scholarly journals Oligomonocytic Chronic Myelomonocytic Leukemia (O-CMML) and Chronic Myelomonocytic Leukemia (CMML) Show Similar Clinical, Morphological, Immunophenotypic and Molecular Features

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4266-4266 ◽  
Author(s):  
Xavier Calvo ◽  
Nieves Garcia-Gisbert ◽  
Ivonne Parraga ◽  
Lourdes Florensa ◽  
Sara Montesdeoca ◽  
...  
Keyword(s):  
False Positive Rate ◽  
Chronic Myelomonocytic Leukemia ◽  
Lower Percentage ◽  
Molecular Profile ◽  
Monocyte Subset ◽  
Monocyte Count ◽  
Monocyte Subsets ◽  
Molecular Features ◽  
Significant Difference ◽  
Myelomonocytic Leukemia

INTRODUCTION The 2017 WHO classification requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB) for the diagnosis of CMML. Recently, Geyer et al. defines oligomonocytic CMML (O-CMML) as those MDS cases with relative monocytosis (≥10% monocytes) and monocyte count 0.5<1x109/L. The authors showed that clinicopathologic and mutational profile of OCMML were similar to overt CMML. The study of PB monocyte subsets by flow cytometry (FC) has gained interest for CMML diagnosis. As showed by Selimoglu-Buet et al, the increase of classical monocytes (Mo1) >94% is a highly sensitive and specific diagnostic marker for CMML. In the extent of our knowledge, there are no data about PB monocyte subset distribution by FC in O-CMML. Moreover, CD2 and CD56 expression is common in CMML and rarely observed in MDS, the group where O-CMML are currently included. Furthermore, we compared: the molecular profile; cytogenetic abnormalities; cytopenias; BM dysplasia; BM blast and monocyte percentage; PB monocyte percentage, and monocyte and leukocyte counts. METHODS 50 CMML and 33 O-CMML from a single institution were prospectively studied from 02/2016 to date. Table 1 summarizes morphologic, cytogenetic, molecular and clinical findings. We studied PB monocyte subsets by FC: Mo1 (CD14bright/CD16-), Mo2 (CD14bright/CD16+) and Mo3 (CD14dim or -/CD16bright). In addition, we assessed the expression of CD56 and CD2 in monocytes (positivity ≥ 20%). Finally, targeted NGS of the entire exonic sequence of 25 genes recurrently mutated in myeloid malignancies was performed (VAF sensitivity: 2%). Chi-Square, Fisher exact or Man-Whitney U tests were used as appropriate. RESULTS AND DISCUSSION The Mo1 percentage (%) was significantly inferior in O-CMML (P=0.007), but it is noteworthy that median and mean of Mo1% in O-CMML were upper the cutoff of 94% (median: 96.1 vs 98.1; mean: 94.7 vs 96.9). Moreover, the % of patients with >94% Mo1 was no significantly different when comparing O-CMML and CMML although a clear trend was observed (72% vs 90%; P=0.082). This result is impressive since, as previously reported, the specificity of the Mo1 >94% test is around 90-95% and only 5-10% of false positive rate (FP) should be expected. However, in O-CMML a 72% of FP was observed since following 2017 WHO recommendation these patients should be considered as MDS. No differences were observed neither in the % of patients showing CD56+ monocytes (65.6% vs 66.7%; P=0.923) nor in the % of them showing CD2+ (28.1% vs 37.5%; P=0.53) when comparing O-CMML and CMML. We observed no significant differences in platelet count, hemoglobin, BM dyserythropoiesis, BM dysgranulopoiesis, BM dysmegacaryopoiesis, BM blast %, percentage of abnormal karyotypes, and Spanish cytogenetic risk stratification. The main differences were observed in leukocyte count, monocyte count, PB monocyte %, BM monocyte %, and BM promonocyte percentage. Table 1. There were no differences in the number of mutated genes or in the number of mutations between CMML and O-CMML (Table 1). As expected, TET2 and SRSF2 were the most frequently mutated genes in both groups. Moreover, no significant difference was observed in the presence of TET2/SRSF2 co-mutation, the gene signature of CMML (32% vs 26% in CMML). The genes mutated at a frequency >10% in O-CMML were: TET2 (79%), SRSF2 (36%), SF3B1 (29%), ZRSR2 (25%), DNMT3A (15%), and ASXL1 (14%). The genes mutated at a frequency >10% in CMML were: TET2 (81%), SRSF2 (28%), ASXL1 (23%), CBL (23%), SF3B1 (16%), and NRAS (14%). Only two genes were mutated at a significant different frequency: CBL (4% vs 23% in CMML, P=0.041) and ZRSR2 (25% vs 7% in CMML, P=0.043). As expected, CMML showed a higher % of RAS pathway mutations (CBL, NRAS or KRAS) since these have been associated with proliferative features (4% vs 40%, P=0.001). This is especially evident in proliferative CMML in which genes associated with proliferation are present at higher frequencies: CBL (4% vs 39% in CMML, P=0.01), NRAS (0 vs 23% in CMML, P=0.029) and ASXL1 (14% vs 62% in CMML, P=0.004). A significant lower percentage of O-CMML with ZRSR2mut presented Mo1 >94% (33% vs 86%, P=0.024). As shown, O-CMML without ZRSR2mut showed this feature in a similar percentage than CMML (86% vs 90%). At a median follow-up of 31.2 months, 19% of O-CMML evolved to CMML showing a median time to evolution of 34 months. CONCLUSION Our data support the diagnosis of O-CMML as a distinctive subtype of CMML. Table 1 Disclosures Bellosillo: Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.

