Cytogenetic and Molecular Profile Analysis in Hispanic Chronic Myelomonocytic Leukemia Patients From Puerto Rico

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S106-S106
Author(s):  
Nawar Matti ◽  
Ruifang Zheng ◽  
Khalid Algarrahi ◽  
Albert Alhatem ◽  
Xinlai Sun ◽  
...  
Keyword(s):  
Puerto Rico ◽  
Incidence Rate ◽  
Lower Incidence ◽  
Patient Population ◽  
Chronic Myelomonocytic Leukemia ◽  
Wild Type ◽  
Cytogenetic Abnormalities ◽  
Molecular Profiles ◽  
Lower Incidence Rate ◽  
Myelomonocytic Leukemia

Abstract Objectives Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy with both myelodysplastic and myeloproliferative features. The clinical and pathological features of CMML are highly heterogeneous. It was reported that Hispanic whites had an age-adjusted lower incidence rate of CMML compared to non-Hispanic whites. The aim of this study is to define the cytogenetic and genomic landscape of Hispanic CMML patients and explore their potential clinical significance. Methods Clinically relevant cytogenetic results and 40-gene molecular profiles of Hispanic CMML patients in Puerto Rico (PR) from 2009 to 2018 were obtained retrospectively. Results Total 111 Hispanic CMML patients from PR were diagnosed in our institute from 2009 to 2018. The age range was from 46 to 96 years with a median age of 74. Sixty-five were male and 46 were female. The epidemiological features are similar to that in a general CMML patient population. In total, 107 patients had karyotypes available; 17 patients had abnormal karyotype (17/107, ~16%). Compared with general CMML patients, Hispanic CMML patients had a significantly lower rate of cytogenetic abnormalities (30% vs 16%). Among total 111 Hispanic CMML patients, 40-gene myeloid molecular profiles were performed in 56 CMML patients. Fifty-five out of 56 patients had mutations identified (~98.2%). The most frequent mutated genes were TET2, SRSF2, ASXL1, NRAS, and ZRSR2. Twenty-six of 56 patients (~46.4%) had mutated TET2/wild-type ASXL1. Previous studies indicated that mutated ASXL1, NRAS, RUNX1, and SETBP1 likely associate with an unfavorable prognosis in a general CMML patient population. Mutated TET2 with wild-type ASXL1 (muTET2/wtASXL1) may associate with a favorable prognosis. Compared with general CMML patients, Hispanic CMML patients in this study had relatively lower mutational rates in ASXL1 (30.4% vs 37.0%), NRAS (10.7% vs 11.7%), RUNX1 (5.3% vs 7.9%), and SETBP1 (5.3% vs 8.9%) and a higher rate of muTET2/wtASXL1 (46.4% vs 37.8%). Conclusion Hispanic CMML patients from PR had a significantly lower rate in cytogenetic abnormalities; relatively lower mutational rates in ASXL1, NRAS, RUNX1, and SETBP1; and a higher mutational rate in muTET2/wtASXL1. The findings raise a possibility of a better prognosis in Hispanic CMML patients and could be one of the explanations of a lower incidence rate of CMML in Hispanic population.

MicroRNA Expression Profiles in Chronic Myelomonocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2699-2699
Author(s):  
Mehdi Nassiri ◽  
Joseph Olczyk ◽  
Samantha Knapp ◽  
Gail Vance ◽  
Anupama Tewari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mirna Expression ◽  
Expression Profiles ◽  
Chronic Myelomonocytic Leukemia ◽  
Differentially Expressed ◽  
Cytogenetic Abnormalities ◽  
Normal Bone ◽  
Normal Reference ◽  
Mirna Expression Profiles ◽  
Myelomonocytic Leukemia

