Sysmex Europe

June 2014 - Test your knowledge in the quiz!

Can you explain the anaemia and thrombocytopenia of this patient? Acute myeloid leukaemia (AML), under chemotherapy
Aplastic anaemia
Refractory cytopenia with multilineage dysplasia (RCMD), under treatment
Chronic myelomonocytic leukaemia (CMML)

Online version of this month`s case:


Refractory cytopenia with multilineage dysplasia (RCMD), under treatment.

Scattergrams and microscopy

Patient history: A 59-year old man undergoing therapy to treat a known condition.

Abnormal lymphocyte and monocyte populations were visible in the WDF scattergram, which would have resulted in the appearance of the flag ‘Blasts/ Abn Lympho?’. After consulting the WPC scattergrams only the ‘Blasts?’ flag was displayed.
The WPC scattergram showed that no abnormal lymphocytes were present.
The SSC-FSC scattergram of the WPC channel showed the presence of abnormal cells and this triggered the flag ‘Blasts?’.
Analysis of the PLT-F channel showed a thrombocytopenia with a normal immature platelet fraction (IPF).
Peripheral blood smear
Bone marrow smear



The answer can be inferred from…


Case history

2 Days prior to the presented haematological analysis, this 59-year old man had visited his primary care physician because of fatigue and easy bruising. He was referred to the hospital and was subsequently diagnosed with low-grade refractory cytopenia with multilineage dysplasia (RCMD), which is a myelodysplastic syndrome (MDS). Initially, <5% blasts were detected in the bone marrow so an acute myeloid leukaemia, which is characterized by >20% blasts, could be ruled out. The low numbers of blasts also excluded refractory anaemia with excess blasts. In addition, chronic myelomonocytic leukaemia was unlikely because the monocyte counts were <1000 /µL. The search for an allogeneic bone marrow donor was initiated immediately.


Case results

The patient was suffering from anaemia and thrombocytopenia, with ineffective erythropoiesis (no increased reticulocyte counts) and ineffective thrombopoiesis (no increase of the immature platelet fraction). In addition, erythropoiesis showed signs of dysplasia, indicated by an increase in red blood cell fragments. Leukocytes also showed some abnormalities: The neutrophil granularity (NEUT-SSC) was considerably decreased (106.1 channels, compared to 140-160 channels in healthy individuals), which may point to dysplasia. Indeed, the peripheral blood smear revealed dysplastic neutrophils with hypo- or non-lobulated nuclei (pseudo-Pelger-Huet cells) and hypogranulation. Normal white blood cell differential counts were observed (even though a slight absolute monocytosis was present), and activated or atypical lymphocytes were absent so an infection could be excluded. In addition, the monocyte counts were only slightly increased and this ruled out a chronic myelomonocytic leukaemia (CMML), which is typically associated with monocyte counts far exceeding 1000 /µl. Blasts were suspected by the haematology analyser and could be confirmed by microscopic analysis (1%, data not shown).

The following answers are incorrect for the described reasons


Acute myeloid leukaemia (AML), under chemotherapy

Acute myeloid leukaemia (AML) is characterized by the accumulation of malignant myeloid cells (blasts). It is characterized by leukocytosis of at least one myeloid lineage and the presence of >20% blasts in the bone marrow. AML may be classified as AML with myelodysplasia-related changes when multilineage dysplasia can be observed morphologically, when patients have a prior history of MDS or myelodysplastic / myeloproliferative neoplasms (MDS/MPN), or when genetic abnormalities related to MDS are present. Chemotherapy may result in cytopenias and could explain the anaemia, thrombocytopenia and the low amount of blasts, but chemotherapy is also associated with an increase in red blood cell volume (increased MacroR or MCV), due to the impairment of cell division by the chemotherapeutic agents. In this patient the percentage macrocytic RBC is decreased rather than increased, which makes an AML under chemotherapy unlikely.


Aplastic anaemia

Aplastic anaemia can be hereditary, as in Fanconi anaemia, or acquired through exposure to chemicals, drugs or viruses such as the Epstein-Barr virus. It is probably caused by decreased numbers of pluripotent haematopoietic stem cells resulting in reduced haematopoiesis. The outcome of this is pancytopenia, which is the reduction of all types of blood cells: White blood cells, red blood cells and platelets. The reduced capability of the stem cells to populate the bone marrow also causes bone marrow aplasia but not dysplasia as observed in the neutrophils shown here. Furthermore, the white blood cell counts in this patient are normal and therefore pancytopenia is not present. Together these observations make an aplastic anaemia unlikely.


Chronic myelomonocytic leukaemia (CMML)

CMML is a clonal disorder with myelodysplastic as well as myeloproliferative features. The median age at diagnosis of CMML is 65 to 75 years, with a male predominance of 2:1. Its exact aetiology is not known, but exposure to occupational and environmental carcinogens, ionising radiation, and cytotoxic agents has been suggested. 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. The diagnostic criteria for CMML include peripheral blood monocytosis in excess of 1000/µl, while the total leukocyte count may be increased, normal or decreased. The dysplasia signs (low NEUT-SSC) and the low neutrophil to monocyte ratio (< 5) observed in the presented case may indicate a CMML. However, monocytosis is a major defining feature of CMML and its absence (MONO# <1000/µl) can be used to exclude CMML here.