scholarly journals Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features

2020 ◽  
Vol 4 (20) ◽  
pp. 5285-5296 ◽  
Author(s):  
Xavier Calvo ◽  
Nieves Garcia-Gisbert ◽  
Ivonne Parraga ◽  
Joan Gibert ◽  
Lourdes Florensa ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Molecular Data ◽  
Chronic Myelomonocytic Leukemia ◽  
World Health ◽  
Lower Percentage ◽  
Molecular Profile ◽  
Monocyte Count ◽  
Blood Monocytes ◽  
Health Organization ◽  
Myelomonocytic Leukemia

Abstract Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to &lt;1 × 109/L. These patients show clinical and genomic features similar to those of overt chronic myelomonocytic leukemia (CMML), although most of them are currently categorized as MDS, according to the World Health Organization 2017 classification. We analyzed the clinicopathologic features of 40 patients with OM-CMML with well-annotated immunophenotypic and molecular data and compared them to those of 56 patients with overt CMML. We found similar clinical, morphological, and cytogenetic features. In addition, OM-CMML mirrored the well-known complex molecular profile of CMML, except for the presence of a lower percentage of RAS pathway mutations. In this regard, of the different genes assessed, only CBL was found to be mutated at a significantly lower frequency. Likewise, the OM-CMML immunophenotypic profile, assessed by the presence of &gt;94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage &gt;94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.

scholarly journals Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia

Blood ◽  
2015 ◽  
Vol 125 (23) ◽  
pp. 3618-3626 ◽  
Author(s):  
Dorothée Selimoglu-Buet ◽  
Orianne Wagner-Ballon ◽  
Véronique Saada ◽  
Valérie Bardet ◽  
Raphaël Itzykson ◽  
...  
Keyword(s):  
High Specificity ◽  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Subset ◽  
Hypomethylating Agents ◽  
Monocyte Subsets ◽  
Key Points ◽  
Diagnostic Signature ◽  
Myelomonocytic Leukemia ◽  
Classical Monocytes

Key Points An increase in the classical monocyte subset to >94% of total monocytes discriminates CMML from other monocytoses with high specificity. This characteristic increase in classical monocytes disappears in CMML patients who respond to hypomethylating agents.

