Myelodysplastic Syndromes 2


Summary of Myelodysplastic Syndromes

In contrast to florid (polyblastic) acute myelogenous leukemia (AML), the myelodysplastic syndrome (MDS) encompasses a group of neoplastic (clonal) myeloid disorders that range from nonprogressive to more slowly progressive than AML. The disorders may appear uncommonly in childhood or young adulthood, especially after cytotoxic therapy for another cancer, but the incidence increases exponentially after age 40 years. The disorders also may develop as a result of inherited syndromes that predispose to MDS or AML, such as Fanconi anemia. Most cases occur between the ages of 50 and 90 years. Cases usually occur de novo, but a proportion result from hematopoietic cell injury during treatment of lymphomas or solid tumors with cytotoxic therapy. The disorders range from clonally derived (refractory) anemias to oligoblastic myelogenous leukemia (refractory anemia with excess blasts). The diseases share a propensity to the development of (1) cytopenias, as a result of exaggerated apoptosis of late-stage marrow precursor cells, and (2) multilineage dysmorphogenesis of blood cells. Red cells often have readily discernible poikilocytosis, anisocytosis, anisochromia, and basophilic stippling. The marrow usually contains increased erythroid precursors with dysmorphic features, including nuclear distortions and scanty, poorly hemoglobinized cytoplasm or macroerythroblasts. Ringed sideroblasts are a frequent feature. Neutrophils have anomalies, including bilobed or hypersegmented nuclei and hypogranulated cytoplasm, in association with increased marrow granulocyte precursors. Giant and microcytic platelets, sometimes with abnormal or absent granulation, in the blood are associated with megakaryocytic hyperplasia and atypical lobulation of the nucleus and decreased marrow megakaryocyte size. In the nonprogressive syndromes, anemia may be accompanied by mild variations in other cell counts, usually decreases in neutrophil and platelet levels, and blast cells are not increased in the marrow (<2%). Clonal cytogenetic abnormalities occur in approximately 50 percent of patients. Chromosomes 5, 7, and 8 are most frequently involved. The classic 5q– syndrome is categorized within the myelodysplastic disorders. The syndrome primarily affects older women, and features anemia and hypercellular and dysmorphic erythropoiesis with lobulated erythroblast nuclei and hypolobulated micromegakaryocyte nuclei, but usually normal or elevated platelet counts. It is the most indolent form of the myelodysplastic syndromes with the lowest propensity to evolve into AML. In the more progressive syndromes, leukemic blast cells are increased, cytopenias are more severe, and the disease has high morbidity and mortality from infection and bleeding. Each of the syndromes has a propensity to evolve into polyblastic AML, ranging from approximately 10 to 15 percent in the clonal (refractory) anemia to approximately 40 percent of patients with trilineage cytopenias and increased marrow blast cells. Mortality from infection is a risk in patients with severe neutropenia. Various scoring systems have been developed to help predict outcome and the timing of various treatments. In the most indolent forms, therapy may not be required. Erythropoietin plus granulocyte colony-stimulating factor may improve the anemia or decrease transfusion requirements, if clonal anemia is the principal feature. Cyclosporine or antithymocyte globulin may transiently improve the anemia in patients with clonal anemia, hypoplastic marrows, and low blast counts. Therapy with cytotoxic drugs, red cell or platelet transfusions, and antibiotics may palliate the progressive syndrome (oligoblastic myelogenous leukemia). Lenalidomide and inhibitors of DNA methylation, such as 5-azacytidine or decitabine, have been useful in some patients. Allogeneic stem cell transplantation may be curative in younger patients, and nonmyeloablative stem cell transplantation is being explored in older patients.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: ALIP, abnormal localized immature precursors; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; ATG, antithymocyte globulin; ATRA, all-trans-retinoic acid; CFU-GM, colony forming unit–granulocyte-monocyte; CI, confidence interval; FISH, fluorescence in situ hybridization; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; IPSS, International Prognosis Scoring System; M-CSF, monocyte colony-stimulating factor; MDS, myelodysplastic syndromes; RAEB, refractory anemia with excess blasts; TNF, tumor necrosis factor; WHO, World Health Organization.

