Myelodysplastic Syndromes — Coping with Ineffective ... · Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Myelodysplastic Syndromes — Coping with Ineffective

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P E R S P E C T I V E

One of the most challenging problems in hema-tology is the heterogeneous group of disordersthat were formally defined as myelodysplastic syn-dromes by the French–American–British Coopera-tive Group in 1982. This set of disorders includesidiopathic conditions as well as the secondary ortherapy-related forms that develop after exposureto alkylating agents, radiation, or both. Idiopathicmyelodysplastic syndromes occur mainly in olderpersons: the incidence of these syndromes is about5 per 100,000 persons per year in the general pop-ulation, but it increases to 20 to 50 per 100,000 per-sons per year after 60 years of age. Approximate-ly 15,000 new cases are expected in the UnitedStates each year, indicating that myelodysplasticsyndromes are at least as common as chronic lym-phocytic leukemia, the most prevalent form of leu-kemia in Western countries.

Most patients with these syndromes are initiallyasymptomatic, and the condition is discovered in-cidentally on a routine blood count. Others havesymptoms of anemia, which is frequently macro-cytic but refractory to treatment with folate and vi-tamin B

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. Neutropenia, thrombocytopenia, or bothmay be found initially or may appear later. Exami-nation of a smear of the peripheral blood revealssuch morphologic abnormalities as hypogranulat-ed neutrophils with hyposegmented nuclei (pseudo-Pelger–Huët anomaly) and large platelets. The bonemarrow is typically cellular and shows various mor-phologic abnormalities (marrow dysplasia); in onefifth of patients, however, the bone marrow is hypo-plastic — similar to the picture in aplastic anemia.

According to the prevailing dogma, myelodys-plastic syndromes are clonal disorders of hemato-poietic stem cells with a propensity to evolve intoacute myeloid leukemia. Clonal transformation, ac-cording to this view, would occur at the level of acommitted myeloid stem cell that can give rise tored cells, platelets, and granulocytes and mono-

cytes. Families with an inherited genetic predispo-sition and multistep progression to a myelodysplas-tic syndrome and acute myeloid leukemia have beenreported

1

but are extremely rare. Whether idiopath-ic myelodysplastic syndromes are truly clonal pro-liferations of multipotent stem cells, however, is un-clear. The biologic hallmark of these stem cells inmyelodysplastic syndromes is, rather, a defectivecapacity for self-renewal and differentiation. Theconsequences of this abnormality are probably am-plified in the elderly because the aging process it-self may not only deplete stem cells, but also alterthe marrow microenvironment, particularly in per-sons with occupational or environmental exposureto chemical and physical hazards. The resulting per-turbed interactions between hematopoietic progen-itors and marrow stromal cells are probably respon-sible for ineffective hematopoiesis and may favorthe emergence of clones as a secondary phenome-non. Pure erythroid disorders, such as refractoryanemia with or without ringed sideroblasts, areessentially due to excessive apoptosis of late eryth-roid precursors within the bone marrow, a mecha-nism of anemia known as ineffective erythropoiesis.

The approach to the diagnosis of a myelodys-plastic syndrome should begin with the exclusionof more common types of anemia — a process thatis of fundamental importance if misdiagnoses areto be avoided. Once common causes of normocyticor macrocytic anemia have been ruled out, the pos-sibility of a myelodysplastic syndrome should beconsidered. Bone marrow aspiration (to evaluatemorphologic abnormalities of hematopoietic pre-cursors), bone marrow biopsy (to assess marrowcellularity and topography), and cytogenetic inves-tigations (to identify nonrandom chromosomal ab-normalities) are all mandatory for diagnosis andprognosis.

The World Health Organization (WHO) classifi-cation of myeloid neoplasms

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is a very useful toolfor defining the different subtypes of myelodysplas-tic syndrome (see table). These variants show im-pressive clinical heterogeneity, ranging from con-ditions with a near-normal standardized mortalityratio (refractory anemia with erythroid dysplasiaonly) to entities that are very close to acute myeloid

Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis


Mario Cazzola, M.D., and Luca Malcovati, M.D.

Related article, page 549

Dr. Cazzola is a professor of hematology and Dr. Malcovatia senior fellow at the University of Pavia Medical School,Pavia, Italy. Dr. Cazzola is an attending physician at theDivision of Hematology, Istituto di Ricovero e Cura a Car-attere Scientifico, Policlinico San Matteo, Pavia, Italy.