Number and Type of TET2 Mutations in Chronic Myelomonocytic Leukemia: Clinical and Prognostic Correlates

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4343-4343 ◽  
Author(s):  
Mrinal M Patnaik ◽  
Mohammad Faizan Zahid ◽  
Terra L. Lasho ◽  
Ezequiel Tolosa ◽  
Christy Finke ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Molecular Model ◽  
Univariate Analysis ◽  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Count ◽  
Missense Mutations ◽  
Survival Difference ◽  
Age Related ◽  
Significant Difference ◽  
Myelomonocytic Leukemia

Abstract Background : TET2, located on chromosome 4q24, is frequently mutated in the majority of patients with chronic myelomonocytic leukemia (CMML). TET2 has 11 exons, and variations, especially in exon 3 have been described as a part of age related clonal hematopoiesis (Jaiswal NEJM 2015). In CMML, somatic TET2 mutations in the absence of ASXL1 mutations (ASXL1wt/TET2mt) were previously shown to impart a favorable outcome on survival (Patnaik BCJ 2015). In the current larger CMML patient cohort, we describe the number and type of TET2 mutations and examine their phenotypic and prognostic effects. Methods : 261 patients with CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. TET2 (NM_001127208.2) coverage extended from exons 3-11, with frame shift, non-sense, and missense variations considered pathogenic. Previously annotated single nucleotide polymorphisms (http//www.hapmap.org) were considered non-pathogenic. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations were documented. Mutational frequencies ≥4% were encountered in; ASXL1 45%, TET2 42%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4% and IDH2 4%. i) TET2 mutations type, number and phenotypic correlates: TET2 mutations were seen in 109 (42%) patients; these included frameshift 33 (30%), nonsense 29 (27%) and missense 11 (10%) variants whereas 36 (33%) had more than one type of mutation. Overall, 57 (52%) patients had more than 1 TET2 mutations: 52 (48%) patients had 1, 46 (42%) 2 and 11 (10%) ≥3 TET2 mutations. Among all 109 TET2 mutated patients, 65% were male, and median age was 71 years with no significant difference in age and gender distribution between mutated and un-mutated cases, or type of TET2 mutations; however, older patients were more likely to carry multiple TET2 mutations (p=0.01). Compared to their un-mutated counterparts, TET2 mutated cases were less likely to have a low hemoglobin (p<0.001), circulating immature myeloid cells (IMC) (p=0.001), peripheral blood (PB) (p=0.009) and BM blasts (p=0.009), and have high-risk stratification per Mayo Molecular Model (p<0.001); these differences were not affected by the type or number of TET2 mutations. TET2 mutated cases were more likely to have a higher frequency of SRSF2 (p=0.004) and lower frequency of ASXL1 (p=0.03), Tp53 (p=0.04) and IDH1/2 mutations (p<0.001); these associations were also not affected by the type or number of TET2 mutations. ii) Impact on survival: Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was superior in TET2 mutated (median 33 months) versus wild-type (median 21 months) patients [p=0.03; HR 1.3 95% CI 1.12-1.86] (figure 1A). This survival difference remained significant after adjustment for age (p=0.04), leukocyte count (p=0.017), absolute monocyte count (p=0.02), absolute lymphocyte count (p=0.02), platelet count (p=0.015), circulating IMC (p=0.03), DNMT3A (p=0.02) and ASXL1 (p=0.045) mutations; however, significance was lost after adjustment for abnormal karyotype (p=0.32) and the Mayo Molecular Model (p=0.0003). These observations were not affected by the type or number of TET2 mutations. Finally, our previous observation regarding the survival advantage of ASXL1wt/TET2mt versus other genotypes was most apparent for patients with multiple TET2 mutations (p=0.02) (figure 1B). Conclusions: TET2 mutations are common in CMML and constitute approximately equal proportions of frameshift and non-sense mutations, while missense mutations are less frequent. Majority of TET2 mutated CMML cases harbor more than one mutant variant. Regardless, the relevance of type and number of TET2 mutations in CMML was limited to an association between older age and number of mutations and the latter with possibly improved survival in the absence of clonal ASXL1 mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia

2020 ◽  
Vol 21 (17) ◽  
pp. 6057
Author(s):  
Klaus Geissler ◽  
Eva Jäger ◽  
Agnes Barna ◽  
Michael Gurbisz ◽  
Temeida Graf ◽  
...  
Keyword(s):  
Growth Factor ◽  
Colony Formation ◽  
Molecular Basis ◽  
Strong Predictor ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Profile ◽  
Molecular Features ◽  
Increased Risk ◽  
Myelomonocytic Leukemia

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p < 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.