Definition of Myelodysplastic Syndromes

Myelodysplasia is a term used to encompass a spectrum of clonal (neoplastic) myeloid disorders marked by ineffective hematopoiesis (exaggerated marrow cell apoptosis), cytopenias, qualitative disorders of blood cells and their precursors, clonal chromosomal abnormalities, and a variable predilection to undergo clonal evolution to florid acute myelogenous leukemia (AML).1 The disorders range from relatively indolent clonally derived anemias, with a relatively lower frequency of progression to AML, to more troublesome clonal multilineage cytopenias or to oligoblastic myelogenous leukemias that often progress to overt AML. The somatic mutations leading to these disorders arise in a multipotential hematopoietic cell. Dysplasia is a term that classically implies a polyclonal and, therefore, nonneoplastic process. The choice of the term myelodysplasia to denote clonal (neoplastic) disorders was unfortunate because the term does not assist students and patients in understanding the relationship of myelodysplasia to other clonal multipotential progenitor stem cell disorders. In addition, diseases such as primary myelofibrosis or paroxysmal nocturnal hemoglobinuria can have the features of “myelodysplasia” but are excluded in its classification. Moreover, drawing diagnostic distinctions among 5, 10, and 20 percent leukemic blast cells is inconsistent with the biologic behavior of cancer and medicine’s classification of cancer.1 Also, separation of clonal anemias into two categories based on whether the anemia has greater than or less than 15 percent pathologic sideroblasts is arbitrary and is not based on the pathobiology of the two variants. The term myelodysplasia and its subsidiary syndromes, for example, refractory anemia, are, however, widely used and deeply ensconced in the medical lexicon.2

The term clonal cytopenias refers to (1) neoplasms arising in a multipotential hematopoietic marrow cell that result in diseases with no discernible leukemic blast cells in the marrow or blood (e.g., refractory anemias or refractory multicytopenias) and (2) oligoblastic myelogenous leukemia (refractory anemia with excess blasts [RAEB] in which an increased proportion of (leukemic) blast cells is present in the marrow but in which, untreated, the course is smoldering or subacute compared to AML.3

The boundary between clonal anemia and oligoblastic myelogenous leukemia may be indistinct because of the insensitivity of the marrow examination; however, continued observation clarifies the situation. If leukemic myeloblasts are evident in marrow, the diagnosis of oligoblastic myelogenous leukemia can be made, maintaining the principle that the histopathologic diagnosis depends on the presence or absence of tumor cells and not the rate of progression or severity of the manifestations of the malignancy. The proportion of marrow myeloblasts is not increased in reactive states, for example, granulocytic hyperplasia as a result of infection, noninfectious inflammation, solid tumors, and drug-induced granulocytosis (e.g., glucocorticoids, lithium). The proportion of blasts usually is less than the normal value of 1.0 ± 0.4 SD percent. A finding of greater than 2.0 percent myeloblasts in a normal marrow is rare in healthy older children and adults. Higher proportions, for example, greater than 2 percent, are confined to cases of oligoblastic myelogenous leukemia. Some patients treated with granulocytic growth factors may have a slight transient increase in blast cells.

Clonal proliferation of multipotential hemopoietic cells in this group of disorders is accompanied by variable effects on all blood cell lineages and usually is associated with pathologically enhanced apoptosis of marrow precursor cells such that leukopenia and thrombocytopenia of varying severity often accompany the anemia. Qualitative abnormalities of cell shape, organelle structure, biochemical pathways, and function can occur in each lineage. The range of clinical expression is broad. Thus, clonal cytopenias can occur with isolated anemia and a nearly normal-appearing marrow, or with severe pancytopenia, profoundly hypercellular marrow, and alterations in blood cell shape, size, and function. The more profound the disorder, the more likely the finding of oligoblastic leukemia on marrow examination.

History of Myelodysplastic Syndromes

At the beginning of the 20th century, reports of highly morbid cytopenic disorders that were refractory to treatment began to appear in the medical literature.4 In 1942, Chevallier and colleagues5 discussed formally the “odo-leukemias.” They chose the Greek word odo, meaning threshold, to highlight disorders on the threshold of leukemia. Chevallier proposed leucoses as the generic term for the leukemias so that marked variations in white cell counts and other highly variable presenting features would not engender inappropriate terminology. His proposal was sage but neglected.

