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April 2014 - Test your knowledge in the quiz!

What causes the observed leukocytosis? Acute bacterial infection
Chronic myelomonocytic leukaemia (CMML)
Post-infectious monocytosis
Atypical chronic myeloid leukaemia (aCML)

Online version of this month`s case:


Chronic myelomonocytic leukaemia (CMML)

Scattergrams and microscopy

Patient history: a 68-year old woman complains about fatigue and repeated bruising.

WDF scattergram
WNR scattergram
RET scattergram
Bone marrow smear
Peripheral blood smear
Peripheral blood smear



The answer can be inferred from…

  • Monocytosis: (MONO# > 1 x 109 /L)                                            
  • No sign of reactive neutrophils: (normal NEUT-SFL)
  • No sign of reactive lymphocytes: (low HFLC counts, absence of  ‘Abnormal Lympho?’ flag)
  • Anaemia: (low HGB and HCT)
  • Low neutrophil to monocyte ratio:  (NEUT# / Mono# ratio < 5)


Case history

A 68-year old woman visited her physician complaining about fatigue, weight loss and repeated bruising. A complete blood count with 5-part differential was ordered to further investigate the woman’s condition.

Case results

The main cause of the observed leukocytosis was a monocytosis (4780 /µL), which may be post-infectious or caused by a myelodysplastic condition with myeloproliferative features such as chronic myelomonocytic leukaemia (CMML), juvenile myelomonocytic leukaemia (JMML) or atypical chronic myeloid leukaemia (aCML). Alternatively, the observed monocytosis may have been caused by a falsely-high monocyte count due to the presence of blasts (‘Blasts?’ flag). Neutrophil activation was normal (NEUT-SFL not increased) as was lymphocyte activation (low HFLC counts and no ‘Atypical Lympho?’ flag) making a reactive monocytosis unlikely. In addition, the low number of immature granulocytes in the peripheral blood (IG, 1%) also made a reactive monocytosis unlikely and the low NEUT-SSC value (127.8 channels, compared to 134-154 in healthy individuals) could indicate the presence of dysplastic neutrophils instead. Together, the extreme monocytosis (4780 /µL), dysplasia signs (low NEUT-SSC) and the low neutrophil to monocyte ratio (< 5) pointed to a CMML. The peripheral blood smear showed the presence of many mature monocytes with some atypical monocytes (promonocytes), and the bone marrow contained approximately 10% blasts (including monoblasts and promonocytes), which confirmed the chronic state of the condition (and excluded AML-M5, which has > 20% blasts).

The combination of low NEUT-SSC and normal NEUT-SFL values, the low IG count and the relative proportion of neutrophils to monocytes could be used to rapidly provide a probable diagnosis. However, analysis of bone marrow biopsy material was required to confirm the final diagnosis of CMML. Flow cytometry analysis of bone marrow material revealed the presence of CD33- and CD13-positive cells and genetic analyses uncovered the presence of mutations in the ASXL1 and SRSF2 genes, suggesting an advanced stage of the disease. Absence of the Philadelphia chromosome and the BCL-ABL1 fusion gene, which are not present in CMML, was confirmed by fluorescence in situ hybridization (FISH).


 The following answers are incorrect for the described reasons


Acute bacterial infection

Looking at the basic differential count alone does not permit identification of the cause of the absolute neutrophilia. It is important to differentiate between reactive causes such as acute bacterial infections and non-reactive causes such as myeloproliferative diseases, as the urgency and nature of the required intervention would be vastly different. In the presented case, further evaluation is possible by considering the parameter NEUT-SFL, which is a measure of neutrophil activation. A normal NEUT-SFL value indicates that the neutrophils are not activated and this doesn’t fit with a reactive cause of neutrophilia. Therefore an acute bacterial infection can be ruled out here.

Post-infectious monocytosis

Similar to neutrophilia, the observed monocytosis may also be a response to either an infective / inflammatory condition or an underlying haematological malignancy. Reactive monocytosis is often associated with viral infections, or with chronic infections or inflammation. In such cases it would be associated with a significant inflammatory response and would have triggered a concomitant immune reaction. However, reactive signs such as a lymphocytosis, an increase of antibody-secreting cells (highly fluorescent lymphocytes or HFLC) or an ‘Atypical Lympho?’ flag were not present in this patient, which makes a reactive condition unlikely.

Atypical chronic myeloid leukaemia

Reactive causes of the observed neutrophilia and monocytosis could be excluded (see above), pointing to an underlying myeloproliferative / myelodysplastic disorder, such as CMML or aCML. Hyposegmentation or degranulated neutrophils are often pronounced in CMML and aCML, but aCML is characterized by higher neutrophil counts and the presence of numerous neutrophil precursors (the IG count is typically > 10-20%). Neutrophils are significantly more prominent than monocytes (NEUT# / Mono# ratio > 5) in aCML. By considering the low IG count and the relative prominence of monocytes in the presented patient, aCML can be excluded.


Myelodysplastic / myeloproliferative diseases

Myelodysplastic / myeloproliferative diseases (MDS/MPD) are clonal myeloid disorders that possess both dysplastic and proliferative features and cannot be properly classified as either myelodysplastic syndromes (MDS) or chronic myeloproliferative disorders (CMPD). The French-American-British (FAB) classification scheme for myeloid disorders did not contain this ‘overlap category’ and this made the classification of such conditions particularly difficult. For example, the FAB classification differentiated between two subgroups of chronic myelomonocytic leukaemia (CMML), a myelodysplastic type (WBC ≤ 13 x 109 /L) and a myeloproliferative type (WBC > 13 x 109 /L), but views on the validity of this subdivision were mixed (1,2). In 2002, the WHO group proposed a new combined MDS/MPD category that would allow more focused clinical and laboratory investigations of myeloid proliferation, abnormal proliferation and dysplasia (3).