MIR150 Is Involved in the Monocyte Subset Differentiation and Its Down-Regulation Leads to Classical Monocyte Accumulation in Chronic Myelomonocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1133-1133
Author(s):  
Dorothee Selimoglu-Buet ◽  
Julie Riviere ◽  
Margot Morabito ◽  
Catherine Lacout ◽  
Aurelie Chauveau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Human Monocyte ◽  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Subset ◽  
Monocyte Subsets ◽  
Down Regulation ◽  
Cd34 Cells ◽  
Myelomonocytic Leukemia ◽  
Classical Monocytes

Abstract Background. Monocytes are a heterogeneous population of peripheral blood leukocytes. The expression of CD14 and CD16 distinguishes CD14+/CD16- classical from CD14+/CD16+ intermediate and CD14low/CD16+ non-classical monocytes. We have shown (Selimoglu-Buet D et al, Blood 2015) that monocytes that accumulate in the peripheral blood of patients with chronic myelomonocytic leukemia (CMML) are predominantly CD14+/CD16- classical monocytes that typically represent more than 94% of total blood monocytes. Strikingly, this phenotypic signature efficiently distinguishes CMML from a reactive monocytosis. Importantly, the CMML-associated increase in classical monocyte fraction disappears in patients who respond to hypomethylating drugs. Whereas in the mouse, the transcription factor Nr4a1 is required for the development of the Ly6Clowmonocytes, the molecular mechanisms that regulate the formation of the three human monocyte populations remain poorly understood. Analysis of the classical monocytes accumulation in CMML may provide insights into the regulation of monocyte subset differentiation. Methods. A microarray screen of miRNA expression was performed in monocytes sorted from 33 CMML and 5 healthy donor blood samples. Validation was performed by qRT-PCR, in monocytes of a cohort of 160 CMML patients and 20 controls, and in CD34+ cells from 44 CMML patients and 19 controls. A mouse model of MIR150-knock-out (Mir150-/-) was used to examine the consequences of the miRNA down-regulation. Multi-color flow cytometry assays were designed to explore mouse and human monocyte subsets. Results. Microarray analyses and validation experiments identified a decreased expression of miR150 in monocytes and CD34+cells from CMML patients compared to controls. Mir150-/- mouse model does not generate monocytosis even in ageing animals. However, an increase in Ly6Chigh inflammatory monocyte fraction at the expense of Ly6Clowpatrolling monocytes was observed in the bone marrow and peripheral blood, leading to further explore the link between MIR150 and monocyte populations. The abnormal repartition of monocyte populations in Mir150-/- mice is a cell-autonomous phenotype as wild-type (WT) mice receiving bone marrow from Mir150-/-mice demonstrated a reduced fraction of Ly6Clow monocytes. This phenotype was rescued by re-expression of MIR150 in LIN- cells of Mir150-/-mice before engraftment. The number of myeloid progenitors was normal in Mir150-/-mice, and the remaining Ly6Clow monocytes did not demonstrate an increased sensitivity to apoptosis. Competitive reconstitution experiments combining WT and Mir150-/-LIN- cells did not identify any significant fitness advantage to Mir150-/-cells, but Mir150-/-donor cells developed reduced numbers of Ly6Clow monocytes than cells from WT donors. These data suggest that MIR150 is involved during late stages of monocyte development and has a key role in the generation of Ly6Clowmonocytes. Finally, TET2 is the main gene mutated in CMML, and Tet2-/- animals develop a monocytosis. Mir150-/- crossed with Tet2-/-mice developed a CMML-like phenotype. In human, the expression of MIR150 decreases along myeloid differentiation and is low in classical compared to intermediate and non-classical monocytes. Depletion or overexpression of MIR150 in human CD34+ cells alters the repartition of CD14+/CD16- and CD14+/CD16+ cells generated in culture. In CMML patients who respond to hypomethylating agents, the normalization of monocyte subset repartition correlates with an increased expression of MIR150, suggesting an epigenetic regulation. MIR150 has several promoters. By combining ChIP-Seq and DNA methylation analyses, a differentially methylated region was detected in one of the MIR150 promoters in CMML patients compared to controls. Using monocyte differentiation conditions, RNA Sequencing performed in CD34+cells overexpressing MIR150, identified ID1 gene as a potential MIR150 target. Conclusion: We demonstrate a role for MIR150 in the generation of intermediate and non-classical monocyte subsets, and its down-regulation in CMML accounts for the characteristic accumulation of classical monocytes. Disclosures Fenaux: Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