In 1949, Hamilton-Paterson6 used the term preleukemic anemia to describe patients with refractory anemia antecedent to AML development. In 1953, Block and coworkers7 expanded the concept to include cytopenias of all lineages and described cases that closely fit with our current concepts of a clonal myeloid hemopathy prior to evolution to overt AML. By mid-20th century, the relationship of acquired idiopathic cytopenias to the subsequent onset of AML had become broadly appreciated.8–15 Terms such as herald state of leukemia, refractory anemia, sideroachrestic anemia, idiopathic refractory sideroblastic anemia, pancytopenia with hyperplastic marrow, and others were coined to describe the various manifestations of the hematopoietic derangement that preceded the onset of florid AML. In the late 1960s numerous reports discussing “refractory anemia,” “refractory sideroblastic anemia,” and “preleukemia” appeared that described cases we now consider “myelodysplastic” syndromes. In 1970, the designation “les anémies réfractaires avec excès de myeloblasts” was proposed,3 and in 1976 a preliminary classification of these syndromes was discussed by Dreyfus in which refractory anemia with an excess of myeloblasts was amplified, parenthetically, as smoldering acute leukemia.13 The synonym, oligoblastic leukemia, had been used also to describe those cases with low proportions of leukemic myeloblasts and relatively protracted courses.16,17

In 1976, at a conference held in Paris, Marcel Bessis and Jean Bernard used the term hematopoietic dysplasia, later shortened to myelodysplasia, for the group of disorders having a more indolent course than AML.18 The concept that neoplasia is a tissue abnormality defined by its origin in the mutation(s) within a single cell (monoclonality) and that dysplasia is a polyclonal tissue change, not neoplasia, was ignored and took a back seat to the participants’ primary interest in the dysmorphia of cells that characterized most of these syndromes, hence the application of the term dysplasia, which has become entrenched.

Classification of Myelodysplastic Syndromes

The World Health Organization (WHO) classification designates six categories in the spectrum of the myelodysplastic syndromes (MDSs): (1) refractory cytopenia with unilineage dysplasia, (2) refractory anemia with ringed sideroblasts, (3) refractory cytopenia with multilineage dysplasia, (4) refractory anemia with excess blasts (type 1 with less than 10 percent blasts in the marrow and type 2 with 10 to 19 percent blasts in the marrow), (5) myelodysplastic syndrome, unclassified, and (6) isolated 5q– abnormality (Table 88–1).19 MDSs include entities that have marrow blast percentages ranging from a mean of less than 2 percent in refractory anemia to a mean of approximately 10 percent and upper limit of 19 percent in RAEB.20 The distinction between refractory anemia in which less than 15 percent of nucleated red cells in marrow are ringed sideroblasts and refractory anemia with ringed sideroblasts in which greater than 15 percent of nucleated red cells are ringed sideroblasts uses the same arbitrary boundary as does classifying a patient as having RAEB if less than 20 percent of nucleated marrow cells are blasts or as having AML if greater than 19 percent of nucleated marrow cells are myeloblasts. This approach to categorization is unfortunate because in no other neoplasm is the designation of the cancer, in this case myelogenous leukemia, which all such patients have, called by another name when a greater or fewer number of tumor cells are present.

Table 88–1. Classification of the Myelodysplastic Syndromes (Clonal Cytopenias and Oligoblastic Leukemia)
1. Clonal (refractory) anemia (with pathologic sideroblasts).*
2. Clonal bicytopenia or tricytopenia (overt multilineage dysmorphic cytopenias).
3. Oligoblastic myelogenous leukemia (refractory anemia with excess myeloblasts).
4. Apparent clonal myeloid disease that does not fit in any category shown above (e.g., chronic clonal monocytosis; isolated thrombocytopenia or isolated neutropenia, only if clonal)19,20 Clonal isolated neutropenia or thrombocytopenia are rare occurrences as initial manifestations of a clonal myeloid disease and their inclusion by the WHO is arguable. Nonclonal diseases should not be in this category.
5. Classical 5q– syndrome.
*The WHO classification distinguishes refractory “nonsideroblastic” from sideroblastic anemia based on whether the case has ≥15% or <15% pathologic sideroblasts in marrow erythroid cells. No basis exists for distinguishing the anemia based on proportion of pathologic sideroblasts because most patients with clonal anemia have pathologic sideroblasts, and the manifestations and course of the disease are virtually identical in patients with a high or low prevalence of pathologic sideroblasts. Given the relatively crude nature of quantification of pathologic sideroblasts and the biologic illegitimacy of such distinctions in any case, it is unjustified to consider them two different diagnostic categories. Indeed, recent survival studies have collapsed the two groups into one category.275NOTE: Other acute and chronic clonal myeloid diseases are categorized in Table 85–1.

