Diagnostic Approach To Oligomonocytic Chronic Myelomonocytic Leukemia

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S112-S112
Author(s):  
J Muldoon ◽  
M Czader
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Molecular Genetic ◽  
Chronic Myelomonocytic Leukemia ◽  
Differential Count ◽  
Normocytic Anemia ◽  
Molecular Testing ◽  
Monocyte Count ◽  
Diagnostic Threshold ◽  
Myelomonocytic Leukemia

Abstract Casestudy: Pathologic diagnosis of chronic myelomonocytic leukemia (CMML) is typically straightforward with the majority of patients presenting with persistent monocytosis (>1x109/L, >=10%) and bone marrow dysplasia. The diagnosis may be challenging in patients with unusual features such as lack pf peripheral blood monocytosis and non-diagnostic bone marrow morphology. In this abstract, we present a 67-year-old female with a 5-year history of anemia of unclear etiology. At the time of initial presentation, the laboratory work-up of normocytic anemia was non- contributory, the bone marrow was reported as normocellular with maturing trilineage hematopoiesis and no significant dysplasia. Over the course of the disease, the peripheral blood monocyte count fluctuated from 11% to 18% with absolute monocyte count ranging from 0.4 to 0.7x109/L. The most recent bone marrow was markedly hypercellular with increased trilineage hematopoiesis with left shift, dysgranulopoiesis and dysmegakaryopoiesis. Blasts (including promonocytes) constituted 10% of the differential count and were immunophenotypically abnormal with uniform expression of CD117, dim to negative CD13, and partial CD15. Monocytes were elevated at 12% and were strongly positive for CD64 and partially for CD14. They were negative for CD16 consistent with classical monocytes, and showed partial loss of CD13. The karyotype was normal. Molecular testing revealed TET2, RELN and SRSF2 mutations at high allelic frequencies. This case illustrates a value of flow cytometric immunophenotyping and molecular genetic studies in diagnosing challenging cases of CMML. While the patient’s absolute monocyte count remained below the diagnostic threshold of 1x109/L throughout the course of the disease, peripheral blood and bone marrow monocytes showed skewed classical immunophenotype, immunophenotypic abnormalities of myeloid series and high allelic frequency mutations. These findings should raise a differential diagnosis of oligomonocytic CMML, even when morphologic abnormalities and monocyte count threshold are not diagnostic.

Prognostic Factors in Chronic Myelomonocytic Leukemia: A Retrospective Analysis of 41 Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4279-4279
Author(s):  
Bobin Chen ◽  
Xiaoping Xu ◽  
Yan Ma ◽  
Xiaoqin Wang ◽  
Guowei Lin
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Prognostic Factor ◽  
Survival Time ◽  
Neutrophil Count ◽  
Peripheral Blood ◽  
Lymphocyte Count ◽  
Chronic Myelomonocytic Leukemia ◽  
Monocyte Count ◽  
Myelomonocytic Leukemia

Abstract Purpose To investigate clinical characteristic and prognostic factors for chronic myelomonocytic leukemia (CMML). Methods Retrospective cohort study was used in the study. Information for CMML patients was collected, including symptoms, CBC, results of bone marrow aspire and pathology, cytogenetic. All patients were followed up regularly. Analysis of survival and prognostic factors was performed by Kaplan-Merier cure, log rank test and Cox regression model. Results Forty-one cases were diagnosed as CMML, including 27 male and 14 female patients. Median WBC was 13.7× 109/L. Five patients had leukocytopenia(1.92- 3.46×109/L). Median monocyte count in the peripheral blood was 2.13×109/L, but lower monocyte count (<1×109/L) occurred in 8 patients. All patients presented with bone marrow dysplasia, and most showed hyperplasia, except 3 cases. Abnormal chromosome was detected in 34% cases. Median survival time was 20 months, and there were no difference of survival duration between CMML-1 and CMML-2. Univariate analysis showed that age (> 60 yrs), neutrophil count (<2.0′109/L), lymphocyte count (<1.0′109/L), mature monocyte count (35′109/L) and anemia (Hb< 60g/L) were associated with poor prognosis for CMML. There was no statistical significance in LDH, gender, abnormal chromosome for survival time. Only lymphocyte count and neutrophil count in peripheral blood were independent prognostic factor for CMML after Multivariate analysis. Conclusion CMML mainly occur in elderly patients. Although most patients have leukocytosis and monocytosis at diagnosis, few case shows leucopenia and monocytopenia. Median survival time for CMML is 20 months. Age, neutrophil, lymphocyte and monocyte count, severe anemia are related to CMML prognosis. Neutropenia and lymphopenia in peripheral blood are independent prognostic factor for CMML.