scholarly journals Multiple TET2 Mutations As a New Biological Clue for Differentiating Oligomonocytic Chronic Myelomonocytic Leukemia from Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1530-1530
Author(s):  
Nieves Garcia-Gisbert ◽  
Leonor Arenillas ◽  
David Roman-Bravo ◽  
Juan José Rodríguez-Sevilla ◽  
Brayan Merchan ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Diagnostic Value ◽  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Count ◽  
Mutational Status ◽  
Idh Mutations ◽  
Significant Difference ◽  
Custom Panel ◽  
Myelomonocytic Leukemia

Abstract Introduction. Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDS) or MDS/MPN unclassifiable cases with relative monocytosis (≥ 10% monocytes) and a total monocyte count of 0.5-&lt;1x10 9/L. These patients show similar clinical, genomic and immunophenotypic features than overt CMML, although the majority of them are currently classified as MDS following WHO 2017 classification. TET2 is the most prevalent mutated gene in CMML and it is frequent to find multiple TET2 mutations in the same patient. Objective. We investigated TET2 mutations in 42 OM-CMML, their diagnostic value and their correlation with immunophenotypic pattern, and compared them with that observed in 54 CMML and 86 MDS. Patients and methods. Samples were collected from 182 patients: 42 OM-CMML, 54 overt CMML, and 86 MDS. Molecular characterization was performed by next-generation sequencing (NGS) using a custom panel (QIAseq Custom DNA Panels, Qiagen) including the whole codifying region of 25 myeloid-associated genes and sequenced using Illumina technology. Multiparametric flow cytometry (FC) analysis of monocyte subsets was performed on whole PB collected on EDTA. Cell surface staining of 2 × 10 6 cells was performed and at least 500 000 total events were acquired per tube (FACS Canto II; BD Biosciences). The FC strategy analysis, the 5-tube experimental panel, and the NGS custom panel are described in Calvo & Garcia-Gisbert, Blood Adv 2020. Results. Patients with multiple TET2 (multi-TET2) mutations (2 or more) were identified with similar percentages in OM-CMML (17/42, 40.5%) and CMML (29/54, 53.7%) while they were infrequent in MDS (5/86, 5.8%) (P&lt;0.001). In MDS patients, 4/5 with multi-TET2 showed a percentage of monocytes &gt;10% though they were not considered OM-CMML since the monocyte count was below 500/microL. CMML and OM-CMML patients with multi-TET2 showed predominantly 2 TET2 mutations (CMML: 20/29, 69%; OM-CMML: 14/17, 82%;). The distribution of patients with &gt;2 TET2 mutations was similar in CMML and OM-CMML. We did not observe differences among the frequency of nonsense, frameshift or missense TET2 mutations, nor between early or late-truncating (early: aa 1-1128, late: 1128-1936) TET2 mutations between OM-CMML and CMML.TET2 variant allele frequency (VAF) was significantly lower in MDS (median 11.83%) than in OM-CMML and CMML (P&lt;0.001 in both comparisons). OM-CMML and CMML showed similar TET2 VAF (medians 41.4% and 40.3%). In those patients with TET2 VAF &gt;55% or a sum of muti-TET2 mutations VAF above 55% (17 OM, 19 CMML, 2 MDS), we could infer a biallelic alteration in the same clone (Coltro, Leukemia 2020). We did not observe differences in the frequency of OM-CMML showing biallelic TET2 mutations when compared to CMML.The main clinical characteristics of CMML patients (overt and OM-CMML), grouped by TET2 mutational status (unmutated: TET2 WT; 1 TET mutation: TET2 single; ≥2 mutations: multi-TET2) are depicted in Table 1. As shown, we did not observed significant differences when comparing TET2 single to TET2 WT or multi-TET2 Of note, multi-TET2 patients showed a higher percentage of PB and BM monocytes, BM promonocytes and more dysgranulopoiesis than TET2 WT patients.Patients with TET2 WT presented a lower number of mutated genes than TET single and multi-TET2 patients (P=0.019 and P=0.029). In line with previous studies, IDH mutations and TET2 mutations where mutually exclusive (P=0.001). Co-mutation of SRSF2 and TET2, the well-accepted gene signature of CMML, was found in 25/96 patients (26.0%, 13 OM-CMML, 12 CMML) in 10 cases co-mutated with TET2 single and in 15 cases with multi-TET2.We assessed the proportion of OM-CMML patients with MO1&gt;94% since this has been shown as very sensitive and specific feature of CMML. In TET2 mutated OM-CMML, we observed a higher proportion of patients with MO1&gt;94% (90% mut. vs 40% WT; P=0.001) and CD56 expression on monocytes (70% mut. vs 30% WT; P=0.025). We observed a trend (non-significant) difference in the proportion of patients showing these features when comparing TET2 single vs multi-TET2 OM-CMML (single, CD56: 57.1%, MO1&gt;94%: 85.7%; multi-TET2, CD56: 81.3%, MO1&gt;94%: 93.8%). Conclusion. The high occurrence of multiple TET2 mutations in overt and OM-CMML and its infrequency in MDS is a new biological clue for supporting the consideration of OM-CMML in the continuum of CMML. Figure 1 Figure 1. Disclosures Salar: Celgene: Consultancy, Speakers Bureau; Gilead: Research Funding; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Bellosillo: Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Thermofisher Scientific: Consultancy, Speakers Bureau.

