Cytogenetic risk stratification in chronic myelomonocytic leukemia

Such, Esperanza; Cervera, José; Costa, Dolors; Solé, Françesc; Vallespı́, Teresa; Luño, Elisa; Collado, Rosa; Calasanz, Marı́a José; Hernández-Rivas, Jesús M.; Cigudosa, Juan C.; Nomdedeu, Benet; Mallo, Mar; Carbonell, Félix; Bueno, Javier; Ardanaz, María Teresa; Ramos, Fernando; Tormo, Mar; Sancho-Tello, Reyes; Cañizo, Consuelo del; Gómez, Valle; Marco, Víctor; Xicoy, Blanca; Bonanad, Santiago; Pedro, Carmen; Bernal, Teresa; Sanz, Guillermo

doi:10.3324/haematol.2010.030957

Cited by 235 publications

(277 citation statements)

References 21 publications

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“…Patients with SF3B1 mutations did have a higher % of BM RS, lower median white count and a lower ALC, perhaps indicators of less aggressive disease. There were no differences in the distribution of patients across the Spanish cytogenetic risk stratification and the MDAPS risk categories [23,24].…”

Section: Discussionmentioning

confidence: 88%

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Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

137

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SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...

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Section: Discussionmentioning

confidence: 88%

“…All BM slides, including iron stains for quantification of BM RS were centrally reviewed. Karyotype risk designation and risk stratification were according to the Spanish cytogenetic risk stratification system [23] and the MD Anderson prognostic scoring system (MDAPS) [24], respectively.…”

Section: Methodsmentioning

confidence: 99%

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

137

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“…The chronic myelomonocytic leukemia karyotypes were also stratified according to the IPSS scoring system, 21 the new Comprehensive Cytogenetic Scoring System (CCSS) for primary myelodysplastic syndrome, 22 and the recently proposed cytogenetic risk stratification system for chronic myelomonocytic leukemia. 23 The CCSS score was also used along with blood counts and bone marrow blast count to classify the chronic myelomonocytic leukemia cases according to the IPSS-R scoring system. 17 NPM1 and FLT3 Mutation Analysis NPM1 and FLT3 mutation status was obtained from available molecular diagnostic reports of acute myeloid leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia cases.…”

Section: Cytogeneticsmentioning

confidence: 99%

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Courville

Kourda

et al. 2013

Modern Pathology

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Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (Po0.01) and less likely to receive aggressive treatment (P ¼ 0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P ¼ 0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

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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%

“…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%

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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Cytogenetic risk stratification in chronic myelomonocytic leukemia

Cited by 235 publications

References 21 publications

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

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

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