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.

Clinical Experience with Azacitidine In Chronic Myelomonocytic Leukemia (CMML) in Spain

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5040-5040
Author(s):  
Pablo Gonzalez Navarro ◽  
Regina García Delgado ◽  
Alicia Bailén Garcia ◽  
Juan Antonio Múñoz Múñoz
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Trials ◽  
Clinical Experience ◽  
Peripheral Blood ◽  
Progression Free Survival ◽  
Complete Response ◽  
Chronic Myelomonocytic Leukemia ◽  
Free Survival ◽  
Myelomonocytic Leukemia

Abstract Abstract 5040 Clinical Experience with Azacitidine In Chronic myelomonocytic leukemia (CMML) in Spain Pablo González Navarro 1*, Regina García Delgado 2*, Alicia Bailén Garcia 3*, Juan Antonio Muñoz Muñoz 4* 1MD, PhD. Hospital San Cecilio, 18014 Granada, Spain, Teléfono: 958023600 [email protected]; 2Hospital Virgen De La Victoria, Málaga, Spain; 3Hospital Carlos Haya, Málaga, Spain; 4MD, PhD. Hospital Universitario Puerta del Mar, Cádiz, Spain Introduction: Chronic myelomonocytic leukemia (CMML) is a clonal disorder of hematopoietic stem cells often occurring in elderly patients. In the new WHO classification, CMML has been reclassified as a myelodysplastic/myeloproliferative disease. CMML has been subdivided in two subclasses: CMML-1:<5% blasts in peripheral blood and 5–9% blasts in bone marrow, and CMML-2: <10% blasts in peripheral blood and 10–19% blasts in bone marrow (Greco et al. Mediterr J Hematol Infect Dis.2011). Azacitidine (AZA) is an hypomethylating agent approved in Europe for the treatment of myelodysplastic syndromes, with an intermediate to high risk of progressing to AML or death; chronic myelomonocytic leukemia (CMML) and AML that has developed from a myelodysplastic syndrome (prescribing information EMEA 2011). Until its approval in May 2009, AZA was used in Spain under compassionate use in clinical trials. AZA produce a direct decrease of DNA methyltransferase activity, reverting aberrant DNA methylation and increasing the expression of silenced genes, leading to celular differentiation and/or apoptosis (Greco et al. Mediterr J Hematol Infect Dis. 2011). Materials and Methods: We report the results of a retrospective, longitudinal, multicenter Spanish study of 27 patients to assess the effectiveness of AZA to treat CMML. We present results of: Response, Overall Response, Overall Survival and Progression Free Survival. Results: Eighteen of the patients (69.23%) had Chronic Myelomonocytic Leukemia (CMML) type 1 and nine (30.77%) CMML type 2. Median age at diagnosis was 69 years. Male/female ratio: 19/8. ECOG performance status score 1–2 was 78%, twenty patients (74%) received an initial dose of 75 mg/m2 of AZA, whereas three patients (11%) received 50mg/ m2. The mean number of cycles received was 8.32, 95%IC (5.91; 10.73). Overall response to treatment was 53% (CR+PR+HI+mCR): 14.81% complete response, 7.4% partial response, 3,7% Medular complete response and 29,62% Hematological Improvement. In addition, 18,51% had stable disease. Thirty-six percent of patients were alive at the end of treatment with AZA. Median Overall Survival and Progression Free Survival were 17.47 months (95%CI 9.33, upper limit not reached) and 10.97 (95%IC 3.97, 17.47) respectively (Figure 1, 2). Conclusion: Our results show that AZA is an active drug in the treatment of patients with CMML, with similar response rates in the published literature. More data from this study and further investigation with different clinical trials are needed to confirm these outcomes as well as safety and effectiveness of this treatment. Disclosures: García Delgado: Celgene and Novartis: Speakers Bureau.