Copyright © 2005 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by CHRISTINA BAJKOWSKY on February 10, 2005 .

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leukemia. The International Prognostic Scoring Sys-tem (IPSS)

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— based on the percentage of marrowblasts, the cytogenetic pattern, and the number anddegree of cytopenias — is useful for predicting sur-vival and the risk of leukemia and facilitates clinicaldecision making in individual cases.

A risk-adapted treatment strategy is mandatoryfor disorders that range from indolent conditionslasting years to forms approaching acute myeloidleukemia. Several treatments for myelodysplasticsyndromes have been proposed in the past few de-cades, but only a few have met evidence-based cri-teria of efficacy. At present, the only treatment thatcan definitely prolong survival is allogeneic hema-topoietic stem-cell transplantation. Approximate-ly one third of patients who receive an allogeneictransplant are cured, but only about 8 percent of allpatients with a myelodysplastic syndrome are eligi-ble for such treatment and have a donor. Intensivechemotherapy can be used in patients who have anincrease in marrow blasts, but complete remissionsare usually achieved only in relatively young patientswith favorable cytogenetic characteristics. Azaciti-dine, which was recently approved by the Food andDrug Administration for the treatment of myelodys-plastic syndromes, can be effective in older patients,possibly through the hypomethylation of particularDNA sequences. The remaining potentially effective

treatments include immunosuppression with anti-thymocyte globulin or cyclosporine (or a combina-tion of the two) and stimulation of red-cell produc-tion with erythropoietin alone or in combinationwith granulocyte colony-stimulating factor. Thesetreatments are effective in small subgroups of pa-tients who do not require transfusions and whohave low marrow cellularity or a low serum level oferythropoietin.

According to evidence-based practice guide-lines,

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most patients with myelodysplastic syn-dromes should receive either no treatment or onlysupportive care. Once anemia is symptomatic, red-cell transfusions and iron chelation are the main-stays of therapy. Dependency on transfusions hasan effect on the likelihood of survival (see graph),probably because it is associated with more severebone marrow inefficiency and because not all trans-fusion-dependent patients receive adequate iron-chelation therapy.

In this issue of the

Journal,

List and colleagues(pages 549–557) report the treatment of patientswith myelodysplastic syndromes and symptomaticanemia with lenalidomide, a thalidomide analoguethat is under investigation for the treatment of mul-tiple myeloma. Thalidomide has been used in pa-tients with myelodysplastic syndromes with the aimof exploiting its anticytokine and antiangiogenic

* Information is from Vardiman et al.

2

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 sideroblasts

Anemia, no blasts Erythroid dysplasia alone, <5% blasts, ≥15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia

Cytopenias (bicytopenia or pancytope-nia), no or rare blasts, no Auer rods, <1 billion monocytes per liter

Dysplasia in ≥10% of cells in ≥2 myeloid cell lines, <5% blasts, no Auer rods, <15% ringed sideroblasts

Refractory cytopenia with multilineage dysplasia and ringed sideroblasts

Cytopenias (bicytopenia or pancytope-nia), no or rare blasts, no Auer rods, <1 billion monocytes per liter

Dysplasia in ≥10% of cells in ≥2 myeloid cell lines, <5% blasts, no Auer rods, ≥15% ringed sideroblasts

Refractory anemia with excess blasts, type 1

Cytopenias, <5% blasts, no Auer rods, <1 billion monocytes per liter

Unilineage or multilineage dysplasia,5–9% blasts, no Auer rods

Refractory anemia with excess blasts, type 2

Cytopenias, 5–19% blasts, occasional Auer rods, <1 billion monocytes per liter

Unilineage or multilineage dysplasia, 10–19% blasts, occasional Auer rods

Myelodysplastic syndrome, unclassified

Cytopenias, no or rare blasts, no Auer rods

Unilineage dysplasia in granulocytes or mega-karyocytes, <5% blasts, no Auer rods

Myelodysplastic syndrome associated with isolated del(5q)

Anemia, <5% blasts, platelet count normal to increased

Normal-to-increased megakaryocytes with hypolobated nuclei, <5% blasts, no Auer rods, isolated del(5q)



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effects to improve the efficiency of hematopoiesis.Some transfusion-dependent patients can ceaserequiring transfusions when treated with thalido-mide, but a response requires several weeks andtreatment is appreciably limited by neurologic tox-icity. Lenalidomide does not have this adverse ef-fect and appears to be more suitable than thalido-mide for long-term treatment.

