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CHRONIC MYELOMONOCYTIC LEUKEMIA -REVIEW AND CLINICAL EXPERIENCE OF THEHEMATOLOGY DEPARTMENT UMHAT “ST.MARINA” VARNA.

Ilina Micheva1, Trifon Chervenkov2, Canka Ruseva3, Liana Gercheva1

1) Clinic of Hematology, Medical University, Varna, University Hospital “St.Marina“, Varna, Bulgaria2) Laboratory of Clinical Immunology, Medical University, Varna, UniversityHospital “St. Marina“, Varna, Bulgaria3) Laboratory of Medical Genetics, Medical University, Varna, University Hospital“St. Marina“, Varna, Bulgaria

Journal of IMAB - Annual Proceeding (Scientific Papers) 2016, vol. 22, issue 1Journal of IMABISSN: 1312-773Xhttp://www.journal-imab-bg.org

ABSTRACT:Chronic myelomonocytic leukemia (CMML) is a rare

de novo myeloid neoplasm that exhibits dysplastic and pro-liferative features at presentation. The diagnosis is problem-atic with several specific controversial issues.

Aim: To analyze the cases with CMML diagnosedin the Hematology clinic, UMHAT “St. Marina”, Varna withassessment of risk, prognosis and survival.

Materials and methods: The results from cytology,flow cytometry, histology, and genetics are re-estimated. Forthe risk stratification the CPSS was used. The statisticalanalysis is performed using SPSS 19.

Results: Fifteen patients with CMML, 12 men and3 women, with median age of 69,8 years were included inthe study. According to the leukocyte count 12 were my-eloproliferative (CMML/MP) and 3 myelodysplastic CMML(CMML/MD). The flow cytometry of peripheral blood andbone marrow was characterized by CD14, CD64, CD16 andCD56 expression. According to the histology of the bonemarrow 2 cases were described as MDS, 1 as MDS/MPN,the rest as MPN with fibrosis in two of the cases. The cy-togenetic risk was high in 5 patients and low in 10. Accord-ing to CPSS one patient was with low risk, 3 with interme-diate 1, 9 with intermediate 2 and 2 with high risk. Acutemyeloid leukemia transformation occurred in 9 patientswithin median period of 13.1 months. The median survivalafter transformation was 2,5 months. The median survivalin the whole group was 21.4 months.

Conclusion: CMML is an aggressive disease. Theprognosis of patients with CMML is poor, with low survivaland high risk of transformation. The therapeutic options arelimited.

Keywords: Chronic myelomonocytic leukemia, riskstratification, survival

INTRODUCTIONChronic myelomonocytic leukemia (CMML) is a

clonal hematologic malignancy characterized by absoluteperipheral monocytosis, ineffective hematopoiesis, and anincreased risk of transformation to acute myeloid leukemia.

The French-American-British (FAB) group introduced thefirst formal definition of CMML in 1978 where CMML wasone of the five subtypes of the myelodysplastic syndromes(MDSs). In addition to the initial classification, the FABgroup sub-classified CMML into myelodysplastic (MD)-CMML and myeloproliferative (MP)-CMML according tothe white blood cell (WBC) count (<13.0x109/L and>13.0x109/L, respectively) [1].

In 2001 the World Health Organization classi-fiedCMML within a novel category myelodysplastic syndromes/myeloproliferative neoplasm’s (MDS/ MPNs), containinghematologic malignancies with features overlapping MPNsand MDSs. CMML cases were further subdivided intoCMML-1 (<5% peripheral blasts and promonocytes, <10%bone marrow blasts and promonocytes) and CMML-2 (5%-19% peripheral and 10%-19% marrow blasts andpromonocytes) depending on the proportion of blasts in pe-ripheral blood (PB) and bone marrow (BM) [2].

