PERSPECTIVE Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Mario Cazzola, M.D., and Luca Malcovati, M.D. Related article, page 549 One of the most challenging problems in hema- cytes. Families with an inherited genetic predispo- tology is the heterogeneous group of disorders sition and multistep progression to a myelodysplas- that were formally defined as myelodysplastic syn- tic syndrome and acute myeloid leukemia have been dromes by the French–American–British Coopera- reported1 but are extremely rare. Whether idiopath- tive Group in 1982. This set of disorders includes ic myelodysplastic syndromes are truly clonal pro- idiopathic conditions as well as the secondary or liferations of multipotent stem cells, however, is un- therapy-related forms that develop after exposure clear. The biologic hallmark of these stem cells in to alkylating agents, radiation, or both. Idiopathic myelodysplastic syndromes is, rather, a defective myelodysplastic syndromes occur mainly in older capacity for self-renewal and differentiation. The persons: the incidence of these syndromes is about consequences of this abnormality are probably am- 5 per 100,000 persons per year in the general pop- plified in the elderly because the aging process it- ulation, but it increases to 20 to 50 per 100,000 per- self may not only deplete stem cells, but also alter sons per year after 60 years of age. Approximate- the marrow microenvironment, particularly in per- ly 15,000 new cases are expected in the United sons with occupational or environmental exposure States each year, indicating that myelodysplastic to chemical and physical hazards. The resulting per- syndromes are at least as common as chronic lym- turbed interactions between hematopoietic progen- phocytic leukemia, the most prevalent form of leu- itors and marrow stromal cells are probably respon- kemia in Western countries. sible for ineffective hematopoiesis and may favor Most patients with these syndromes are initially the emergence of clones as a secondary phenome- asymptomatic, and the condition is discovered in- non. Pure erythroid disorders, such as refractory cidentally on a routine blood count. Others have anemia with or without ringed sideroblasts, are symptoms of anemia, which is frequently macro- essentially due to excessive apoptosis of late eryth- cytic but refractory to treatment with folate and vi- roid precursors within the bone marrow, a mecha- tamin B12. Neutropenia, thrombocytopenia, or both nism of anemia known as ineffective erythropoiesis. may be found initially or may appear later. Exami- The approach to the diagnosis of a myelodys- nation of a smear of the peripheral blood reveals plastic syndrome should begin with the exclusion such morphologic abnormalities as hypogranulat- of more common types of anemia — a process that ed neutrophils with hyposegmented nuclei (pseudo- is of fundamental importance if misdiagnoses are Pelger–Huët anomaly) and large platelets. The bone to be avoided. Once common causes of normocytic marrow is typically cellular and shows various mor- or macrocytic anemia have been ruled out, the pos- phologic abnormalities (marrow dysplasia); in one sibility of a myelodysplastic syndrome should be fifth of patients, however, the bone marrow is hypo- considered. Bone marrow aspiration (to evaluate plastic — similar to the picture in aplastic anemia. morphologic abnormalities of hematopoietic pre- According to the prevailing dogma, myelodys- cursors), bone marrow biopsy (to assess marrow plastic syndromes are clonal disorders of hemato- cellularity and topography), and cytogenetic inves- poietic stem cells with a propensity to evolve into tigations (to identify nonrandom chromosomal ab- acute myeloid leukemia. Clonal transformation, ac- normalities) are all mandatory for diagnosis and cording to this view, would occur at the level of a prognosis. committed myeloid stem cell that can give rise to The World Health Organization (WHO) classifi- red cells, platelets, and granulocytes and mono- cation of myeloid neoplasms2 is a very useful tool for defining the different subtypes of myelodysplas- tic syndrome (see table). These variants show im- Dr. Cazzola is a professor of hematology and Dr. Malcovati a senior fellow at the University of Pavia Medical School, pressive clinical heterogeneity, ranging from con- Pavia, Italy. Dr. Cazzola is an attending physician at the ditions with a near-normal standardized mortality Division of Hematology, Istituto di Ricovero e Cura a Car- ratio (refractory anemia with erythroid dysplasia attere Scientifico, Policlinico San Matteo, Pavia, Italy. only) to entities that are very close to acute myeloid 536 n engl j med 352;6 www.nejm.org february 10, 2005 Downloaded from www.nejm.org by CHRISTINA BAJKOWSKY on February 10, 2005 . Copyright © 2005 Massachusetts Medical Society. All rights reserved. PERSPECTIVE Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis WHO Classification and Criteria for the Myelodysplastic Syndromes.