The myelodysplasias (MDSs) are a heterogeneous group of hematologic disorders broadly characterized by cytopenias associated with a dysmorphic (or abnormal appearing) and usually cellular bone marrow, and by consequent ineffective blood cell production. A clinically useful nosology of these entities was first developed by the French-American-British Cooperative Group in 1983. Five entities were defined: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The World Health Organization classification (2002) recognizes that the distinction between RAEB-t and acute myeloid leukemia is arbitrary and groups them together as acute leukemia, notes that CMML behaves as a myeloproliferative disease, and separates refractory anemias with dysmorphic change restricted to erythroid lineage from those with multilineage changes
Idiopathic MDS is a disease of the elderly; the mean age at onset is 68 years. There is a slight male preponderance. MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to >100 per million persons in the general population and 120 to >500 per million in the elderly. MDS is rare in children, but monocytic leukemia can be seen. Therapy-related MDS is not age-related and may occur in as many as 15% of patients within a decade following intensive combined modality treatment for cancer. Rates of MDS have increased over time, due to the recognition of the syndrome by physicians and the aging of the population.
Etiology and Pathophysiology
MDS is caused by environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5-7 years) or the DNA topoisomerase inhibitors (2 years). Both acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia can evolve into MDS.
MDS is a clonal hematopoietic stem cell disorder leading to impaired cell proliferation and differentiation. Cytogenetic abnormalities are found in about half of patients, and some of the same specific lesions are also seen in frank leukemia; aneuploidy is more frequent than translocations. Both presenting and evolving hematologic manifestations result from the accumulation of multiple genetic lesions: loss of tumor suppressor genes, activating oncogene mutations, or other harmful alterations. Cytogenetic abnormalities are not random (loss of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology (11q23 following topoisomerase II inhibitors); chronic myelomonocytic leukemia is often associated with t(5;12) that creates a chimeric tel-PDGF β gene. The type and number of cytogenetic abnormalities strongly correlate with the probability of leukemic transformation and survival. Mutations of N-ras (an oncogene), p53 and IRF-1 (tumor suppressor genes), Bcl-2 (an antiapoptotic gene), and others have been reported in some patients but likely occur late in the sequence leading to leukemic transformation. Apoptosis of marrow cells is increased in MDS, presumably due to these acquired genetic alterations or possibly to an overlaid immune response. An immune pathophysiology has been suggested for trisomy 8 MDS, which often responds clinically to immunosuppressive therapy. Such patients have T cell activity directed to the cytogenetically aberrant clone. Sideroblastic anemia may be related to mutations in mitochondrial genes; ineffective erythropoiesis and disordered iron metabolism are the functional consequences of the genetic alterations.
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi's anemia.
The physical examination is remarkable for signs of anemia; about 20% of patients have splenomegaly. Some unusual skin lesions, including Sweet's syndrome (febrile neutrophilic dermatosis), occur with MDS. Autoimmune syndromes are not infrequent.
Anemia is present in the majority of cases, either alone or as part of bi- or pancytopenia; isolated neutropenia or thrombocytopenia is more unusual. Macrocytosis is common, and the smear may be dimorphic with a distinctive population of large red blood cells. Platelets are also large and lack granules. In functional studies, they may show marked abnormalities, and patients may have bleeding symptoms despite seemingly adequate numbers. Neutrophils are hypogranulated; have hyposegmented, ringed, or abnormally segmented nuclei; contain Dohle bodies; and may be functionally deficient. Circulating myeloblasts usually correlate with marrow blast numbers, and their quantitation is important for classification and prognosis. The total white blood cell count is usually normal or low, except in chronic myelomonocytic leukemia. As in aplastic anemia, MDS can be associated with a clonal population of PNH cells.
The bone marrow is usually normal or hypercellular, but in 20% of cases it is sufficiently hypocellular to be confused with aplasia. No single characteristic feature of marrow morphology distinguishes MDS, but the following are commonly observed: dyserythropoietic changes (especially nuclear abnormalities) and ringed sideroblasts in the erythroid lineage; hypogranulation and hyposegmentation in granulocytic precursors, with an increase in myeloblasts; and megakaryocytes showing reduced numbers or disorganized nuclei. Megaloblastic nuclei associated with defective hemoglobinization in the erythroid lineage are common. Prognosis strongly correlates with the proportion of marrow blasts. Cytogenetic analysis and fluorescent in situ hybridization can identify chromosomal abnormalities.