scholarly journals Monocyte subsets to differentiate chronic myelomonocytic leukemia from reactive monocytosis

2020 ◽  
Author(s):  
Sang Mee Hwang ◽  
Haejin Ahn ◽  
Seungah Jeon ◽  
Jun Park ◽  
Yunye Chang ◽  
...  
Keyword(s):  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Subsets ◽  
Myelomonocytic Leukemia

Chronic Myelomonocytic Leukemia (CMML) with More Than 15% of Ring Sideroblasts in Bone Marrow: An Overlapping Disorder Between CMML and Refractory Anemia with Ring Sideroblasts.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 290-290 ◽  
Author(s):  
Esperanza Such ◽  
Leonor Senent ◽  
Benet Nomdedeu ◽  
Javier Bueno ◽  
Teresa Bernal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Who Classification ◽  
Multivariate Analyses ◽  
Lower Proportion ◽  
Chronic Myelomonocytic Leukemia ◽  
Refractory Anemia ◽  
Monocyte Count ◽  
Ring Sideroblasts ◽  
Myelomonocytic Leukemia

Abstract Abstract 290 The main diagnostic criteria for chronic myelomonocytic leukemia (CMML), a heterogeneous disorder sharing features of myelodysplastic syndromes (MDS) and chronic myeloproliferative disorders, is the existence of a sustained absolute monocyte count in peripheral blood (PB) above 1 × 109/L. On the other hand, the presence of more than 15% ring sideroblasts (RS) in bone marrow (BM) is a well recognized morphological feature of dyserithropoiesis and, in the absence of blasts in PB and less than 5% blasts in BM, is diagnostic of refractory anemia with ring sideroblasts (RARS) with or without multilineage dysplasia. In FAB as well as in WHO classification systems for myeloid neoplasms those cases presenting with both an absolute monocyte count in PB above 1 × 109/L and more than 15% RS in BM are diagnosed of CMML but the preeminence given to the monocyte count in PB over the proportion of RS in BM is not evidence-based. The main purpose of this study was to assess the clinical and biological characteristics and outcome [overall survival (OS) and acute leukemic (AL) evolution] of a series of 77 patients diagnosed of CMML by FAB and WHO criteria who had more than 15% RS in BM at presentation (CMML-RS) and to compare them with those of a series of 417 patients with CMML with less than 15% RS (classical CMML) and those of a series of 178 patients with classical RARS (38 patients with and 140 patients without multilineage dysplasia). Comparisons of proportions and ranks of variables between different groups were performed by chi square or Mann-Whitney-U tests as appropriate. Actuarial curves of OS and risk of AL evolution were built by Kaplan-Meier method and differences between curves compared with log-rank tests. Multivariate analyses of OS and risk of AL evolution were performed by Cox proportional hazards regression method. Patients with CMML-RS had lower hemoglobin level (P=0.008), lower absolute counts of leukocytes (P<0.001), neutrophils (P=0.002), and monocytes (P<0.001), higher platelet count (P<0.001), lower