* Disease Blood Findings Bone Marrow Findings Refractory anemia Anemia, no or rare blasts Erythroid dysplasia alone, <5% blasts, <15% ringed sideroblasts Refractory anemia with ringed Anemia, no blasts Erythroid dysplasia alone, <5% blasts, sideroblasts ≥15% ringed sideroblasts Refractory cytopenia with Cytopenias (bicytopenia or pancytope- Dysplasia in ≥10% of cells in ≥2 myeloid multilineage dysplasia nia), no or rare blasts, no Auer rods, cell lines, <5% blasts, no Auer rods, <1 billion monocytes per liter <15% ringed sideroblasts Refractory cytopenia with Cytopenias (bicytopenia or pancytope- Dysplasia in ≥10% of cells in ≥2 myeloid multilineage dysplasia nia), no or rare blasts, no Auer rods, cell lines, <5% blasts, no Auer rods, and ringed sideroblasts <1 billion monocytes per liter ≥15% ringed sideroblasts Refractory anemia with excess Cytopenias, <5% blasts, no Auer rods, Unilineage or multilineage dysplasia, blasts, type 1 <1 billion monocytes per liter 5–9% blasts, no Auer rods Refractory anemia with excess Cytopenias, 5–19% blasts, occasional Unilineage or multilineage dysplasia, blasts, type 2 Auer rods, <1 billion monocytes 10–19% blasts, occasional Auer rods per liter Myelodysplastic syndrome, Cytopenias, no or rare blasts, no Auer Unilineage dysplasia in granulocytes or mega- unclassified rods karyocytes, <5% blasts, no Auer rods Myelodysplastic syndrome Anemia, <5% blasts, platelet count Normal-to-increased megakaryocytes with associated with isolated normal to increased hypolobated nuclei, <5% blasts, no Auer del(5q) rods, isolated del(5q) * Information is from Vardiman et al.2 leukemia. The International Prognostic Scoring Sys- treatments include immunosuppression with anti- tem (IPSS)3 — based on the percentage of marrow thymocyte globulin or cyclosporine (or a combina- blasts, the cytogenetic pattern, and the number and tion of the two) and stimulation of red-cell produc- degree of cytopenias — is useful for predicting sur- tion with erythropoietin alone or in combination vival and the risk of leukemia and facilitates clinical with granulocyte colony-stimulating factor. These decision making in individual cases. treatments are effective in small subgroups of pa- A risk-adapted treatment strategy is mandatory tients who do not require transfusions and who for disorders that range from indolent conditions have low marrow cellularity or a low serum level of lasting years to forms approaching acute myeloid erythropoietin. leukemia. Several treatments for myelodysplastic According to evidence-based practice guide- syndromes have been proposed in the past few de- lines,4 most patients with myelodysplastic syn- cades, but only a few have met evidence-based cri- dromes should receive either no treatment or only teria of efficacy. At present, the only treatment that supportive care. Once anemia is symptomatic, red- can definitely prolong survival is allogeneic hema- cell transfusions and iron chelation are the main- topoietic stem-cell transplantation. Approximate- stays of therapy. Dependency on transfusions has ly one third of patients who receive an allogeneic an effect on the likelihood of survival (see graph), transplant are cured, but only about 8 percent of all probably because it is associated with more severe patients with a myelodysplastic syndrome are eligi- bone marrow inefficiency and because not all trans- ble for such treatment and have a donor. Intensive fusion-dependent patients receive adequate iron- chemotherapy can be used in patients who have an chelation therapy. increase in marrow blasts, but complete remissions In this issue of the Journal, List and colleagues are usually achieved only in relatively young patients (pages 549–557) report the treatment of patients with favorable cytogenetic characteristics. Azaciti- with myelodysplastic syndromes and symptomatic dine, which was recently approved by the Food and anemia with lenalidomide, a thalidomide analogue Drug Administration for the treatment of myelodys- that is under investigation for the treatment of mul- plastic syndromes, can be effective in older patients, tiple myeloma. Thalidomide has been used in pa- possibly through the hypomethylation of particular tients with myelodysplastic syndromes with the aim DNA sequences. The remaining potentially effective of exploiting its anticytokine and antiangiogenic n engl j med 352;6 www.nejm.org february 10, 2005 537 Downloaded from www.nejm.org by CHRISTINA BAJKOWSKY on February