Several laboratories that explored the use of flow cytometry in the classification of these heterogenous disorders have found it to be of limited value or largely confirmatory of the findings on blood film and marrow examination.20,21

Clonal (refractory) cytopenia or oligoblastic myelogenous leukemia arising de novo in children is very infrequent. These syndromes may occur somewhat more frequently after radiation or chemotherapeutic treatment of children with other cancers. Although some pediatric oncologists have included juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia in children among the myelodysplastic syndromes, they stand alone and are discussed in Chap. 90 with the chronic myelogenous leukemias.

Epidemiology of Myelodysplastic Syndromes

Incidence by Age, Sex, and Occupation

Disease onset before age 50 years is uncommon except in cases preceded by irradiation or chemotherapy given for another malignancy.22–25 MDS, as defined by the WHO classification, occurs in children ages 5 months to 15 years at a rate of approximately 1 per 1 million children per year. In contrast to adults, most pediatric cases are oligoblastic myelogenous leukemia (RAEB); clonal sideroblastic anemia is rare.26–29 A proportion of childhood cases evolve from inherited predisposing diseases, such as Down syndrome and Fanconi anemia. The annual incidence of MDS increases logarithmically after age 40 years from about 2 per 1 million persons to more than 40 per 100,000 persons in septuagenarians (see Fig. 88–1).24 In the United States, the annual incidence is approximately equivalent to that of annual new cases of AML.30 Reporting of clonal anemia and other low-risk MDSs is inadequate and, thus, population age-adjusted incidence estimates of MDS (~3/100,000 population) are underestimates.31 Males are affected approximately 1.5 times as often as females. Case-control studies of possible occupational or environmental associations have provided many possible candidates as contributors to MDS, but none other than benzene (exposure of ≥40 parts per million [ppm]-years) has reached a level of scientific validity

Etiology and Pathogenesis


Not unexpectedly, the etiologic factors that increase the incidence of MDS are similar to the factors affecting the incidence of AML. Exposure to prolonged, high levels of benzene,34,35 chemotherapeutic agents, particularly alkylating agents and topoisomerase inhibitors,36–43 and radiation44,45 increase the risk of these clonal hemopathies. These agents may cause DNA damage, impair DNA repair enzymes, and induce loss of chromosome integrity. Most cases of secondary or posttreatment MDS occur in patients treated for a lymphoma or a solid tumor. Increasing reports of MDS as a complication of treatment of myeloid diseases, such as acute promyelocytic leukemia, reflect a second clonal myeloid disease from another primitive hematopoietic cell injured during therapy.43 The increased life span of patients with acute promyelocytic leukemia after effective therapy may make this event more common.

Inherited diseases, such as Fanconi anemia, known to predispose to AML development occasionally evolve instead into a clonal myeloid hemopathy.46 In addition, as is the case in all hematologic malignancies,47 familial myelodysplasia occurs rarely as a result of as-yet undefined germ-line susceptibility genes.48–50

Acquired copper deficiency, especially after gastric bypass surgery, intestinal surgery, parenteral nutrition, and sometimes without an evident cause may result in a reversible low-risk MDS picture with anemia, neutropenia, sometimes thrombocytopenia, and marrow dysplasia, including ringed sideroblasts. Neurologic changes mimicking subacute combined degeneration may also occur.51,52


These disorders arise from the clonal expansion of a multipotential hematopoietic cell. The clonal origin is supported by studies of women who were heterozygotes for glucose-6-phosphate dehydrogenase isoenzymes A and B and who had such a syndrome. The hematopoietic progenitors,53,54 and in some cases B lymphocytes,55 of such patients had only one isoenzyme present, supporting the concept of clonal expansion of a neoplastic marrow cell. Clonal studies using X-linked restriction fragment length polymorphisms with probes for hypoxanthine phosphoribosyl transferase or phosphoglycerate kinase also supported the origin of these disorders from a single multipotential stem cell.56–58

