Myelodysplastic syndromes (MDS) are a group of hematologic malignancies of the pluripotent hematopoietic stem cells. These disorders are characterized by ineffective hematopoiesis, including abnormalities in proliferation, differentiation, and apoptosis. The overall clinical phenotype is peripheral cytopenias in the setting of a normocellular or hypercellular bone marrow and an increased risk for transformation to acute leukemia.
The incidence of MDS approximates 3 to 4 cases per 100,000 population per year, with 30 cases per 100,000 population per year in patients > 70 years old. It is estimated that approximately 10,000 to 15,000 new cases are diagnosed annually in the United States. Data on the epidemiology of MDS are now starting to emerge.
The overall incidence of MDS is slightly higher in males than in females (1.5 to 2:1).
The incidence of MDS increases with age, with a median age at diagnosis of about 70 years. MDS is rare in children; childhood cases are more frequently associated with monosomy of chromosome 7.
MDS is a clonal disorder of bone marrow stem cells. The vast majority of cases (80% to 90%) occur de novo, whereas 10% to 20% of cases are secondary. The etiology of de novo MDS is unclear. Exposure to radiation and/or cytotoxic agents is a recognized etiologic factor in secondary disease forms. Cumulative exposure to environmental toxins and chronic inflammation, genetic differences in leukemogen susceptibility and metabolism, and hematopoietic stem-cell genomic senescence may contribute to disease pathogenesis in de novo cases.
It has been suggested that a genetic insult causes an irreversible alteration in the structure and function of the stem cell, with disruption of a multistep process involving control of cell proliferation, maturation, and interactions with growth factors; mutations of tumor-suppressor genes and proto-oncogenes; and deregulation of apoptosis.
Constitutional childhood disorders, such as Fanconi’s anemia, Shwachman-Diamond syndrome, Down syndrome, neurofibromatosis, and mitochondrial cytopathies, have been associated with MDS and monosomy of chromosome 7. Recently, heritable mutations of the RUNX1, GATA2, CEBPA, DDX41, ETV6, ANKRD26, SRP72, TERT, and TERC genes have been linked to familial cases of adult MDS.
Exposure to benzene and its derivatives may result in karyotypic abnormalities often seen in MDS and acute myelogenous leukemia (AML). Persons chronically exposed to insecticides and pesticides may have a higher incidence of MDS than the general population.
An increased incidence of MDS has been reported among smokers and ex-smokers, possibly linked to associated exposures to polycyclic hydrocarbons and radioactive polonium present in tobacco smoke.
An association of MDS with magnetic fields, alcohol, or occupational exposure to other chemicals has not been demonstrated.
Therapy-related myelodysplasia and therapy-related AML are recognized long-term complications of chemotherapy and radiotherapy. Therapy-related MDS usually develops in 0.8% to 6.3% at 20 years after conventional chemotherapy, with a median time to development of 3 to 7 years post treatment. It is most frequently related to complete or partial loss of chromosomes 5 or 7 in patients previously treated with alkylating agents. Approximately 80% of cases of AML occurring after exposure to antineoplastic drugs, particularly alkylating agents, are preceded by MDS.
More than 85% of patients who develop chemotherapy-related leukemia or MDS have been exposed to alkylating agents. Patients exposed to nitrosoureas have a relative risk of developing MDS or AML of 14.4 and a 6-year actuarial risk of 4%. The mean cumulative risk of leukemia in patients exposed to epipodophyllotoxins (eg, etoposide and teniposide [Vumon]) is about 5% at 5 years. Most of these therapy-related leukemias are not preceded by a dysplastic phase and are associated with abnormalities in chromosome 11q23.
Autologous Bone Marrow Transplantation
Autologous Bone Marrow Transplantation (BMT) has also been associated with a 5-year actuarial risk of MDS of 15% (95% CI = 3.4%–16.6%), with a median time to development of 12 to 24 months. Fluorescence in situ hybridization analyses of pretreatment bone marrow specimens for informative cytogenetic markers indicate that these secondary myeloid malignancies derive from clones demonstrable before the transplant procedure. Prior therapy with fludarabine, older age, low CD34+ dose, and prolonged platelet reconstitution have been associated with the development of MDS or AML in patients with lymphoid malignancies after autologous stem cell transplantation (SCT).
In 1982, the French-American-British (FAB) group proposed a classification system for MDS that consists of five subgroups, based on the percentage of blast cells in the peripheral blood and bone marrow, the presence of ringed sideroblasts in the bone marrow, and the monocyte count in the peripheral blood (Table 1). The five subgroups are:
- refractory anemia (RA)
- refractory anemia with ringed sideroblasts (RARS)
- refractory anemia with excess blasts (RAEB)
- refractory anemia with excess blasts in transformation (RAEB-t)
- chronic myelomonocytic leukemia (CMML).
The presence of Auer rods in granulocyte precursors classifies a patient as having RAEB-t, even if blasts comprise < 20% of bone marrow cells. The presence of > 30% blast cells in the bone marrow or peripheral blood establishes the diagnosis of AML rather than MDS.
In 2008, the World Health Organization (WHO) proposed a modified classification of hematologic malignancies (Table 2). The following changes were proposed, based on the effect of cytogenetics and the number of dysplastic lineages on clinical behavior:
- Elimination of the FAB classification of RAEB-t.
- Changing the blast percentage that defines AML to ≥ 20%.
- Defining RA and RARS by dysplasia restricted to the erythroid lineage either with or without ringed sideroblasts, respectively.
- Including RA and single lineage dysplasias limited to the myeloid or megakaryocyte lineage in the category of refractory cytopenia with unit lineage dysplasia (RCUD).
- Regarding the presence of dysplasia in erythroid and nonerythroid lineages (multilineage dysplasia with or without ringed sideroblasts) and MDS with isolated deletion 5q as separate entities of MDS.
- Division of RAEB into two categories distinguished by marrow blast percentage (ie, RAEB-1: 5%–9%; RAEB-2: 10%–19%) or the presence of Auer rods (RAEB-2).
In addition, two new provisional categories were introduced in the 2008 proposal:
(a) RARS with thrombocytosis (RARS-T), ie, ≥ 450,000 μL platelet count
(b) MDS with minimal cytogenetic criteria, ie, absence of dysplasia in the presence of a clonal cytogenetic abnormality characteristic of MDS.
- CMML is included in a separate category of myelodysplastic/myeloproliferative neoplasms that also includes atypical CML and juvenile myelomonocytic leukemia. CMML is further classified into CMML-1 (≤ 9% blasts), CMML-2 (10%–19% blasts), and CMML-Eos (eosinophils ≥ 1,500 μL).
This proposal represents a step ahead, but there are some aspects that still need to be addressed. For example, some biologic features that have been associated with MDS, such as the presence of spontaneous apoptosis, increased angiogenesis, and presence of specific mutations such as TET2, SF3B1, SRSF2, JAK2, or NRAS may define better specific subsets, and the WHO classification does not incorporate unfavorable cytogenetic patterns. In fact, as will be addressed later in this chapter (see the section, “Cytogenetic and Molecular Findings”), since this last WHO proposal in 2008 noticeable progress has been made in characterization of mutational patterns, as well as certain disease phenotypes and their biology.