scholarly journals Deubiquitnase BAP1 Downregulation in Myeloid Malignances: A New Pathogenic Mechanism, Dominant in Chronic Myelomonocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5594-5594
Author(s):  
Ana Maria Hurtado ◽  
Eva Caparrós ◽  
Jose Miguel Torregrosa ◽  
Ginés Luengo ◽  
Mara Toderici ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Common Mechanism ◽  
Regulation Of Transcription ◽  
Brca1 Protein ◽  
Protein Levels ◽  
Increased Risk ◽  
Myelomonocytic Leukemia

Abstract Background: De-ubiquitinating enzyme BAP1, a fundamental deubiquitinase in the epigenetic regulation of transcription factors and functionally related to ASXL1, is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. In a recent murine study, absolute BAP1 depletion generated specimens with similar characteristics to myelodysplastic / myeloproliferative syndromes in humans (ineffective hematopoiesis and myeloproliferation), mainly to chronic myelomonocytic leukemia (CMML) (Dey, et al. Science 2012). Aim: The aim of this study was to quantify BAP1 gene expression in patients diagnosed with a variety of myeloid neoplasms, and compared it with healthy donors. We furthermore explored the possible association of BAP1 low expression level and the presence of ASXL1 mutations or BRCA1 protein levels. In addition, a regression analysis to determine the possible correlation of peripheral blood and bone marrow expression levels was performed. Methods: We included patients diagnosed between 2008-2014 of CMML, myelodysplastic sydrome (MDS) chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), of whom bone marrow DNA and RNA were available at diagnosis. As controls, 6 healthy bone marrow donors were used. BAP1 and BRCA1 expressions levels were quantified by RT-qPCR, using the same healthy bone marrow donor sample as an inter-assay normalizing- calibrator. The study of somatic ASXL1 mutations was carried out by the Sanger method. For statistical studies, the T-Student, Pearson correlation and/or U Mann-Whitney test, were used when needed. For survival analysis COX regression and the ROC curves were used. A two-side P<0.05 was used as statistical significance threshold. Results: Samples of 116 patients were included in the study: CMML=26; MDS=15; AML=50; CML=25 and 6 controls. This study shows that levels of BAP1 expressions are decreased when compared to controls along the spectrum of myeloid diseases. In the comparison among entities, CMML shows the lowest values (percentage respect to the calibrator), significantly lower than the other groups, except for CML patients: CMML vs MDS, p=0.001; CMML vs AML, p<0.001; CMML vs Controls, p<0.001; LMMC vs CML, p=0.346. No differences were found between CMML patients with dysplastic and myeloproliferative variant, WHO types I and II or according to the presence of ASXL1 mutations (33% CMML patients were mutated). Of potential clinical interest, BAP1 expression in bone marrow and peripheral blood showed a direct and significant correlation ( r=0.884, p= 0.001). BRCA1 expression were decreased uniformly through the different myeloid diseases, suggesting that the heterogeneous BAP1 expression could be responsible for different BRCA1 protein levels by posttranslational regulation. Conclusion:In summary; this study shows that BAP1 decreased expression is a common mechanism among the myeloid malignances, being CMML mainly affected. This mechanism is independent of the presence of ASXL1 mutations, and it could constitute a new therapeutic target in chronic myelomonocytic leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Diagnostic Utility of Flow Cytometric Immunophenotyping in Chronic Myelomonocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5526-5526
Author(s):  
Leonor Arenillas ◽  
Ivonne Parraga ◽  
Lourdes Florensa ◽  
Sara Montesdeoca Romero ◽  
Anna Puiggros ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chronic Myelomonocytic Leukemia ◽  
Nonspecific Esterase ◽  
Age Related ◽  
Hla Dr ◽  
Myelomonocytic Leukemia ◽  
Classical Monocytes