Abstract Chronic myelomonocytic leukemia (CMML) is a hematopoietic malignancy with hybrid myeloproliferative and myelodysplastic features. The diagnostic criteria for CMML are evolving with the progress of our knowledge on various genetic lesions involved in the pathogenesis of myeloid neoplasms. This shift, including molecular genetic lesions in the diagnosis process, is highlighted in updated 2008 WHO classification system, which excludes myeloproliferative neoplasms with PDGFRB rearrangement, monocytosis and eosinophilia from CMML category. Despite these recent advancements, CMML remains a heterogeneous group of diseases with variable patient outcomes and no well-defined targeted therapy. To further investigate the biological diversity of this disorder, we studied microRNA (miRNA) expression profiles, their relation to the diagnostic and clinical parameters in CMML, and compared these profiles to global miRNA expression in normal reference bone marrow samples. MicroRNAs are a class of non-coding RNA molecules that alter gene expression by targeting and blocking mRNA. The role of miRNAs in carcinogenesis is related to their targeting of messenger RNAs encoding for oncogenes and tumor suppressor genes. Bone marrow samples from 22 patients with CMML were included in the study. Median age of the patients was 71 years with a range from 39 to 92 years. There were 15 males and 7 females. Seventeen patients presented with CMML-1 (blasts less than 5% in peripheral blood and less than 10% of bone marrow differential count). The remaining patients showed CMML-2. Nine patients had WBC below 13×109/L defining a myelodysplastic type of CMML. Cytogenetic results were available in 20 patients. Fourteen patients demonstrated a normal karyotype. Normal pooled bone marrow samples were used as a reference. The total RNA was isolated using RecoverAll RNA extraction kit. Micoroarray studies were performed using Agilent human miRNA microarrays (version 1.0) containing probes for 470 human and 64 human viral miRNAs cataloged in the Sanger database v9.1. The results were analyzed using BRB array tool and Genesis software. Unsupervised hierarchical clustering discovered two different groups of CMML samples with patterns of miRNA expression distinct from normal bone marrows (oneway ANOVA). Twenty seven miRNAs were differentially expressed in normal bone marrow reference samples vs. CMML-1 and -2. There was an overlap in miRNA profiles between groups of CMML based on blast percentage (CMML-1 vs. CMML-2), WBC count (<13×109/L vs. ≥13×109/L) and presence or absence of cytogenetic abnormalities. However, using PAM algorithm the following miRNAs showed predictive power: hsa-miR-519b (in CMML-1 vs. 2); hsa-miR-15b and hsa-miR-432* (in groups of samples separated by a cut-off WBC of 13×109/L) and hsa-miR-223 (comparing CMML with and without cytogenetic abnormalities). In summary, significantly different miRNA profiles were seen in CMML as compared to normal reference bone marrow. Two distinct subgroups of CMML were defined by the miRNA expression profiles. Select miRNAs were differentially expressed in known biological and clinical subgroups of CMML. Further correlation of clinical and outcome data with subgroups of CMML defined by miRNA expression profiles will be presented.

Analyses of 81 Chronic Myelomonocytic Leukemia (CMML) for EZH2, TET2, ASXL1, CBL, KRAS, NRAS, RUNX1, IDH1, IDH2, and NPM1 Revealed Mutations In 86.4% of All Patients with TET2 and EZH2 Being of High Prognostic Relevance

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 296-296 ◽  
Author(s):  
Vera Grossmann ◽  
Alexander Kohlmann ◽  
Christiane Eder ◽  
Nicholas C.P. Cross ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Chronic Myelomonocytic Leukemia ◽  
Molecular Heterogeneity ◽  
Cell Renewal ◽  
Wild Type ◽  
Employment Equity ◽  
Ras Pathway ◽  
Equity Ownership ◽  
Exon 4 ◽  
Myelomonocytic Leukemia