proportion of blasts in PB (P=0.015) and BM (P=0.035), and higher serum level of ferritin (P<0.001) and LDH (P=0.06) than patients with classical CMML. Patients with CMML-RS had significantly better OS than patients with classical CMML (median, 79 mo and 26 mo respectively; P<0.001; Figure) as well as lower risk of AL evolution (cumulative proportion at 5 yr, 7% and 20% respectively; P=0.07). Further, the beneficial prognostic relevance of the proportion of RS in BM on OS was maintained in multivariate analyses (P<0.001). In marked contrast, OS (median, 64 mo; Figure) and risk of AL evolution (cumulative proportion at 5 yr, 9%) of patients with classical RARS were closely similar to those observed in patients with CMML-RS (P>0.90). Patients with classical RARS were more anemic (P=0.001), had lower absolute counts of leukocytes (P<0.001), neutrophils (P=0.01), and monocytes (P<0.001), higher platelet count (P=0.002), lower proportion of blasts in PB (P=0.01) and BM (P<0.001), and lower serum level of ferritin (P=0.01) and LDH (P=0.11) than patients with CMML-RS. To avoid the potential interference in the analyses of disparities in the proportion of blasts in BM in the different groups of patients all the analyses were repeated excluding from all the groups those cases with 5% or more blasts in BM. Fifty-three patients with CMML-RS, 245 with classical CMML, and all 178 with classical RARS were evaluable for these sub-analyses. The results obtained were similar to those in the overall series of patients (data not showed). To sum up, all these results show that the proportion of RS in BM is a much powerful prognostic indicator than absolute monocyte count in PB in CMML and demonstrate that the presence of a proportion of RS greater than 15% in BM in patients with CMML defines a subset of patients that clearly differ in their biological characteristics from classical CMML and classical RARS. CMML-RS has a clinical course very close to that of classical RARS and markedly better than classical CMML. These data strongly suggest that CMML-RS is an overlapping syndrome between CMML and RARS. For clinical purposes patients with >1 × 109 monocytes/L in PB and >15% RS in BM should be better classified as RARS than as CMML. The WHO classification needs to be revisited to account for those findings. Disclosures: No relevant conflicts of interest to declare.

Spliceosome Mutations Involving SRSF2, SF3B1 and U2AF35 in World Health Organization Defined Chronic Myelomonocytic Leukemia; Prevalence, Clinical Correlates and Prognosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1711-1711
Author(s):  
Mrinal M. Patnaik ◽  
Terra L Lasho ◽  
Christy Finke ◽  
Curtis A Hanson ◽  
Janice M Hodnefield ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myelomonocytic Leukemia ◽  
Low Risk ◽  
World Health ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Free Survival ◽  
Clinical Correlates ◽  
Significant Difference ◽  
Myelomonocytic Leukemia