Abstract INTRODUCTION The diagnosis of chronic myelomonocytic leukemia (CMML) according to WHO 2017 requires the presence of ≥1x109/L and ≥10% of monocytes in peripheral blood (PB). Establish an accurate diagnostic is difficult since many clinical situations present persistent monocytosis. The presence of dysplasia, mainly dysgranulopoiesis, is frequent but not always present in CMML. Cytogenetic aberrations are infrequent in this disease (20-25% of cases). Although 85-90% of CMML patients present at least one mutation in TET2, SRSF2 or ASXL1 genes, the use of NGS panels is not widespread. Furthermore, mutations in these genes are among the most frequently observed in age-related clonal hematopoiesis. Therefore, complementary techniques are required to support the diagnosis of this entity. The study of the peripheral monocyte subsets by flow cytometry (FC) has gained special interest due to a high sensitivity and specificity for the diagnosis of CMML (S = 90.6%, E = 95.1%, Selimoglu-Buet et al., Blood, 2015). An increase in the fraction of classical monocytes (Mo1) to >94% of total monocytes is an event frequently observed in CMML. There are no specific bone marrow (BM) FC panels for the diagnosis of CMML and very few have been validated for the diagnosis of MDS. "Ogata score", the only multicenter validated score in MDS, has not been applied in CMML. The aim of our study was to evaluate the usefulness of FC in PB and BM for the diagnosis of CMML. METHODS Twenty-two CMML were prospectively studied from 02/2016 to 04/2018. Patients' characteristics are summarized in Table 1. Diagnostic procedure consisted of morphological, cytochemical (Perls, myeloperoxidase, nonspecific esterase), cytogenetic and FC studies in BM, and morphological and FC studies in PB. "Ogata Score" was applied in BM samples (Table 2). Aberrant coexpression of CD2, CD7 and CD56 in BM monocytes was assessed. Immunophenotypic maturation profile of the monocytic elements in BM distinguishes: promonocytes (CD34-/CD117-/CD64++/CD14- or dim/CD45+/HLA-DR+++), mature monocytes (CD34-/CD117-/CD64++/CD14++/CD45++/HLA-DR++) and mature monocytes in terminal stage (CD300e+). In PB, the monocytes FC subsets (Mo1, Mo2 and Mo3) were studied, as well as the aberrant coexpression of CD2, CD7 and CD56 (Table 3). RESULTSThe presence of ≥2 aberrations in Ogata Score predicted properly the diagnosis of CMML in all patients analyzed (100% sensitivity). Due to the study design, we could not obtain results about specificity.An increase in Mo1 (classical monocytes) > 94% was detected in 18/20 patients (Table 3). This method predicted the diagnosis of CMML with a sensitivity of 91%, a result almost identical to the original study (Selimoglu-Buet et al., Blood, 2015).A good positive correlation was established between the percentage of BM promonocytes detected by morphology and by FC (Rho Spearman 0.61, P = 0.003).A negative correlation was found between the percentage of promonocytes by FC in MO and the expression of CD56 (Rho Spearman -0.612, P = 0.002). Similarly, CD56+ CMML presented a percentage of promonocytes by FC significantly lower than the CD56- CMML group (median: 24.5% (14-40) vs. 41% (23-71), P = 0.005). The expression of CD56 seems to be related to a more mature immunophenotypic profile of the monocytic population. On the other hand, the correlation between the percentage of CD56+ monocytes in BM and PB was almost perfect (Rho Spearman 0.928, P <0.001). CONCLUSION Our findings support the usefulness of flow cytometry in bone marrow and peripheral blood for the diagnosis of CMML. Disclosures No relevant conflicts of interest to declare.