There are three major myeloid disorders within the MDS/MPD category including CMML, juvenile myelomonocytic leukaemia (JMML), and atypical chronic myeloid leukaemia (aCML). A fourth entity, which shows features of both MDS and CMPD but does not meet the criteria for any of the three major MDS/MPD entities is designated as myelodysplastic / myeloproliferative disease, unclassifiable (MDS/MPD-U) (4).

Chronic myelomonocytic leukaemia (4,5)

The first description of CMML was published in 1972 (6), and the FAB group classified the condition as a subgroup of the myelodysplastic syndromes in 1982 (7). In the new WHO classification of myeloid disorders CMML is included in the MDS/MPD category.

CMML is a clonal disorder with variable features but the nosology of CMML is less controversial since the publication of the new WHO classification of myeloid neoplasms. The median age at diagnosis of CMML is 65 to 75 years, with a male predominance of 2:1. CMML is primarily a disease of older adults, but it can also occur in children where distinction from JMML can be difficult or impossible. The exact aetiology of CMML is not known, but exposure to occupational and environmental carcinogens, ionising radiation, and cytotoxic agents has been suggested (8). Survival was higher in the myelodysplastic group than in the myeloproliferative group but the frequency of leukaemic transformation was similar in both groups (1,2).

While monocytosis is a major defining feature, the haematological presentation is heterogeneous ranging from isolated monocytosis to myelodysplasia or from a mixed myelodysplastic / myeloproliferative disorder to a forthright myeloproliferative disorder with leukocytosis and splenomegaly, similar to chronic myeloid leukaemia (9). The diagnostic criteria for CMML include peripheral blood monocytosis in excess of 1.0 x 109 /L, while the total leukocyte count may be increased, normal or decreased. Normocytic or macrocytic anaemia is common as is mild thrombocytopenia, and Auer rods are absent. In addition, CMML bone marrow samples may show dysplasia of the erythrocytic, megakaryocytic, and/or granulocytic lineages and an increase in monocyte precursors. Dysplastic monocytes and neutrophils are usually evident. The bone marrow blast count (including myeloblasts and promonocytes) may be less than 5% but can occasionally be as high as 20% (4). Myeloblasts and promonocytes comprise less than 5% of nucleated cells in the peripheral blood.

Neutrophilia occurs in about 50% of patients, with neutrophil precursors (promyelocytes, myelocytes and metamyelocytes) accounting for less than 10% of the white blood cells (4).

An elevated white cell count is also observed in approximately 50% of CMML patients, which are consequently diagnosed with the myeloproliferative form of the disease. Patients lacking these features are generally considered to have the myelodysplastic form of the disease. The progression from myelodysplastic to myeloproliferative CMML may be a frequent event so myelodysplastic CMML could be an early stage of CMML in most cases (2). Clinical studies that divided CMML into two categories according to the FAB recommendations (myelodysplastic versus myeloproliferative CMML) concluded that neither the magnitude of the blood cell count nor cytogenetic or molecular differences identify subgroups with major biological or prognostic differences (1,2).



The median survival time for CMML is 12 to 24 months. Prognostic factors associated with shorter survival include low haemoglobin concentration, high total WBC, monocyte and lymphocyte counts, circulating immature myeloid cells, high blast cell count, low percentage of marrow erythroid cells, abnormal cytogenetics and high levels of serum LDH and β2-microglobulin (10). Progression to acute leukaemia occurs in approximately 15-20% of cases.




              Literature myelodysplastic / myeloproliferative diseases

  1. Germing U, Gattermann N, Minning H et al (1998): Problems in the classification of CMML - dysplastic versus proliferative type. Leuk Res 22 (10) : 879-880
  2. Voglova J, Chrobak L, Neuwirtova R et al (2001): Myelodysplastic and myeloproliferative type of chronic myelomonocytic leukaemia - distinct subgroups or two stages of the same disease? Leuk Res 25 (6): 493-499
  3. Vardiman JW, Harris NL, Brunning RD (2002): The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-2302

    Literature CMML
  4.  Orazi A, Bennett JM, Germing U, et al (2007): Chronic myelomonocytic leukaemia. In: Swerdlow SH, Campo E, Harris NL, et al (Editors): World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th Edition. Lyon, France. International Agency for Research on Cancer (IARC) Press: 49-52
  5. Patnaik MM, Parikh SA, Hanson CA, et al (2014): Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol: early online publication
  6. Zittoun R, Bernadou A, Bilski-Pasquier G, et al (1972): Subacute myelo-monocytic leukemia. Study of 27 cases and review of the literature [in French]. Sem Hop 48 (27): 1943-1956
  7. Bennett JM, Catovsky D, Daniel MT, et al (1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199
  8. Takahashi K, Pemmaraju N, Strati P, et al (2013): Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood 122 (16):2807-2811
  9. Martiat P, Michaud JL, Ordain J (1991): Philadelphia-negative (Ph-) chronic myeloid leukaemia (CML): Comparison with Ph+ CML and chronic myelomonocytic leukaemia. Blood 78 (1): 205-211
  10. Onida F, Kantarjian HM, Smith TL, et al (2001): Prognostic factors and scoring systems in chronic myelomonocytic leukaemia: a retrospective analysis of 213 patients. Blood 99 (3): 840-84

Advanced clinical parameters

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