Diagnosis is based on cytology, flow cytometry, his-tology, and genetics. The bone marrow aspirate demon-strates features of dysplasia but, unlike MDSs, this is notabsolutely required for the diagnosis of CMML [2]. An el-evated ratio of myeloid to erythroid cells is often identifiedin the bone marrow, myeloblasts and promonocyte in thebone marrow and peripheral blood must be less than 20%.The morphological criteria, defining 4 monocytic subtypesin the bone marrow, were validated by Guasguen et al [3].Trephine histology shows hypercellularity, granulocytic hy-perplasia, monocytosis, variable reticulin fibrosis, and mayalso detect other causes of monocytosis or additional pa-thology.

Flow cytometry can be applied to the diagnosis ofCMML. Monocytes in CMML exhibit aberrant antigen ex-pression, such as reduced HLA-DR and aberrant CD56 andCD2. A combination of monocytosis with 2 or moreimmunophenotypic aberrancies with 20% or more of mar-row monocytes showing moderate CD14 expression wasfound 100% specific for CMML [4]. CMML patients dem-onstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells which appeared a highly sensitive and spe-cific diagnostic marker that rapidly and accurately distin-

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guishes CMML from confounding diagnoses [5].Cytogenetic abnormalities are found in less than 30

% of patients with CMML with no specific aberration (+8,-Y, -7/7q-, 20q-, +21, der(3q)); trisomy 8 is the most fre-quent of these. Such et al. showed the strong prognostic im-pact of the cytogenetic findings and proposed a newCMML-specific cytogenetic risk classification [6].

Several CMML-specific prognostic tools have beendeveloped in conjunction with the IPSS in MDSs that at-tempt to look at risk stratification of a CMML specific co-hort. The most recent models are the CMML prognosticscoring system (CPSS) developed by the Spanish MDS co-operative group [7] and a model proposed by the GFMgroup (Groupe Francophone des Myélodysplasies) that isthe first CMML specific model that incorporates ASXL1mutations [8].

The aim of the study was to analyze the cases withCMML diagnosed in the Clinic of Hematology, UMHAT“St. Marina”, Varna with assessment of risk, prognosis andsurvival.

PATIENTS AND METHODSFifteen patients with CMML, diagnosed and treated

in the Clinic of Hematology, UMHAT “St. Marina”, Varnafor the period 2009 - 2015, were included in the study, 12men and 3 women, with median age of 69,8 years. Diag-nosis of CMML was made according to World Health Or-ganization (WHO) criteria [2]. The results from cytology,flow cytometry, histology, and genetics were re-estimated.CPSS was used for the risk stratification.

The statistical analysis was performed using SPSS 19.

RESULTSAccording to the leukocyte count 12 are CMML/MP

and 3 CMML/MD. Thirteen of the patients were anemic, 5with Hb lower than 70g/l. In nine of the cases thrombocy-topenia was detected, 11 were with splenomegaly.JAK2V617F mutation was detected only in one patient.Treatment was performed mainly with Hydroxyurea.Cytarabine or 5+2 (Cytarabine + Idarubicin) was used in 4cases, supportive care in two cases. Patient characteristicsare presented in Table 1.

The flow cytometry of peripheral blood (PB) andbone marrow (BM) was characteristic for the malignantclone with the expression of CD14, CD64, CD16 and aber-rant expression of CD56 (fig. 1).