Ruxolitinib Treatment Outcome In a Patient With Secondary Chronic Myelomonocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5230-5230
Author(s):  
Dina Istasi ◽  
Sylvain Chantepie ◽  
Edouard Cornet ◽  
Veronique Salaun ◽  
Michele Malet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Conflicts Of Interest ◽  
White Blood Cells ◽  
Chronic Myelomonocytic Leukemia ◽  
Rapid Decline ◽  
Published Data ◽  
Rapid Progression ◽  
Monocyte Count ◽  
Myelomonocytic Leukemia

Abstract Chronic myelomonocytic leukemia ( CMML) is a de novo myelodysplastic/myeloproliferative disease with an unfavorable prognosis. Secondary CMML cases are rare and sporadically reported. Published data have shown that development of monocytosis in patients during the course of PMF or MDS is associated with poor prognosis (M.A. Elliott, Leukemia Research, 31 (2007). Essential thrombocythemia (ET) is an indolent myeloproliferative disorder characterized by long symptom-free intervals. Uncommonly, few patients with ET may develop bone marrow (BM) fibrosis which to be distinguished from cases with early PMF accompanied by thrombocytosis. Progression to acute leukemia or myelodysplastic syndrome (MDS) occurs in < 5% of patients and is likely related to previous cytotoxic therapy. We report here a rare case of a patient with ET who developed BM fibrosis and rapidly progressed to a secondary myelomonocytic leukemia. A 54 years old  female patient, diagnosed with ET in 2003,  as she presented a persistent isolated high platelet count of 700 G/L, with normal white blood cells (WBCs): 8 G/L, hemoglobin (hb): 15 g/dl,  monocytes: 0.5 G/L and no splenomegaly.  She was treated with Anagrelide 1.5 -2 mg daily due to intolerance to hydroxyurea. No major event has been declared during the last 10 years and a median platelet count of 450 G/L. In January 2013, a routine check-up showed leukocytosis (WBCs: 25 G/L), slight anemia (hb: 11.6 g/dl), with relative thrombocytopenia, 266 G/L, monocytosis:  2 G/L with 3% circulating blasts and a palpable spleen.  The bone marrow biopsy revealed BM fibrosis grade III and 7% of blasts.  Progression to secondary myelofibrosis was declared and treatment with hydroxyurea was initiated to control peripheral blood counts prior to transplantation.  Treatment with ruxolitinib started in May, at a dose of 20 mg bid due to failure of blood count reduction with hydroyurea. A rapid decline in WBCs count to 3 G/L was achieved but with sustained median monocytosis of 1.4 G/L.  The patient developed marked anemia (7.5 g/dl) as well as thrombocytopenia (13 G/L) and ruxolitinib was interrupted by the end of June 2013. Within 15 days, the patient showed rapid progression, her WBCs count attained 105 G/L, anemia and thrombocytopenia persisted. The absolute monocyte count increased up to 66 G/L with marked dysplastic features and morphological shifting to aspects compatible with overt secondary myelomonocytic leukemia in both blood and bone marrow smears, 3% circulating and 8% bone marrow blastes  (WHO criteria for CMML diagnosis). Molecular studies showed the presence of JAK2 V617F allele burden at 66% and absence of BCR/ABL transcript. Only two mitosis, with an unidentified additional marker were obtained on chromosome analysis. Unfortunately, the patient died 2 weeks later. This observation shows the adverse prognostic development of monocytosis in ET which is similar to that published in PMF in 10 patients (Leonardo Boiocchi, Modern pathology, 2013), thus requiring particular attention in the treatment of these patients. As chromosomal analysis was unavailable at diagnosis, we weren’t able to prove the presence of clonal heterogeneity, a concept developed recently to explain the mechanism of development of two different diseases. Ruxolitinib is an inhibitor of JAK1 and JAK2 resulting in a dramatic decrease in cytokines and growth factors that are important for hematopoiesis and growth function.  Of note, in this case, ruxolitinib which was administrated for the treatment of 2ry myelofibrosis, inhibited as well the increase in monocytosis and controlled the progression of CMML evidenced by the remarkable increase in dysplastic monocytes after its interruption. To our knowledge a clinical trial is actually on going to assess if its administration can improve the outcome of patients with CMML and the optimal dose to be administrated. Disclosures: No relevant conflicts of interest to declare.