Deficiencies of vitamin B12 or folate should be excluded by appropriate blood tests; vitamin B6 deficiency can be assessed by a therapeutic trial of pyridoxine if the bone marrow shows ringed sideroblasts. Marrow dysplasia can be observed in acute viral infections, drug reactions, or chemical toxicity but should be transient. More difficult are the distinctions between hypocellular MDS and aplasia or between refractory anemia with excess blasts and early acute leukemia. The World Health Organization considers the presence of 20% blasts in the marrow as the criterion that separates acute myeloid leukemia from MDS.
The median survival varies greatly from years for patients with 5q- or sideroblastic anemia to a few months in refractory anemia with excess blasts or severe pancytopenia associated with monosomy 7; an International Prognostic Scoring System assists in making predictions. Most patients die as a result of complications of pancytopenia and not due to leukemic transformation; perhaps one-third will succumb to other diseases unrelated to their MDS. Precipitous worsening of pancytopenia, acquisition of new chromosomal abnormalities on serial cytogenetic determination, and increase in the number of blasts are all poor prognostic indicators. The outlook in therapy-related MDS, regardless of type, is very poor, and most patients will progress within a few months to refractory acute myeloid leukemia.
The therapy of MDS has been unsatisfactory. Only stem cell transplantation offers cure: survival rates of 50% at 3 years have been reported, but older patients are particularly prone to develop treatment-related mortality and morbidity. Results of transplant using matched unrelated donors are comparable, although most series contain younger and more highly selected cases.
MDS has been regarded as particularly refractory to cytotoxic chemotherapy regimens but is probably no more resistant to effective treatment than acute myeloid leukemia in the elderly, in whom drug toxicity is often fatal and remissions, if achieved, are brief.
Low doses of cytotoxic drugs have been administered for their "differentiating" potential, and from this experience has emerged drug therapies based on pyrimidine analogues. Azacitidine is directly cytotoxic but also inhibits DNA methylation, thereby altering gene expression. Azacitidine improves blood counts and modestly improves survival in about 16% of MDS patients, compared to best supportive care. Azacitidine is administered subcutaneously at a dose of 75 mg/m2, daily for 7 days, at 4-week intervals, for at least four cycles, although further cycles may be required to observe a response. Decitabine is closely related to azacitidine and more potent. Similar to azacitidine, about 20% of patients show responses in blood counts, with a duration of response of almost a year. Activity may be higher in more advanced MDS subtypes. Decitabine dose is 15 mg/m2 by continuous intravenous infusion, every eight hours for three days, repeating the cycle every 6 weeks for at least four cycles. The major toxicity of both azacitidine and decitabine is myelosuppression, leading to worsened blood counts. Other symptoms associated with cancer chemotherapy frequently occur. Ironically, it has been difficult to establish that either agent acts in patients by a mechanism of DNA demethylation.
Thalidomide, a drug with many activities including antiangiogenesis and immunomodulation, has modest biologic activity in MDS. Lenalidomide, a thalidomide derivative with a more favorable toxicity profile, is particularly effective in reversing anemia in MDS patients with 5q- syndrome; not only do a high proportion of these patients become transfusion-independent with normal or near-normal hemoglobin levels, but their cytogenetics also become normal. Lenalidomide is administered orally, 10 mg daily. Most patients will improve within 3 months of initiating therapy. Toxicities include myelosuppression (worsening thrombocytopenia and neutropenia, necessitating blood count monitoring) and an increased risk of deep vein thrombosis and pulmonary embolism.
Other treatments for MDS include amifostine, an organic thiophosphonate that blocks apoptosis; it can improve blood counts but has significant toxicities. ATG and cyclosporine, as employed in aplastic anemia, also may produce sustained independence from transfusion, especially in younger MDS patients with more favorable International Prognostic Scoring System (IPSS) scores.
Hematopoietic growth factors can improve blood counts but, as in most other marrow failure states, have been most beneficial to patients with the least severe pancytopenia. G-CSF treatment alone failed to improve survival in a controlled trial. Erythropoietin alone or in combination with G-CSF can improve hemoglobin levels, but mainly in those with low serum erythropoietin levels who have no or only a modest need for transfusions.
The same principles of supportive care described for aplastic anemia apply to MDS. Despite improvements in drug therapy, many patients will be anemic for years. RBC transfusion support should be accompanied by iron chelation in order to prevent secondary hemochromatosis.
Categories: Hematologic Disorders