Abstract Abstract 296 Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that is characterized by features of both a myeloproliferative neoplasm and a myelodysplastic syndrome. Recently, we investigated 81 CMML cases (45 CMML-1, 36 CMML-2) diagnosed between 10/2005 - 9/2008, which had been characterized by chromosome banding analysis and mutation analysis in 6 candidate genes: Mutations were detected in TET2 (44.4%), CBL (22.2%), NRAS (22.2%), KRAS (12.3%), JAK2 (9.8%), RUNX1 (8.7%) (Kohlmann et al., J Clin Oncol. 2010 Jul 19). We now applied amplicon-based deep-sequencing using the small volume Titanium chemistry assay (454 Life Sciences, Branford, CT) to investigate additional 4 candidate genes: IDH1 (exon 4), IDH2 (exon 4) and NPM1 (exon 12) (at known mutational hotspot regions) and the complete coding region of EZH2. EZH2 encodes a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone H3 lysine 27 methyltransferase that influences stem cell renewal. Mutations in EZH2 were recently described to play a role in MPN/MDS. The sequencing library preparation for IDH1, IDH2, NPM1, and EZH2, in total 22 amplicons, was performed using 48.48 Access Array technology (Fluidigm, South San Francisco, CA) to cope with the number of amplicons. In median, 498 reads per amplicon were obtained, thus yielding sufficient coverage for detection of mutations with high sensitivity. After excluding polymorphisms and silent mutations aberrations were detected in IDH1 (1/81; 1.2%), IDH2 (3/81; 3.7%), NPM1 (1/81; 1.2%), and EZH2 (10/81; 12.3%). Another gene recently described in hematological diseases is ASXL1 (additional sex combs like 1) on chromosome 20q11.1. Therefore, the hotspot region of ASXL1 exon 12 was additionally investigated by Sanger sequencing in those 20 cases, in which no mutation had been observed thus far. Nine of these 20 cases (45%) harbored a mutation in ASXL1, thus only 11 cases (13.6%) remained in this cohort in which no mutation was detected. Summarizing this data, 86.4% of these CMMLs harbored at least one molecular aberration with a median of two genes mutated (range 1–4). In more detail, we observed 11 novel distinct EZH2 mutations in ten patients: 7 missense, 3 frameshifts (2 deletions, 1 insertion), and one splice site mutation. EZH2 mutations were found to be heterogeneous and were spread over several exons, predominantly located in the four conserved regions (6/11 in the conserved SET domain; e.g. H680R, N659S). No case revealed a Tyr641 of EZH2 mutation as described for follicular and diffuse large B-cell lymphomas. In median, the burden of EZH2 mutations was 42.5% of sequencing reads per patient (range 1.4–98%). Similarly, a high mutation burden was detected in RUNX1 (median 46.7%), TET2 (median 44.6%), and CBL (median 42.5%) whereas the burden was low in RAS pathway alterations, i.e. NRAS (median 11.1%), KRAS (median 27%), or JAK2 V617F mutations (median 6.9%). With respect to associations of distinct mutations no specific pattern was observed, i.e. EZH2 mutations were concomitantly detected with TET2 (4/10), RUNX1 (3/10), CBL (3/10), JAK2 (3/10), NRAS (2/10), KRAS (1/10), and IDH2 (1/10), respectively. Further, EZH2 mutations were associated neither with morphologic CMML subtype or dysplastic or myeloproliferative characteristics nor with age, white blood cell count, thrombocytes count, or hemoglobin. However, with respect to clinical data a very poor outcome was observed for patients that carried EZH2 mutations compared to EZH2 wild-type cases (median OS 4.3 vs. 130.4 months; p<0.001). In contrast, a significantly better outcome was seen for patients who carried TET2 mutations compared to TET2 wild-type cases (median OS 130.4 vs. 53.6 months, p=0.013). Subsequently, we performed a survival analysis taking both EZH2 and TET2 mutations into account. Here, the cohort was significantly separated into three distinct prognostic groups, i.e. EZH2-mutated with a poor median OS of 4.3 months, EZH2/TET2 wild-type with a median OS of 90 months and TET2-mutated cases with a median OS of 130.4 months (p<0.001). In conclusion, our study revealed molecular mutations in 86.4% of 81 CMML patients providing new insights into the molecular heterogeneity of this disease. Besides alterations in TET2, CBL, ASXL1, and the RAS pathway, EZH2 is targeted by various types of frameshift and point mutations and is a novel biomarker with unfavorable prognosis and clinical utility. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Limited Effect of TET2 Mutations on Promoter DNA Methylation in Chronic Myelomonocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1365-1365
Author(s):  
Jumpei Yamazaki ◽  
Rodolphe F Taby ◽  
Aparna Vasanthakumar ◽  
Trisha Macrae ◽  
Kelly R Ostler ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Myeloid Leukemia ◽  
Cpg Island ◽  
Cpg Islands ◽  
Chronic Myelomonocytic Leukemia ◽  
Gene Promoters ◽  
Wild Type ◽  
Promoter Dna Methylation ◽  
Promoter Dna ◽  
Myelomonocytic Leukemia