The effect of lenalidomide on myelodysplastichematopoiesis appears to be dual, at least initially:it increases red-cell production and decreases neu-trophil and platelet production. This observationcannot be explained by a direct effect on clonal stemcells alone, which should cause parallel changes inperipheral-blood cells. Rather, lenalidomide is like-ly to modify the marrow microenvironment, andwe must assume that the modified hematopoieticmilieu favors the efficiency of erythropoiesis whileinhibiting granulocytopoiesis and megakaryocyto-poiesis. These effects are consistent with an anticy-tokine activity of lenalidomide and, in turn, with theenhancement of the antiapoptotic activity of eryth-

ropoietin on erythroid progenitors and the diminu-tion of the antiapoptotic activity of inflammatorycytokines on myeloid and megakaryocytic progeni-tors. Apart from these effects, the complete cytoge-netic remissions seen in patients with the 5q syn-drome who were treated with lenalidomide areimpressive, making it difficult to rule out a directeffect of the drug on myelodysplastic clones withthe 5q31.1 deletion. It should be noted that themolecular basis of the hypereosinophilic syndromewas identified after this disorder was found to beresponsive to imatinib mesylate.

5

Lenalidomide appears to be a promising treat-ment for the approximately one third of patientswith a myelodysplastic syndrome who have a pureerythroid disorder (according to the WHO classifi-cation) or a low-risk condition (according to theIPSS score), and in particular for those with the 5qsyndrome. Achievement of transfusion indepen-dence and a cytogenetic remission are major accom-plishments that might translate into a prolongationof survival. However, the feasibility and adverseeffects of treatment need to be defined more precise-ly, since in the study by List et al., only 21 of the 55candidates who were screened for eligibility bene-fited from lenalidomide in terms of a major eryth-roid response.

In the past 20 years, several therapeutic mete-ors have passed through the dark sky of treatmentfor myelodysplastic syndromes, only to disappear.We look forward to prospective studies that canunequivocally confirm the hematologic activity oflenalidomide in these syndromes, and given the cur-rent uncertainties, we recommend the use of thisdrug only within clinical trials.

Dr. Cazzola’s studies on myelodysplastic syndromes are support-ed by the Associazone Italiana per la Ricerca sul Cancro, Milan.

1.

Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiencyof CBFA2 causes familial thrombocytopenia with propensity to de-velop acute myelogenous leukaemia. Nat Genet 1999;23:166-75.

2.

Vardiman JW, Harris NL, Brunning RD. The World HealthOrganization (WHO) classification of the myeloid neoplasms.Blood 2002;100:2292-302.

3.

Greenberg P, Cox C, LeBeau MM, et al. International scoringsystem for evaluating prognosis in myelodysplastic syndromes.Blood 1997;89:2079-88. [Erratum, Blood 1998;91:1100.]

4.

Alessandrino EP, Amadori S, Barosi G, et al. Evidence- andconsensus-based practice guidelines for the therapy of primarymyelodysplastic syndromes: a statement from the Italian Societyof Hematology. Haematologica 2002;87:1286-306.

5.

Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase createdby fusion of the

PDGFRA

and

FIP1L1

genes as a therapeutic tar-get of imatinib in idiopathic hypereosinophilic syndrome. N EnglJ Med 2003;348:1201-14.

Cumulative Probability of Survival among 374 Patients Given a Diagnosis of Myelodysplastic Syndrome at the Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy, 1992–2002.

Patients were grouped according to whether or not a transfusion requirement developed during their clinical course. The two groups were compared by means of a Cox proportional-hazards regression model with time-dependent covariates. Each patient was considered as part of the transfusion-independent group (blue curve) as long as he or she had no need for blood transfusion and was recategorized in the transfusion-dependent group when a transfusion re-quirement developed (red curve). Once a regular need for blood transfusion developed, patients had a significantly lower probability of survival (hazard ratio for death, 1.58; P=0.005). The survival curves do not account for the time-dependency of the transfusion requirement.

Transfusion-independent group

Transfusion-dependent group

Cum

ulat

ive

Prop

ortio

n Su

rviv

ing

0.8

0.9

0.7

0.6

0.4

0.3

0.1

0.5

0.2

0.00 20 40 60 80 100 120 140

Survival Time (mo)

1.0

Transfusion-independent

Transfusion-dependent



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Myelodysplastic Syndromes — Coping with Ineffective ... · Myelodysplastic Syndromes — Coping with Ineffective Hematopoiesis Myelodysplastic Syndromes — Coping with Ineffective