Impact of <scp>SNP</scp> array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases

Palomo, Laura; Xicoy, Blanca; García, Olga; Mallo, Mar; Ademà, Vera; Cabezón, Marta; Arnan, Montse; Pomares, Helena; Larráyoz, María José; Calasanz, Marı́a José; Maciejewski, Jaroslaw P.; Huang, Dayong; Shih, Lee Yung; Ogawa, Seishi; Cervera, José; Such, Esperanza; Coll, Rosa; Grau, Javier; Solé, Françesc; Zamora, Lurdes

doi:10.1002/ajh.24227

Cited by 18 publications

(19 citation statements)

References 31 publications

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“…Across the entire cohort, 14/48 (29.2%) patients presented with interstitial CNN-LOH, as previously reported by our group [ 18 ]. All patients with CNN-LOH in 4q24 harbored a TET2 mutation and all cases with CNN-LOH in 11q23.3 presented with a CBL mutation, confirming the association between both types of molecular events [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 80%

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Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

et al. 2016

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Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC.

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Section: Discussionsupporting

confidence: 80%

“…Most of the patients in this cohort (n=48/56, 85.7%) had been previously studied by our group using single nucleotide polymorphism arrays (SNP-A) [ 18 ]. Therefore, we investigated whether some of the mutations detected in the present study correlated with the alterations previously detected by SNP-A.…”

Section: Resultsmentioning

confidence: 99%

Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

et al. 2016

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“…[50][51][52] Among these, the most common are trisomy 8, -Y, monosomy 7 and del(7q), trisomy 21, and complex karyotypes. [52][53][54] Such cytogenetic abnormalities are shared with other myeloid malignancies and none is specific of CMML. However, they can help in cases which do not meet the other criteria (ie, absence of overt dysplasia) to establish "clonality."…”

Section: Cytogenetic Findingsmentioning

confidence: 99%

How I investigate chronic myelomonocytic leukemia

Sangiorgio

Arber

Orazi

2019

Int J Lab Hematology

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The 2016 revised 4th edition of the World Health Organization classification of hematopoietic neoplasms updated the diagnostic criteria for chronic myelomonocytic leukemia (CMML). Persistent peripheral blood monocytosis of at least 1 × 109/L and a percentage of monocytes ≥10% of the circulating white blood cell count (WBC) are both prerequisite criteria for this diagnosis. CMML represents the prototype of “overlapping” myeloid neoplasms with concurrent myeloproliferative and myelodysplastic features. However, clinical presentation is heterogeneous, with cases showing prevailing “dysplastic” features and others a predominant “proliferative” phenotype. Accounting for this diversity, two variants of CMML are recognized: “dysplastic” CMML defined by WBC < 13 × 109/L and “proliferative” CMML with WBC ≥ 13 × 109/L often showing features mimicking a myeloproliferative neoplasm. Although not an official WHO category, the “oligomonocytic” variant of CMML is defined by relative monocytosis with an absolute monocyte count of 0.5‐0.9 × 109/L. It can be considered a “pre‐phase,” as it frequently anticipates the development of an overt, classic CMML. In an attempt at improving disease prognostication, the blast count based grading system for CMML of the WHO 2008 Classification has been expanded in 2016 to include a new “CMML‐0” category. Lastly, the large body of knowledge on the molecular events occurring in CMML has been used to assist diagnosis and assess prognosis. Despite the step forwards, diagnosis of CMML still remains one of exclusion as no clinical, pathologic or molecular findings are specific for this disease. The current review brings insight into the spectrum of CMML and provides practical advice to approach suspected cases of CMML.

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“…Copy-neutral loss of heterozygosity (LOH) is frequent in CMML, most often targeting hemizygous mutated tumor suppressors such as TET2 or CBL, but recurrent copy number alterations in regions lacking formally identified oncogenes have also been reported [38].…”

Section: Molecular Lesions and Pathogenesismentioning

confidence: 99%