Abstract Abstract 1365 TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine, possibly leading to loss of DNA methylation. TET2 mutations are common in myeloid leukemia and were proposed to contribute to leukemogenesis through DNA methylation. To expand on this concept, we studied chronic myelomonocytic leukemia (CMML) samples. TET2 missense or nonsense mutations were detected in 53% (16/30 patients). By contrast, only 1/30 patients had a mutation in IDH1 or IDH2, and none of them had a mutation in DNMT3A. By bisulfite pyrosequencing, global methylation measured by the LINE-1 assay and DNA methylation levels of 10 promoter CpG islands frequently abnormal in myeloid leukemia were not different between TET2 mutant and wild-type cases. This was also true for 9 out of 11 gene promoters reported by others as differentially methylated by TET2 mutations. We confirmed only two non-CpG island promoters, AIM2 and SP140, as hypermethylated in patients with mutant TET2. These were the only two gene promoters (out of 14 475 genes) previously found to be hypermethylated in TET2 mutant cases. This finding shows that hypermethylation of both AIM2 and SP140 are bona fide markers of TET2 mutant cases in CMML. On the other hand, total 5-methylcytosine levels in TET2 mutant cases were significantly higher than TET2 wild-type cases. Thus, TET2 mutations have a limited impact on promoter DNA methylation in CMML. To confirm this, we performed genome-wide analysis using a next-generation sequencing method for DNA methylation levels in three TET2 mutant cases. TET2 mutant CMMLs had an average of 230 (1.9%) promoter CpG island sites hypermethylated compared to normal blood, which is close to what is generally observed when one compares cancer to normal. By contrast, all three cases had near normal to increased levels of methylation outside CpG islands. The median methylation levels in non-promoter, non-CpG island sites was 88.7% in normal blood compared to 91.7%, 92.1% and 94.6% in the three TET2 mutant cases. Thus, TET2 mutant CMMLs escape the general hypomethylation phenomenon seen in many cancers. All together, our data suggest that TET2 mutant CMML cases may have distinct DNA methylation patterns primarily outside gene promoters. Disclosures: No relevant conflicts of interest to declare.

Molecular and Prognostic Correlates of Cytogenetic Abnormalities in Chronic Myelomonocytic Leukemia: A Mayo Clinic-French Consortium Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 412-412
Author(s):  
Emnet A Wassie ◽  
Raphael Itzykson ◽  
Terra L Lasho ◽  
Olivier Kosmider ◽  
Christy Finke ◽  
...  
Keyword(s):  
Mayo Clinic ◽  
Risk Model ◽  
Normal Karyotype ◽  
Chronic Myelomonocytic Leukemia ◽  
Older Age ◽  
World Health ◽  
Abnormal Karyotype ◽  
Cytogenetic Abnormalities ◽  
Myelomonocytic Leukemia ◽  
Monosomal Karyotype

Abstract Background: The prognostic significance of cytogenetic abnormalities in chronic myelomonocytic leukemia (CMML) was recently revisited (AJH, 89; 813-818, 2014 and Blood April, 2013). Using a large Mayo Clinic-French Consortium database, we analyzed the molecular and prognostic correlates of cytogenetic abnormalities in CMML. Methods: CMML diagnosis was according to World Health Organization criteria. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature. Statistical analyses considered clinical and laboratory parameters obtained at time of cytogenetic studies. Results: Spectrum and frequency of cytogenetic abnormalities: A total of 409 patients participated in this study including, 268 (66%) from the Mayo Clinic and 141 (34%) from the French CMML consortium. Of these, 396 (97%) had ≥20 metaphases and 13 (3%) had ten to 19, analyzed. One hundred and fifteen (30%) patients displayed an abnormal karyotype, including 82 (71%) sole, 20 (17%) two and 13 (11%) complex abnormalities. The most common abnormalities were; +8 (23%), -Y (20%), -7/7q- (14%), 20q- (8%), +21 (8%) and der (3q) (8%). Other cytogenetic abnormalities included 5q-, 12p-, 13q- and i(17q), present at a much lower frequency (0.9-4%). Phenotypic correlates: Abnormal vs normal karyotype was associated with older age (p=0.03), hemoglobin<10 g/dL (p=0.0009), white blood cell count (WBC) >15 x 109/L (p=0.02), absolute neutrophil count (ANC) >10 x 109/L (p=0.03), absolute lymphocyte count (ALC) >2.5 x109/L ( p=0.04), peripheral blood (PB) blast ≥1% (p<0.0001), bone marrow (BM) blast ≥10% (p<0.0001) and circulating immature myeloid cells (IMC) (p=0.0003). +8 (p=0.01), +21 (p=0.03) and der (3q) (p=0.03) were associated with hemoglobin <10 g/dL. -Y was associated with older age (p=0.04), lower PB (p=0.04) and BM (p=0.02) blasts. -7/7q was associated with leukocytosis (p=0.005), neutrophilia (p=0.04), and higher PB blasts (p=0.004). 20q- was associated with thrombocytopenia (p=0.04). Molecular correlates: ASXL1 mutations were associated with abnormal karyotype (p=0.04) and SRSF2 with normal karyotype (p=0.02). In comparison to other abnormal karyotypes, the incidence of ASXL1 mutations was lower in –Y (P=0.04) and der(3q) (p=0.03). U2AF1 mutations were associated with monosomal karyotype (p=0.03) and SF3B1 with der (3q) (p<0.0001). Prognostic relevance : Median follow-up was 1.8 years with 244 (60%) deaths and 79 leukemic transformations (19%). A step-wise survival analysis resulted in three distinct cytogenetic risk categories (Figure 1): high (complex and monosomal karyotype), intermediate (all abnormalities not in high or low risk) and low (normal, sole -Y and sole der (3q)); the corresponding median survivals were 0.2 (HR 8.1, 95% CI 4.6-14.2), 1.7 (HR 1.7, 95% CI 1.2-2.3). In multivariable analysis, the particular cytogenetic risk stratification remained significant in the context of Mayo molecular model (p<0.0001), MDAPS (p<0.0001), and the GFM risk model (P<0.0001). The Mayo-French cytogenetic risk model was also effective in predicting leukemic transformation with HR of 10.9 (95% CI 4.2-27.8) for high and 2.2 (95% CI 1.3-3.7) for intermediate risk groups. Conclusion: Cytogenetic abnormalities are seen in approximately 30% of patients with CMML and display significant associations with certain molecular and phenotypic characteristics. We describe a novel cytogenetic prognostic model for both over-all and leukemia free survival in CMML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia

2019 ◽  
Vol 3 (3) ◽  
pp. 339-349 ◽  
Author(s):  
Hassan Awada ◽  
Yasunobu Nagata ◽  
Abhinav Goyal ◽  
Mohammad F. Asad ◽  
Bhumika Patel ◽  
...  
Keyword(s):  
Lower Risk ◽  
Assessment Tool ◽  
Uniparental Disomy ◽  
Chronic Myelomonocytic Leukemia ◽  
Loss Of Function ◽  
Wild Type ◽  
Monocytic Differentiation ◽  
Hematopoietic Stem ◽  
Myeloid Neoplasia ◽  
Myelomonocytic Leukemia

Abstract Somatic TET2 mutations (TET2MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2i) in CMML. We speculated that biTET2i might be associated with distinct clinicohematological features. We analyzed TET2MT in 1045 patients with MN. Of 82 biTET2i cases, 66 were biTET2MT, 13 were hemizygous TET2MT, and 3 were homozygous TET2MT (uniparental disomy); the remaining patients (denoted biTET2− hereafter) were either monoallelic TET2MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2i vs 65% of biTET2− cases (P = .02). TET2 hits were founder lesions in 72% of biTET2i vs 38% of biTET2− cases (P &lt; .0001). In biTET2i, significantly concurrent hits included SRSF2MT (33%; P &lt; .0001) and KRAS/NRASMT (16%; P = .03) as compared with biTET2−. When the first TET2 hit was ancestral in biTET2i, the most common subsequent hits affected a second TET2MT, followed by SRSF2MT, ASXL1MT, RASMT, and DNMT3AMT. BiTET2i patients without any monocytosis showed an absence of SRSF2MT. BiTET2i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2− patients. Hence, while a second TET2 hit occurred frequently, biTET2i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2i showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2i might represent an auxiliary assessment tool in MN.

Chronic Myelomonocytic Leukemia With Preexisting Myelodysplastic Syndrome Or Myeloproliferative Neoplasm: Two Stages Of One Disease With Poor Prognosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1342-1342 ◽  
Author(s):  
Yin Xu ◽  
Aine Yung ◽  
Brian Kwok ◽  
Karen Macdonell ◽  
Bashar Dabbas ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
De Novo ◽  
Myeloproliferative Neoplasm ◽  
Chronic Myelomonocytic Leukemia ◽  
Chromosome Abnormalities ◽  
Refractory Anemia ◽  
Jak2 Mutation ◽  
Cytogenetic Abnormalities ◽  
Two Stages ◽  
Myelomonocytic Leukemia