Abstract Abstract 1711 Background: Mutations in genes of the splicing machinery, such as SF3B1, SRSF2 and U2AF35 are common in patients with myelodysplastic syndromes [MDS] (Nature 2011;478:64) and chronic myelomonocytic leukemia [CMML] (Haematologica 2012;Epub). In MDS, SRSF2 gene mutations are an independent risk factor for shortened over-all (OS) and leukemia-free survival (LFS) (Blood 2012;119:3578). In MDS with ring sideroblasts (RS), SF3B1 mutations have a high prevalence (∼50%), but do not influence either, the OS or the LFS (Blood 2012;119:569). We carried out this study to evaluate the prevalence, clinical correlates and prognosis of the aforementioned spliceosome mutations in CMML. Methods: The study included 227 patients with WHO defined CMML who were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. DNA was interrogated in the three most frequent spliceosome genes with somatic mutations; SRSF2, SF3B1 and U2AF35. Results I: Prevalence and clinical correlates Among the 227 study patients, 153 (67%) were male, median age was 71 years (range, 17–90 years) and 192 (85%) met the WHO criteria for CMML-1. Ninety (40%) patients had SRSF2 mutations (86% CMML-1), 13 (6%) had SF3B1 mutations (75% CMML-1) and 20 (9%) had U2AF35 mutations (95% CMML-1). One-hundred and twenty three (54%) patients had at least one of three spliceosome mutations (86% CMML-1). Mutational hot spots were P95 for SRSF2 (P95L-n=36/H-n=32/R-n=13/A-n=1), K700E (n=7) and H662Q (n=2) for SF3B1, and Q157 (Q157R-n=5/P-n=5/G-n=1) and S34F (n=7) for U2AF35. Seven patients (54%) with SF3B1 mutations had ≥1% RS, with 5 (38%) showing ≥15% RS. Mutations involving all three spliceosome genes were mutually exclusive. The cytogenetic distribution based on the Spanish risk stratification system (Haematologica 2011;96:375) was; SRSF2 mutations: 69 (77%) low risk, 11 (12%) intermediate risk, and 10 (11%) high risk (+8-n=3, del/monosomy 7-n=2, monosomal karyotype-n=5); SF3B1 mutations: 8 (62%) low risk and 5 (38%) intermediate risk; U2AF35 mutations: 15 (75%) low risk, 3 (15%) intermediate risk and 2 (10%) high risk (p=0.89). The distribution of mutations according to the MD Anderson prognostic scoring system [MDAPS] (Blood 2002;99:840) was; SRSF2 - low-n=41, intermediate-1-n=26, intermediate-2-n=18, high-n=5, SF3B1- low-n=7, intermediate-1-n=3, intermediate-2-n=2, high-n=1, and U2AF35- low-n=11, intermediate-1-n=5, intermediate-2-n=3, high-n=1 (p=0.73). There was no statistically significant difference, among the three mutation groups, in prognostically relevant parameters, including gender distribution, median age, hemoglobin values, platelet counts, peripheral blood (PB) and BM blast counts, absolute neutrophil counts (ANC) and absolute monocyte counts (AMC). The only notable difference was that patients with the SF3B1 mutation had a lower median white blood cell count (p=0.04) and a lower absolute lymphocyte count (p=0.045). Results II: Prognostic impact of spliceosome mutations At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. Median survivals for patients with mutations involving SRSF2, SF3B1 and U2AF35 were 24, 17 and 12 months, respectively. In univariate analysis, the presence of SRSF2 (p=0.67), SF3B1 (p=0.96) or U2AF35 (p=0.49) mutations had no prognostic impact on OS. Similarly, none of the three spliceosome mutations affected LFS; corresponding p values were 0.55 for SRSF2, 0.9 for SF3B1 and 0.38 for U2AF35 mutations respectively. We then examined possible prognostic value of having none of these mutations (n=104) vs otherwise (n=123) and the results were once again negative (p=0.87). Conclusions: SRSF2 is the most frequently mutated spliceosome gene in CMML, but neither it nor SF3B1 or U2AF35 mutations affect overall or leukemia-free survival in CMML. Furthermore, the current study suggests limited genotype-phenotype association, save for the already established association between SF3B1 mutations and RS. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document