Table. 1. Clinical characteristics of patients

No WBC x Hb x Pltx PB Mo Spleen109/l g/l 109/l % size/mm BM biopsy LDH Treatment

1 15.9 89 43 15 150 MPN 1032 Hydroxyurea

2 42.9 96 82 16 170 CML 1010 Hydroxyurea

3 32 131 211 10 splenectomy MPN/fibrosos 1725 Hydroxyurea

4 25.97 119 83 20 142 449 Hydroxyurea

5 15.4 54 53 15 122 1734 Hydroxyurea

6 81.9 76 95 28 168 667 Cytarabine

7 13.89 103 126 22 126 MDS 326 Hydroxyurea

8 11.5 127 148 50 120 MDS 333 Hydroxyurea

9 42.17 112 51 15 177 MPN 612Hydroxyurea,

Cytarabine

10 23.7 70 229 10 164 MPN 2029 Hydroxyurea, 5+2

11 11.06 105 368 13 160 MPN 307 Supportive care

12 11.59 69 17 37 173 MPN/MDS 283 Hydroxyurea

13 17.4 60 57 26 180 267 Supportive care

14 23.7 93 196 15 150 705 Hydroxyurea

15 15 61 39 34 230CMML/MPN,

1038Cytarabine

fibrosis Hydroxyurea

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Bone marrow biopsy was performed in 10 of the pa-tients. According to the histology 2 of the cases were re-ported as MDS, 1 as MDS/MPN, 4 as MPN, 1-CML. In twoof the cases fibrosis was described.

Cytogenetic abnormalities were detected in 40% ofthe patients (45XY -7, 45,X-Y, 47,XY+8, complex karyo-

Fig. 1. Flow cytometry of PB and BM. Monocytic population in PB and BM expressing CD14, CD64, CD16 andCD56.

type) (fig. 2a). The cytogenetic risk, determined accordingto the classification of the Spanish Group [6] was high in 5patients (3 with trisomy 8, one with monosomy 7, one withcomplex karyotype) and low in 10 (one –Y, the rest withnormal karyotype) (fig. 2b).

Fig. 2. Cytogenetic study. Distribution of the cytogenetic abnormalities (a). Cytogenetic risk groups according tothe Spanish cytogenetic classification (b).

According to CPSS one patient was with low risk, 3with intermediate 1, 9 with intermediate 2 and 3 with highrisk (fig. 3). Acute myeloid leukemia (AML) transformationoccurs in 60% of the patients within median period of 13,1months. 6 from 9 of the transforming cases are intermedi-ate 2 and high risk. One patient with low risk transformedinto AML after 47 months (fig. 4a). AML transformationoccurred in all cases with trisomy 8 (fig. 4b).

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Fig. 4. Transformation into AML according to CPSS (a) and cytogenetic abnormalities (b).

The mean survival in the whole group was 21,5 months (fig. 5a). The mean survival after transformation was 2,5months (fig. 5b).

Fig. 5. The mean survival in the whole group (a) is 21,5 months. The mean survival after transformation (b) is 2,5months.

DISCUSSIONCMML is a rare de novo myeloid neoplasm. In our

clinic, for the six years period CMML was confirmed onlyin fifteen patients. The diagnosis of CMML is usually prob-lematic because of the heterogeneous morphological vari-

ables, difficult distinguish of reactive vs. clonal monocyto-sis, the overlapping morphology and phenotype of CMMLand AML, especially in transforming CMML. All othercauses of monocytosis, such as aggressive solid tumors, in-fectious and autoimmune disorders, must be excluded. Other

Fig. 3. Distribution of the patients according toCPSS.

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Address for correspondence:Ilina Micheva, MD, PhD, Associate ProfessorDepartment Hematology, Medical University of Varna,1, Hristo Smirnenski str., 9010 Varna, BulgariaTel.: +359/52 978 855 (work)E-mail: IlianaMicheva@mu-varna.bg (work)ilinamicheva@gmail.com (personal)

1. Bennett JM, Catovsky D, DanielMT, Flandrin G, Galton DA, GralnickHR, et al. Proposals for the Classifica-tion of the Acute Leukaemias French-American-British (FAB) Co-operativeGroup. Br J Haematol. 1976 Aug;33(4):451-458. [PubMed] [CrossRef]

2. Vardiman JW, Thiele J, Arber DA,Brunning RD, Borowitz MJ, Porwit A,et al. The 2008 revision of the WorldHealth Organization (WHO) classifica-tion of myeloid neoplasms and acuteleukemia: rationale and importantchanges. Blood. 2009 Jul;114(5):937-951. [PubMed] [CrossRef]

3. Goasguen JE, Bennett JM, BainBJ, Vallespi T, Brunning R, Mufti GJ.Morphological evaluation of monocytesand their precursor. Haematologica.2009 Jul;94(7):994–997. [PubMed][CrossRef]