Abstract Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy characterized by persistent monocytosis with features of a myelodysplastic syndrome (MDS) and/or myeloproliferative neoplasm (MPN). While most cases present as de novo disease, a subset of CMML has been described in the literature to evolve from a preexisting MDS (MDS-CMML). CMML with preexisting MPN (MPN-CMML) has not been characterized to our knowledge. It is uncertain whether CMML patients with preexisting MDS or MPN have one or more disease processes and if such patients behave differently from patients who present with de novo CMML. In an attempt to address these questions, we compared the clinicopathologic features between groups of MDS-CMML, MPN-CMML, and de novo CMML in the present study. Methods 126 cases with newly diagnosed CMML were retrieved from our database over a 3-year period. 22 cases had preexisting MDS (n=15) or MPN (n=7). Prior diagnoses of MDS included refractory anemia (n=5), refractory anemia with ring sideroblasts (n=2), MDS with isolated 5q deletion (n=1), refractory cytopenia with multilineage dysplasia (n=6), and refractory anemia with excess blasts-1 (n=1). Prior diagnoses of MPN included essential thrombocythemia (n=1), primary myelofibrosis (n=3), and MPN NOS (n=3). Cytogenetic studies were performed in all cases. Other parameters obtained included age, gender, hemoglobin, white blood cell count, monocytes, platelets, bone marrow blasts and histology, and JAK2/MPL mutations. 22 consecutive cases of de novo CMML were included for comparative analysis. Results CMML with preexisting MDS or MPN comprised 17% of CMML (22/126 patients). Among these 22 patients, 15 were male and 7 female with a median age of 79 (range 61-86) years. Median age of the patients at CMML stage was similar to that of patients with de novo CMML (77 years; range 65-89). The median time between disease presentation as MDS or MPN and CMML was 22 months. Patients presented with marked monocytosis at the CMML stage (mean: 23% and 4564/uL) as compared to the stage of MDS (mean: 13% and 794/uL; p<0.001) or MPN (mean: 6.4% and 1216/uL; p<0.001); and the monocyte count was similar to that present in de novo CMML (mean: 24% and 4313/uL). Marrow blasts were significantly increased at the CMML stage as compared to the stage of MDS (mean: 5.3 vs. 1.6; p=0.017), MPN (mean: 5.1 vs. 1.9; p=0.048), or de novo CMML (5.2 vs. 1.9; p=0.009). There was no significant difference in average hemoglobin, platelet count or marrow cellularity between cases at the two disease stages or among the MDS-CMML and MPN-CMML subgroups. However, the marrows of MPN-CMML showed significantly increased diffuse reticulin fibrosis (p=0.002) and marked megakaryocytic hyperplasia (p=0.002) as compared to MDS-CMML. CMML with preexisting MDS or MPN is more frequently associated with cytogenetic abnormalities than de novo CMML (50% vs. 23%), although this difference did not reach statistical significance (p=0.116). 8 (36%) cases had chromosome abnormalities at the MDS or MPN stages; 7 (87%) of the 8 cases demonstrated persistent chromosome abnormalities at the CMML stage. In addition, 4 (18%) patients acquired chromosome abnormalities at the CMML stage. JAK2 mutation was seen in 1 (7%) of 15 cases of MDS-CMML and 4 (57%) of 7 cases of MPN-CMML. Notably, 2 cases of JAK2 positive MPN became JAK2 negative at the CMML stage; one of the patients had been previously treated with a JAK2 inhibitor. No MPL mutation was found in any case. Conclusions CMML with preexisting MDS or MPN is not uncommon. The majority of cases exhibit persistent chromosomal abnormalities from the preexisting MDS or MPN, supporting the notion of one disease with two stages of presentation. The findings of a higher frequency of cytogenetic abnormalities and occasional cytogenetic evolution may suggest that chromosome alteration is one of the mechanisms involved in triggering disease progression to CMML. JAK2 V617F was more frequent in MPN-CMML, which correlated with myelofibrosis and megakaryocytic hyperplasia. However, loss of JAK2 mutation can occur at CMML stage. Loss/inhibition of JAK2 activity may contribute to a change in disease course. Our study revealed that CMML with preexisting MDS or MPN is characterized by more advanced disease with increased marrow blasts and therefore may be associated with a poorer prognosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia

Haematologica ◽  
2019 ◽  
Vol 105 (3) ◽  
pp. 652-660 ◽  
Author(s):  
Janghee Woo ◽  
Dae Ro Choi ◽  
Barry E. Storer ◽  
Cecilia Yeung ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Chronic Myelomonocytic Leukemia ◽  
Term Survival ◽  
Long Term Survival ◽  
Molecular Profiles ◽  
Myelomonocytic Leukemia
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