy in true CNL diagnosis: we performed s review of the literature from that point on (2013) and identified a total 57 reported cases of CSF3R ‐mutated CNL, the majority (88%) carrying the CSF3R T618I mutation . The median age (range) was 65 years (10–92) and 70% were male.…”

Section: Epidemiology and Demographicsmentioning

confidence: 99%

Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management

Elliott

Tefferi

2018

American J Hematol

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Disease Overview and Diagnosis: Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of 25 x 10 9 /L of which 80% are neutrophils, with < 10% circulating neutrophil precursors with blasts rarely observed. In addition, there is no dysplasia, nor clinical or molecular criteria for other myeloproliferative neoplasms.Update on Diagnosis: Previously the diagnosis of CNL was often as one of exclusion based on no identifiable cause for physiologic neutrophilia in patients fulfilling the aforementioned criteria. The 2016 WHO classification now recognizes somatic activating mutations of CSF3R (most commonly CSF3RT618I) as diagnostic, allowing for an accurate diagnosis for the majority of suspected cases through molecular testing. These mutations are primary driver mutations, accounting for the characteristic clinical phenotype and potential susceptibility to molecularly targeted therapy.Risk Stratification: Concurrent mutations, common to myeloid neoplasms and their precursor states, most frequently in SETBP1 and ASXL1, are frequent and appear to be of prognostic significance. Although data are evolving on the full genomic profile, the rarity of CNL has delayed complete understanding of its full molecular pathogenesis and individual patient prognosis.

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Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer

Zhang

Yang

et al. 2023

Molecular Oncology

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A good response to neoadjuvant chemotherapy (NACT) is strongly associated with a higher curative resection rate and favorable outcomes for patients with gastric cancer (GC). We examined the utility of serial circulating tumor DNA (ctDNA) testing for monitoring NACT response and prognosis in stage II–III GC. Seventy‐nine patients were enrolled to receive two cycles of NACT following gastrectomy with D2‐lymphadenectomy. Plasma at baseline, post‐NACT, and after surgery, and tissue at pretreatment and surgery were collected. We used a 425‐gene panel to detect genomic alterations (GAs). Results show that the mean cell‐free DNA concentration of patients with clinical stage III was significantly higher than patients with stage II (15.43 ng·mL−1 vs 14.40 ng·mL−1). After receiving NACT and surgery, the overall detection rate of ctDNA gradually reduced (59.5%, 50.8%, and 47.4% for baseline, post‐NACT, and postsurgery). The maximum variant allele frequency (max‐VAF) and the number of GAs decreased from 0.50% to 0.08% and from 2.9 to 1.7 after NACT. For patients with a partial response after NACT, the max‐VAF and the number of GAs declined significantly, but they increased for patients with progressive disease. Patients with detectable ctDNA at baseline, after NACT, or after surgery have a worse overall survival (OS) than patients with undetectable ctDNA. The estimated 3‐year OS was 73% for the post‐NACT ctDNA‐negative patients and 34% for ctDNA‐positive. Patients with perpetual negative ctDNA before and after NACT have the best prognosis. In conclusion, ctDNA was proposed as a potential biomarker to predict prognosis and monitor the NACT response for stage II–III GC patients.

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Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Abstract: The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

Cited by 16 publications

References 24 publications

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

Chronic neutrophilic leukemia: 2018 update on diagnosis, molecular genetics and management

Liquid biopsy: circulating tumor DNA monitors neoadjuvant chemotherapy response and prognosis in stage II/III gastric cancer

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