Myelodysplastic syndromes

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 result is peripheral cytopenias in the setting of a normocellular or hypercellular bone marrow and a high incidence of transformation to acute leukemia. The incidence of MDS approximates 2 cases per 100,000 population per year, with 30 cases per 100,000 population per year in patients > 70 years old. Approximately 20,000 to 30,000 new cases are diagnosed annually in the United States. Epidemiology Gender The overall incidence of MDS is slightly higher in males than in females (1.5-2.0:1). Age MDS is a disease whose incidence 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. Etiology and risk factors MDS is a clonal disorder of bone marrow stem cells. The vast majority of cases (80%-90%) occur de novo, whereas 10%-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, genetic differences in leukemogen susceptibility and metabolism, and genomic senescence may contribute to disease pathogenesis in de novo cases. Genetic factors It has been suggested that a genetic change 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 protooncogenes; and deregulation of apoptosis. Constitutional childhood disorders, such as Fanconi's anemia, Shwachman- Diamond syndrome, Down's syndrome, neurofibromatosis, and mitochondrial cytopathies, have been associated with MDS and monosomy of chromosome 7. Environmental factors Exposure to benzene and its derivatives may result in karyotypic abnormalities often seen in MDS and acute myelogenous leukemia (AML). Persons chronically exposed to high concentrations of 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 exsmokers, possibly linked to associated exposures to polycyclic hydrocarbons and radioactive polodium present in tobacco smoke. An association of MDS with magnetic fields, alcohol, or occupational exposure to other chemicals has not been confirmed. Antineoplastic drugs Therapy-related myelodysplasia and therapy-related AML are recognized long-term complications of cancer chemotherapy and radiotherapy. Therapy-related MDS usually develops 3-7 years after exposure to chemotherapy and is most frequently related to complete or partial loss of chromosome 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 (BMT) has also been associated with a 5-year actuarial risk of MDS of 15% (95% confidence interval, 3.4- 16.6). Fluorescent in situ hybridization (FISH) analyses of pretreatment bone marrow specimens for informative cytogenetic markers indicate that these secondary myeloid malignancies derive from clones demonstrable before the transplant procedure. A recent study suggested that prior therapy with fludarabine (Fludara), older age, low CD34+ dose, and prolonged platelet reconstitution were associated with the development of MDS or AML in patients with lymphoid malignancies after autologous stem-cell transplantation (SCT). Classification 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. More recently, the World Health Organization (WHO) has proposed a modified classification of hematologic malignancies (Table 2). The following changes have been proposed, based on the effect of cytogenetics, molecular genetics, and the number of dysplastic lineages on clinical behavior:

• The FAB classification of RAEB-t is eliminated.
• The blast percentage that defines AML is ≥ 20%.
• RA and RARS are defined by dysplasia restricted to the erythroid lineage either with or without ringed sideroblasts, respectively.
• The presence of dysplasia in two or more cell lines (multilineage dysplasia) and 5q- syndrome are regarded as separate entities of MDS (with or without ringed sideroblasts).
• RAEB is divided 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).
• A category is added to include unclassifiable MDS defined by nonerythroid, single-lineage dysplasia.
• CMML is included in a separate category of myelodysplastic/myeloproliferative diseases that also includes atypical chronic myelogenous leukemia 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 is controversial because some biologic features that have been associated with MDS, such as the presence of spontaneous apoptosis, increased angiogenesis, and infrequent FLT₃ mutations, are similar between RAEB-t and other MDS but different from those of AML. Thus, the change of blast threshold from 30% to 20% is still arbitrary. Nonetheless, it is now frequently applied. Signs and symptoms Nearly 50% of patients with MDS are asymptomatic at the time of initial diagnosis. Signs and symptoms relate to hematopoietic failure, leading to anemia, thrombocytopenia, or leukopenia. Symptoms related to anemia may range from fatigue to exertional dyspnea that may exacerbate angina or cause congestive heart failure. Infection Approximately one-third of patients report recurrent localized or systemic infections as a result of granulocytopenia or dysfunctional granulocytes and monocytes. Bleeding manifestations, such as petechiae or gross hemorrhage, can occur with thrombocytopenia. However, < 10% of patients present with serious bleeding. Organomegaly and lymphadenopathy Splenomegaly and/or hepatomegaly may be found in 5%-25% of patients. A large spleen is more frequently seen in CMML. Acute neutrophilic dermatosis (Sweet's syndrome) and pyoderma gangrenosum may be observed, particularly in patients with CMML or advanced MDS. Paraneoplastic syndromes Diabetes insipidus vasculitis and other rare paraneoplastic syndromes have been described in patients with MDS.