Fluorescence in situ hybridization (FISH) of interphase blood cell populations with probes for chromosome 7 or 8 in patients with monosomy 7 or trisomy 8 indicates chromosome abnormalities may not be present in lymphoid populations.58,59 Studies of immunoglobulin heavy-chain gene rearrangement and assay of the human androgen receptor and other genes on the X chromosome also have concluded that lymphocytes are not derived from the neoplastic clone.57,60–62 However, pseudodiploidy was observed in Epstein-Barr virus-stimulated cell populations of two patients with idiopathic refractory sideroblastic anemia63; and T-cell receptor analysis and X chromosome inactivation analysis indicate that marrow and, to a lesser extent, blood T, natural killer (NK), and B cells are part of the malignant clone in at least 50 percent of patients.64,65 Mesenchymal stem cells from patients with MDS may harbor chromosomal abnormalities.66

The frequency of deletions of part or all of chromosomes 5, 7, 9, 11, 12, 13, 17, 18, 20, and 21 indicates a role for tumor suppressor genes in disease onset, but identification of these genes has been elusive (see “5q– Syndrome” below). Molecular genetic studies of patient’s cells show identifiable gene mutations in approximately 60 percent of patients. Presumably, such mutations contribute to the apparent maintenance of proliferation of early progenitors, the abnormalities in maturation seen in each hematopoietic lineage, and the high proportional loss of mature cells in the marrow. Mutated RAS is most common,67–71 and lower frequencies of FMS and p53 mutations are present. Codon 12 of RAS and codon 969 of FMS are the predominant sites of alteration in the respective genes.72,73 Hypermethylation of p15, an inhibitor of cyclin-dependent kinases 4 and 6, is present in more than one-third of patients and may contribute to disease progression.74 A variety of other mutations in protooncogenes, or genes encoding proteins involved in the cell cycle, or of transcription factors have been described sporadically.72,73 Interpretation of these molecular studies is difficult because the mutations are present in patients with advanced disease and may be late changes, not seminal in the neoplastic transformation. Overexpression of DLK (delta-like) and GATA-1 and GATA-2 have been suggested as a marker for MDS in the former case and as contributing to the maturation abnormalities in the case of the latter two genes.75,76 The role of mutations in mitochondrial DNA in the cells of older persons and in the hematopoietic cells of patients with MDS and AML has not been integrated into the pathogenesis of the disease.77

The major specific pathophysiologic mechanism in MDS is ineffective hematopoiesis, that is, defective maturation and death of marrow precursor cells.78–80 The specific characteristics of ineffective erythropoiesis and granulopoiesis include a decreased proportion of cells in the DNA synthesis phase of the mitotic cycle and a marked increase in the fraction of late precursor cells undergoing apoptosis.81 Increased levels of apoptotic mediators are present in cells, including tumor necrosis factor (TNF)-, FAS antigen (CD95), and calcium-dependent nuclease activity.82–84 Stepwise degradation of DNA, which is characteristic of apoptosis, is evident in late precursors.82–84 The apoptosis of erythroid precursors may involve BCL-2 related proteins in the endoplasmic reticulum upstream of the mitochondria, and downstream of FAS. Erythropoietin may protect against FAS-induced apoptosis.85 The proliferation of progenitor and early precursor cells usually is normal or enhanced, resulting in a hypercellular marrow, but failure to accumulate adequate numbers of mature cells has been observed. Mild shortening of cell life span also contributes to the cytopenias.

Immune dysregulation involving B and T lymphocytes in MDS has been described. CD40 expression on monocytes is increased, as is CD40L on T lymphocytes, and has been postulated as being a contributing factor to hematopoietic failure in some patients with less-advanced disease.86 Heightened apoptosis of marrow B lymphocytes is a feature of the disease.87 Depletion of autologous T lymphocytes in cultures of the marrow of patients with early MDS (clonal anemia) results in improved growth of marrow cells, apparently from residual normal stem cells.88 The T-cell inhibitory effect is highlighted by transient improvement in cell counts in a minority of patients with early disease after treatment with antithymocyte globulin (ATG) and cyclosporine.89 However, evidence that lymphocytes are part of the leukemic clone has been contradictory,60,89,90 and when found, is present in no more than 50 percent of the population of MDS patients examined.64,65 Interleukin (IL)-32, secreted by MDS stromal cells in response to TNF- may modulate apoptosis and interfere with NK cell function.91 Immune dysregulation may be secondary to the neoplasia and not a factor in its origin.92