Myelodysplastic syndromes (1,2)

Myelodysplastic syndromes (MDS), historically also called “preleukaemia”, are a heterogeneous group of clonal haematological disorders characterised by hyperproliferative, but ineffective haematopoiesis resulting in cytopenias, dysplasia in one or more cell lines and increased risk of progression to acute myeloid leukaemia (AML). MDS constitutes a group of disorders in which the pluripotential stem cells are damaged; hence all cell lines may be affected. The clinical manifestations commonly include anaemia and/or thrombocytopenia, often requiring blood transfusions on a regular basis. Eventually, the ultimate outcome is bone marrow failure and death due to bleeding or infection, or, in about 30–40% of patients, AML. The aetiology of MDS is largely unknown with 90% of cases occurring spontaneously as “primary MDS” and only 10% as “secondary MDS” as a complication of chemotherapy, radiology or other genotoxic exposure.

To predict the course of the disease and plan the appropriate treatment of a patient, this diverse conglomerate of diseases can be classified in a number of subgroups, depending on the lineages that are involved. Some diseases previously considered part of the MDS group have been reclassified with the new WHO criteria. For example, the MDS type chronic myelomonocytic leukaemia (CMML) with a proliferative monocytic cell line was moved to the group myelodysplastic syndromes / myeloproliferative neoplasms (MDS/MPN).

The most recent (2008) revision of the WHO classification is listed below:

  • Refractory cytopenias with unilineage dysplasia (RCUD): Refractory anaemia (RA), refractory neutropenia (RN) or refractory thrombocytopenia (RT),
  • Refractory anaemia with ring sideroblasts (RARS),
  • Refractory cytopenia with multilineage dysplasia (RCMD),
  • Refractory anaemia with excess blasts 1 and 2 (RAEB-1 and RAEB-2),
  • Myelodysplastic syndrome – unclassified (MDS-U),
  • MDS associated with isolated del(5q) (deletion in chromosome 5, q branch),
  • Childhood myelodysplastic syndrome,
  • Refractory cytopenia of childhood.


Secondary MDS

Both chemotherapy and radiation therapy, used to treat cancer, are genotoxic and therefore may induce clonal changes which give rise to a secondary malignancy. The most common culprits are alkylating agents, epipodophyllotoxins and anthracyclins. Patients with a prior diagnosis of cancer have an above average risk of developing MDS at a later stage. As secondary MDS progresses rapidly, many patients will have already progressed to AML at the time of diagnosis.


Refractory cytopenia with multilineage dysplasia (3)

Refractory cytopenia with multilineage dysplasia (RCMD) is a myelodysplastic syndrome in which more than one haematopoietic lineage is affected by dysplasia and an isolated cytopenia or bicytopenia may be observed. It is further characterised by absent or minimal blasts (<1%) in the peripheral blood, less than 5% blasts in the bone marrow and the absence of Auer rods. While there are recommended levels for defining cytopenia for the different lineages, their absence does not necessarily exclude RCMD and the diagnosis may still be made when morphologic or cytogenetic factors support it. Cases with 2–4% blasts in peripheral blood and no Auer rods should be classified as RAEB-1. Patients with pancytopenia or 1% blasts in the peripheral blood and no Auer rods are classified as myelodysplastic syndrome – unclassifiable (MDS-U). If Auer rods are present, a diagnosis of RAEB-2 is assigned. RCMD accounts for about 30% of MDS cases. The clinical course is influenced by the lineages affected and the degree of cytopenia and dysplasia, hence it is highly variable. The median survival is 30 months but individuals with complex cytogenetic abnormalities have a much poorer prognosis. In addition, a marrow blast percentage of 3.5% is associated with lower survival (4) and RCMD patients with 1% blasts have a lower survival compared to RCMD patients with no blasts in the peripheral blood (5).


Literature myelodysplastic syndromes

  1.  Brunning RD, Orazi A, Germing U, et al (2007): Myelodysplastic Syndromes/neoplasms, overview. 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
  2. Adès L, Itzykson R, Fenaux P (2014): Myelodysplastic syndromes. Lancet: Early online publication

  3. Literature RCMD

  4. Brunning RD, Bennett JM, Matutes E, et al (2007): Refractory cytopenia with multilineage dysplasia. 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. Wang H, Wang XQ, Xu XP, et al (2009): Bone marrow blasts level predicts prognosis in patients with refractory cytopenia with multilineage dysplasia. Eur J Haematol 83 (6): 550-558
  6. Knipp S, Strupp C, Gattermann N, et al (2008): Presence of peripheral blasts in refractory anemia and refractory cytopenia with multilineage dysplasia predicts an unfavourable outcome. Leuk Res 32 (1): 33-37



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