4. Xu Y, McKenna RW, KarandikarNJ, Pildain AJ, Kroft SH. Flowcytometric analysis of monocytes as atool for distinguishing chronic myelo-monocytic leukemia from reactive mo-

nocytosis. Am J Clin Pathol. 2005 Nov;124(5):799-806. [PubMed] [CrossRef]

5. Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, ItzyksonR, Bencheikh L, et al. Francophone My-elodysplasia Group. Characteristicrepartition of monocyte subsets as a di-agnostic signature of chronic myelo-monocytic leukemia. Blood. 2015 Jun4;125(23):3618-26. [PubMed][CrossRef]

6. Such E, Cervera J, Costa D, SoléF, Vallespí T, Luño E, et al. Cytogeneticrisk stratification in chronic myelo-monocytic leukemia. Haematologica.2011 Mar;96(3):375-83. [PubMed][CrossRef]

7. Such E, Germing U, Malcovati L,Cervera J, Kuendgen A, Della PortaMG, et al. Development and validationof a prognostic scoring system for pa-tients with chronic myelomonocyticleukemia. Blood. 2013 Apr 11;121(15):3005-15. [PubMed] [CrossRef]

8. Itzykson R, Kosmider O,Renneville A, Gelsi-Boyer V,

myeloid malignancies should be considered, with specialattention on chronic myeloid leukemia, CMML with eosi-nophilia and rearrangements of PDGFRA or PDGFRB. Di-agnosis CMML must be based on the precise interpretationof morphological, phenotypic and genetic features.

The results from our analysis confirm the aggressive-ness of the disease. The prognosis of patients with CMMLis poor, with a mean survival of only 21,4 months and highleukemic transformation rates of 60% with mean survivalafter transformation of 2,5 months. The prognostic valueof trisomy 8 can be suggested, since it is the most frequent

abnormality in CMML related to high cytogenetic risk, poorsurvival and high transformation rates [6]. Recently theprognostic impact of several mutations in CMML was stud-ied and the independent prognostic relevance of ASXL1gene mutations confirmed [8]. The combination of clinicaland molecular information may be required to improve theaccuracy of CMML prognostication.

The therapeutic options are limited. The results fromthe clinical trials with azacytidin are promising [9]. Severalnovel treatment approaches using JAK2 to MEK inhibitionare now in clinical studies [10, 11].

REFERENCES:Meggendorfer M, Morabito M, et al.Prognostic score including gene muta-tions in chronic myelomonocyticleukemia. J Clin Oncol. 2013 Jul 1;31(19):2428-36. [PubMed] [CrossRef]

9. Itzykson R, Kosmider O, CluzeauT, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 muta-tions on response rate to azacitidine inmyelodysplastic syndromes and lowblast count acute myeloid leukemias.Leukemia. 2011 Jul;25(7):1147-1152.[PubMed] [CrossRef]

10. Padron E, Painter JS, KunigalS, Mailloux AW, McGraw K, McDanielJM, et al. GM-CSF-dependent pSTAT5sensitivity is a feature with therapeuticpotential in chronic myelomonocyticleukemia. Blood. 2013 Jun;121(25):5068-5077. [PubMed] [CrossRef]

11. Chang T, Krisman K, TheobaldEH, Xu J, Akutagawa J, Lauchle JO, etal. Sustained MEK inhibition abrogatesmyeloproliferative disease in Nf1 mu-tant mice. J Clin Invest. 2013 Jan;123(1):335-339. [PubMed] [CrossRef]

Please cite this article as: Micheva I, Chervenkov T, Ruseva C, Gercheva L. Chronic myelomonocytic leukemia - reviewand clinical experience of the Hematology Department UMHAT “St. Marina” Varna. J of IMAB. 2016 Jan-Mar;22(1):1091-1095. DOI: http://dx.doi.org/10.5272/jimab.2016221.1091

Received: 15/12/2015; Published online: 31/03/2016