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 Myeloproliferative/Myelodysplastic Neoplasms Presenting All Diagnostic Criteria of Chronic Myelomonocytic Leukemia but with Absolute Peripheral Blood Monocytosis 0.5-1× 109/L Should be Classified As CMML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Sandra Castaño-Díez ◽  
Monica Lopez-Guerra ◽  
Daniel Esteban ◽  
Francesca Guijarro ◽  
Alex Bataller Torralba ◽  
...  
Keyword(s):  
Overall Survival ◽  
Diagnostic Criteria ◽  
Median Time ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Chronic Myelomonocytic Leukemia ◽  
Transformation Rate ◽  
Monocyte Count ◽  
Myelomonocytic Leukemia

Introduction Current diagnosis of chronic myelomonocytic leukemia (CMML) requires peripheral blood (pb) monocytosis ≥1×109/L. Accordingly, cases which fulfill other diagnostic criteria of CMML but not reaching the required pb monocytosis threshold would be classified as MDS or unclassifiable MPN/MDS according to WHO classification (Arber et al, Blood 2016) Recently, a group of authors (Geyer et al, Modern Pathology 2017) proposed the term oligomonocytic CMML (OM-CMML) for these patients with blood monocytes ≥10% of the WBCs, but only accounting for 0.5-1 × 109/L as an absolute value and fulfilling all other criteria of CMML and suggested that they should be managed as other patients with classical CMML despite lacking pb monocytosis ≥1×109/L. To address clinical value of this proposed newly entity, we analyzed the incidence, clinico-biological characteristics and outcome of a series of patients fulfilling the proposed criteria for OM-CMML from a single center with a long follow-up. Methods We included patients diagnosed between 1997 and 2019 who gathered the proposed criteria for OM-CMML (Geyer et al, Modern Pathology 2017). These patients were compared with a cohort of patients from the same study period diagnosed with classical CMML. Statistical analyses were performed using Rv3.1 and SPSS v20. Next generation targeted sequencing (NGS) was performed with Ion Ampliseq AML Research and Oncomine Myeloid Research Assay panel Results Overall, we included in the study 213 patients, including 35 (16%) who fulfilled the proposed criteria for OM-CMML. Median follow-up of alive patients was 42 months. In the OM-CMML group, 71% were males, median age was 74 years (51-92). OM-CMML patients presented at diagnosis with a lower leucocyte count (WBC) (median value, 4.6(2.2-7.5)x109/L vs 10(3-119)x109/L, p&lt;0.001), neutrophil count (2(0.7-5.7)x109/Lvs5.1(0.5-57)x109/L; p&lt;0.001), and monocyte count, both in terms of absolute figures (0.75(0.5-0.9)x109/Lvs1.9(0.6-33)x109/L;p&lt;0.001) and relative percentage (15% (10-30) vs 20% (1.8-51);p&lt;0.001). All OM-CMML patients corresponded to FAB non-leucocytosis, CMML-Myelodysplastic type (CMML-MD), whereas 62% of c-CMML patients were diagnosed as a CMML-MD subtype p&lt;0.001). No other different clinical characteristic were observed (Table 1). Cytogenetic analysis showed an abnormal karyotype in 23% of OM-CMML patients. NGS at diagnosis was available in 26 pt, without observing significant differences regarding gene mutation frequency. At diagnosis 17% of OM-CMML patients were transfusion-dependent and the distribution according to CPSS categories was: low (48%), int-1 (23%), int-2 (26%) and high (3%) risk, without difference with c-CMML (Table 1). Progression to a c-CMML was observed in 67% (24) of OM-CMML pts with a median time to progression of 7 months (m) (1-149 m). We did not observe differences in transformation rate to AML (AML-t; 10 (28.5%) vs 44 (24.7%) among OM-CMML and c-CMML group, p=0.6) or cumulative incidence (CI) of AML-t between OM-CMML and c-CMML patients (50m-CI AML-t: 35%±7 vs 21±12, p=0.3) (Fig 1). Eight out of the 10 pt (80%) who developed an AML previously presented a c-CMML phase. Median time to AML-t was longer in OM-CMML pt: 60m (3-219) vs 13.7m (0.8-124), p=0.011. The percentage of patients who received treatment in OM-CMML cohort was similar to that of c-CMML pts: (28% vs 21%, p=0.37, respectively). Moreover, time to treatment requirement was similar in both patient cohorts (15m (0.9-211m) vs 10m (0.1-112), p=0.5, respectively). Finally, overall survival of OM-CMML did not differ from that of c-CMML (5-year Overall Survival: 45±16% vs 30±7%; p=0.31, Figure 2). Conclusion: Clinical features and evolution of patients with OM-CMML were comparable to that of patients with c-CMML, supporting similar classification and management criteria. Acknowledgement: PI16/01027 (JE; MDB), PI19/01476 (JE; MDB) Disclosures No relevant conflicts of interest to declare.

Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood.

1997 ◽  
Vol 15 (2) ◽  
pp. 566-573 ◽  
Author(s):  
F Locatelli ◽  
C Niemeyer ◽  
E Angelucci ◽  
C Bender-Götze ◽  
S Burdach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Myelodysplastic Syndrome ◽  
Marrow Transplantation ◽  
Working Group ◽  
Allogeneic Bone Marrow Transplantation ◽  
Chronic Myelomonocytic Leukemia ◽  
Allogeneic Bone ◽  
European Working ◽  
Myelomonocytic Leukemia

PURPOSE To evaluate the role of allogeneic bone marrow transplantation (BMT) in children with chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS Forty-three children with CMML given BMT and reported to the European Working Group on Myelodysplastic Syndrome in Childhood (EWOG-MDS) data base were evaluated. In 25 cases, the donor was a human leukocyte antigen (HLA)-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 a matched unrelated donor (MUD). Conditioning regimens consisted of total-body irradiation (TBI) and chemotherapy in 22 patients, whereas busulfan (Bu) with other cytotoxic drugs was used in the remaining patients. RESULTS Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. There was a significant difference in the incidences of chronic graft-versus-host disease (GVHD) between children transplanted from compatible/one-antigen-mismatched relatives and from alternative donors (23% and 87%, respectively; P < .005). Probabilities of transplant-related mortality for children given BMT from HLA-identical/one-antigen-disparate relatives or from MUD/ mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%, whereas the 5-year event-free survival (EFS) rate was 31%. The EFS rate for children given BMT from an HLA-identical sibling or one-antigen-disparate relative was 38%. In this latter group, patients who received Bu had a better EFS compared with those given TBI (62% v 11%, P < .01). CONCLUSION Children with CMML and an HLA-compatible relative should be transplanted as early as possible. Improvement of donor selection, GVHD prophylaxis, and supportive care are needed to ameliorate results of BMT from alternative donors.

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