The myelodysplastic syndromes (MDS, formerly known as "preleukemia") are a diverse collection of haematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia. Anemia requiring chronic blood transfusion is frequently present.

Signs and symptoms

Abnormalities include:

• neutropenia, anemia and thrombocytopenia (low cell counts of white & red blood cells and platelets, respectively)
• abnormal granules in cells, abnormal nuclear shape and size
• chromosomal abnormalities, including chromosomal translocations.

Symptoms of myelodysplastic conditions:

• Anemia - chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
• Neutropenia (low white cell count) - increased susceptibility to infection
• Thrombocytopenia (low platelet count) - increased susceptibility to bleeding

All these conditions have an increased risk of developing acute leukaemia, which is notoriously resistant to treatment ("secondary leukaemia").

Diagnosis

Investigation:

• Full blood count and examination of blood film
• Bone marrow aspirate and biopsy with examination by an experience hematopathologist
• Cytogenetics or chromosomal studies. This is performed on the bone marrow aspirate.

Pathophysiology

MDS is due to genetic defects in the multi-potent blood stem cell of the bone marrow. Most of these are not yet described. Differentiation of the abnormal cells is impaired. Clonal expansion of the abnormal cells lead to production of abnormal cells and decreased production of normal bone marrow products.

Death from bleeding (due to lack of platelets) or infection (due to lack of white blood cells) is the outcome for about 60% of MDS patients. In about 25-35% of patients there is a further genetic mutation in one of the abnormal blood stem cells which eventually results in acute leukemia. The progression of MDS to leukemia is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.

Types and classification

In 1974 and 1975 a group of pathologists from France, the United States, and Britain met and deliberated and derived the first widely used classification of these diseases. This French-American-British (FAB) classification was published in 1976 and revised in 1982. Cases were classified into 5 categories:

• Refractory anemia (RA) - characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors;
• Refractory anemia with ringed sideroblasts (RARS) - also characterized by less than 5% myeloblasts in the bone marrow, but distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts";
• Refractory anemia with excess blasts (RAEB) - characterized by 5-19% myeloblasts in the marrow;
• Refractory anemia with excess blasts in transformation (RAEB-T) - characterized by 20-29% myeloblasts in the marrow (30% blasts is defined as acute myeloid leukemia);
• Chronic myelomonocytic leukaemia (CMML) - not to be confused with chronic myelogenous leukemia or CML - characterized by less than 20% myeloblasts in the bone marrow and greater than 1000 * 10⁹/uL monocytes (a type of white blood cell) circulating in the peripheral blood.

The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some patients live more than a decade (the average is on the order of 3-5 years); the worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About 1/4 of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determing the prognosis of MDS, published in Blood in 1997.^[1] This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

The FAB classification was used by pathologists and clinicians for almost 20 years. In the late 1990s a group of pathologists and clinicians working under the auspices of the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others.

One new category was refractory cytopenia with multilineage dysplasia (RCMD), which includes patients with pathological changes not restricted to red cells (i.e., prominent white cell precurso and platelet precursor (megakaryocyte) dysplasia.

RAEB was divided into *RAEB-I (5-10% blasts) and RAEB-II (11-19%) blasts, which has a poorer prognosis than RAEB-I.

The category of RAEB-T was eliminated; such patients are now considered (by the WHO authors, at least) to have acute leukemia. 5q- syndrome, typically seen in older women with normal or high platelet counts and isolated deletions of the long arm of chromosome 5 in bone marrow cells, was added to the classification.

CMML was removed from the myelodysplastic syndromes and put in a new category of myelodysplastic-myeloproliferative overlap syndromes. Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.

The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, mustard, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females.

All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).

Epidemiology

The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The incidence is probably increasing as the age of the population increases.

Therapy

The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia.

The IPSS scoring system can help triage patients more aggressive treatment (i.e. bone marrow transplant) as well as the timing of this therapy.^[2] Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy. Chemotherapy with 5-azacytidine has been shown to decrease blood transfusion requirements and the progression to AML. Biological agents such as thalidomide and the investigational agent lenalidomide are additional treatment options.

Bone marrow transplant, particularly in younger, more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score.

History

Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al. The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.

References

• Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189. PMID 6952920.
• Block M, Jacobson LO, Bethard WF. Preleukemic acute human leukemia. J Am Med Assoc 1953;152:1018-28. PMID 13052490.
• Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835-49. PMID 10577857.

Notes