Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia

Itzykson, Raphaël; Kosmider, Olivier; Renneville, Aline; Gelsi‐Boyer, Véronique; Meggendorfer, Manja; Morabito, Margot; Berthon, Céline; Adès, Lionel; Fenaux, Pierre; Beyne‐Rauzy, Odile; Vey, Norbert; Braun, Thorsten; Haferlach, Torsten; Dreyfus, François; Cross, Nicholas C. P.; Preudhomme, Claude; Bernard, Olivier A.; Fontenay, Michaëla; Vainchenker, William; Schnittger, Susanne; Birnbaum, Daniel; Droin, Nathalie; Solary, Éric

doi:10.1200/jco.2012.47.3314

Cited by 468 publications

(631 citation statements)

References 62 publications

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“…This results in dysregulated transcription and promotes oncogenic transformation. Nonsense and frame shift ASXL1 mutations, negatively impact OS in CMML [11,19,24]. In the current study, 29% of patients had nonsense and frameshift ASXL1 mutations, with a trend towards inferior survival (P 5 0.08).…”

Section: Discussionsupporting

confidence: 45%

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had 1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n 5 82), anemia (P 5 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P 5.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n 5 48), univariate analysis showed association between poor survival and presence of SETBP1 (P 5 0.04) or ASXL1 (P 5 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P 5 0.04); the number of concurrent mutations did not provide additional prognostication (P 5 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high ( 2 points), with median survivals of 80, 42 and 11 months respectively (P 5 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutationenhanced prognostic model.

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Section: Discussionsupporting

confidence: 45%

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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“…Another pathogenic mutation frequently observed in chronic myeloid malignancies is ASXL1 with reported frequencies of 14, 40-50, and 21% in MDS, CMML, and PMF, respectively [72][73][74][75][76]. In a recent series of fourteen patients with CSF3R-mutated WHO-defined CNL, 57% harbored an ASXL1 mutation [7].…”

Section: Asxl1 Mutationsmentioning

confidence: 99%

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

Elliott

Tefferi

2016

American J Hematol

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Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 109/L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R. The clinical presentation, disease course and prognosis of CSF‐R mutated CNL have been recently outlined. Co‐operative mutations in SETBP1 and ASXL1 appear to be of prognostic significance and correlate with disease progression. Advances in the understanding of the molecular pathogenesis of CNL, have not yet fully translated into satisfactory therapeutic strategies, but the foundations for these are strengthening. Am. J. Hematol. 91:342–349, 2016. © 2015 Wiley Periodicals, Inc.

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“…Clinical parameters, such as older age, low hemoglobin level, high WBC count, presence of IMC, and high percentage of bone marrow blasts have been reported to be associated with an inferior survival [2,[7][8][9][17][18][19][20]. Recently, cytogenetic data and gene mutations have been recognized as important prognostic factors and incorporated into the CMML risk stratification system [1,8,11,20].…”

Section: Discussionmentioning

confidence: 99%

“…However, ACA appeared to occur more frequently in patients with a normal karyotype or a karyotype falling into the low-risk category. Mutations, which have been recently discovered to highly correlate with CMML patient outcomes [9,[20][21][22], were studied in variable subsets of cases in this cohort (data not shown). While NRAS/KRAS mutations seemed more frequent in patients with ACA, mutations involving FLT3, JAK2, KIT, IDH1/IDH2, NPM1, and TP53 detected at the time of diagnosis were similar between patients with or without ACA.…”

Section: Discussionmentioning

confidence: 99%

“…Cytogenetic abnormalities are detected in about 20-40% of CMML patients at the time of diagnosis [1][2][3][4][5][6][7][8][9][10][11] and have been shown to be prognostically relevant [1,[7][8][9][10][11]. In an earlier study [1], we found that CMML patients with an abnormal karyotype had a poorer overall survival (OS) compared with patients who had a normal karyotype.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic impact of acquisition of cytogenetic abnormalities during the course of chronic myelomonocytic leukemia

Tang

et al. 2015

American J Hematol

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Karyotypic abnormalities are detected in 20-40% of chronic myelomonocytic leukemia (CMML) patients at initial diagnosis and have been shown to correlate with patients' outcome. The significance of acquisition of cytogenetic abnormalities (ACA) during the course of CMML, however, is largely unknown. In a cohort of 314 CMML patients, karyotypic abnormalities were detected in 106 (34%) patients at the time of diagnosis; and ACA were detected in 80 (25%) patients after a median interval of 17 months (range, 2-117 months). The most frequently observed ACA were a complex karyotype, followed by 121, 27/del(7q), del(20q), i(17q), and 217/del(17p). ACA appeared to occur more frequently in patients with a normal or lower risk karyotype. Progression to AML was seen in 44 of 80 (55%) patients with ACA versus 67 of 234 (29%) patients without ACA (P < 0.0001). Presence of ACA predicted an inferior leukemia-free survival (LFS) by univariate (P 5 0.0435) and multivariate analysis (HR 5 1.892, P 5 0.006). While acquisition of a complex karyotype was positively correlated with AML progression (P 5 0.0086), del(20q) was associated with a stable disease (P 5 0.0198). We conclude that ACA occur in~20-30% of CMML patients during the course of disease, and are significantly associated with AML progression and a shorter LFS. Karyotypic abnormalities, either present at diagnosis or acquired during the course of disease, have prognostic implication in CMML patients.

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Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia

Abstract: A new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.

Cited by 468 publications

References 62 publications

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Chronic neutrophilic leukemia 2016: Update on diagnosis, molecular genetics, prognosis, and management

Prognostic impact of acquisition of cytogenetic abnormalities during the course of chronic myelomonocytic leukemia

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