CHAPTER 37

Myelodysplastic syndromes
Jorge E. Cortes, MD, Alan List, MD, and Hagop Kantarjian, MD
Myelodysplastic syndromes (MDS) are a group of hematologic disorders 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 is about 2 cases per 100,000 population per year, with 30 cases per 100,000 population per year in patients > 70 years old. At least 10,000 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 associated with age, with a median age at diagnosis of about 70 years. MDS is rare in children; childhood cases are usually 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.
MDS

MYELODYSPLASTIC SYNDROMES

785

Constitutional childhood disorders, such as Fanconis anemia, ShwachmanDiamond syndrome, Downs syndrome, neurofibromatosis, and mitochondrial cytopathies, have been associated with MDS and monosomy 7. Environmental factors Exposure to benzene and its derivatives results in karyotypic abnormalities often seen in MDS and acute myelogenous leukemia (AML). Persons chronically exposed to 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 palladium 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. Approximately 80% of cases of AML occurring after exposure to antineoplastic drugs 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. 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) and older age were associated with the development of MDS or AML in patients with lymphoid malignancies after autologous stemcell transplantation (SCT).

Classification
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, presence of ringed sideroblasts in the bone marrow, and 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 of blasts (RAEB)
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MDS
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TABLE 1: Main features of MDS according to the FAB classification

Chromosomal abnormalities (%) Associated karyotype 5q-, -7, +8, 20q+8, 5q-, 20q-7, 7q-, -5, 5q-, +8 -7, 7q-, -5, 5q-, +8 -7, +8, t(5;12), 7q-, 12q8 44 66 14 12 30 20 45 60 30 Rate of leukemic progression (%) Median survival (mo) 32 42 12 5 20

MYELODYSPLASTIC SYNDROMES

FAB subgroup

BM blasts (%)

Ringed sideroblasts (%)

PB monocytes (109/L)

RA

<5

< 15

<1

RARS

<5

> 15

<1

RAEB

5-20

Variable

<1

RAEB-t

21-30

Variable

Variable

CMML

1-20

Variable

>1

BM = bone marrow; CMML = chronic myelomonocytic leukemia; FAB = French-American-British; PB = peripheral blood; RA = refractory anemia; RAEB = refractory anemia with excess of blasts; RAEB-t = refractory anemia with excess of blasts in transformation; RARS = refractory anemia with ringed sideroblasts

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refractory anemia with excess of 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 establishes the diagnosis of AML rather than MDS. More recently, the World Health Organization (WHO) has proposed a modified classification of hematologic malignancies. The following changes have been proposed, based on the effect of cytogenetics, molecular genetics, history of prior therapy, and history of prior myelodysplasia on clinical behavior:

The FAB classification of refractory anemia with excess blasts in transformation (RAEB-t) is eliminated. The blast percentage that defines AML is > 20%. The presence of dysplasia in two or more cell lines (multilineage dysplasia) and 5q- syndrome are regarded as separate entities of MDS within the categories of RA or RARS. 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 myelodysplastic syndrome 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.

This proposal has raised controversy because biologic features like spontaneous apoptosis and measures of angiogenesis are similar between RAEB-t and other MDS but different from those of AML.

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 develop 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
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may be found in 5%-25% of patients. When a large spleen is seen, the possibility of CMML is raised. Acute neutrophilic dermatosis (Sweets syndrome) and pyoderma gangrenosum may be observed in patients with CMML or AML. Paraneoplastic syndromes Diabetes insipidus vasculitis and other rare paraneoplastic syndromes have been described in patients with MDS associated with monosomy 7.

Laboratory features
Peripheral blood Anemia is the most frequent abnormality in MDS, with > 80% of patients presenting with hemoglobin concentrations < 10 g/dL. The anemia is usually normocytic or macrocytic, but the mean corpuscular volume rarely exceeds 120 m3.
Other RBC abnormalities Hypochromic changes and red shape abnormalities are frequent, including poikilocytosis, anisocytosis, elliptocytosis, macroovalocytosis, and sometimes stomatocytes. Stippled and nucleated RBCs can be observed in 10% of cases. Reticulocyte counts are usually reduced. WBC abnormalities The peripheral WBC count may be normal or low. The proportion of monocytes may be increased, and a circulating monocyte count of 1 109 defines CMML. Neutropenia is seen in about 50% of MDS patients at diagnosis, often associated with pseudoPelger-Hut anomaly (neutrophils have a condensed chromatin and unilobed or bilobed nuclei with a pince-nez shape), ring-shaped nuclei, hypogranulation, and hypolobulation or other signs of dysgranulopoiesis. Granulocytes frequently disclose reduced myeloperoxidase activity, increased -naphthyl acetate esterase activity, and other functional abnormalities. Abnormalities in the surface marker expression of leukocytes have also been observed. Chemotactic and bactericidal capability is impaired, which can potentiate the risk of infection, even in the presence of normal WBC counts. Patients frequently have a decreased number of natural killer cells and helper T lymphocytes. Platelet abnormalities Thrombocytopenia is present at diagnosis in approximately 30% of patients; isolated thrombocytopenia may precede the development of overt MDS by 2-10 years. Platelets may be abnormally large, have poor granulation, or have large, fused central granules. Decreased platelet aggregation is observed when patients with MDS are challenged with collagen or epinephrine.
MYELODYSPLASTIC SYNDROMES 789

Thrombocytosis may be seen in association with the 5q- syndrome.

Bone marrow Bone marrow aspiration and biopsy should be performed in every patient suspected of having MDS. The bone marrow is normocellular or hypercellular in 85%-90% of patients with MDS but may be hypocellular in as many as 10%-15%.
Trilineage dyspoiesis The main feature of MDS is trilineage dyspoiesis, although myelodysplastic features do not always involve all three lineages. Dyserythropoiesis Erythroblasts usually have a megaloblastoid appearance, although most frequently this is less pronounced than in vitamin B12 or folic acid deficiency. Iron may be abnormally deposited in mitochondria and is easily stained with Prussian blue, producing a ring-shaped stain around the nucleus. Pathologic sideroblasts have five or more granules/cell. Dysgranulopoiesis The characteristic findings in dysgranulopoiesis are hypogranulation and hyposegmentation with nuclear morphology abnormalities. Excess bone marrow blasts Bone marrow blasts > 5% but < 30% are seen in approximately 50% of patients with MDS; in the context of myelodysplasia, this finding is specific for MDS. The FAB group distinguishes three types of blasts on the basis of maturation morphology. Type I blasts have an uncondensed nuclear chromatin, one to three nucleoli, and basophilic cytoplasm without a Golgi zone. Cytoplasmic granules and Auer rods are absent. In type II blasts, the nuclear/cytoplasm ratio is lower than in type I blasts, and few primary granules are seen. Type III blasts have 20 or more azurophilic granules without a Golgi zone. Dysmegakaryocytopoiesis At least 10 megakaryocytes should be evaluated. Micromegakaryo-cytes are small cells with a diameter two times smaller than the normal megakaryocyte (< 80 m). Multiple dispersed small nuclei or mononucleated forms, as well as hypogranulated Identification of genes specific to megakaryocytes, also can be found.
MDS is an active area of research. Such genes could not only aid in the molecular diagnosis of this disease but could potentially provide a target for specific therapy. Using DNA microarrays, Miyazato et al identified a number of genes with differential expression in MDS and AML. Among them, one encoding a delta-like protein was considered particularly interesting. This gene was overexpressed in 12 of 22 (55%) of patients with MDS and 3 of 31 (10%) with AML. Additional studies investigating these potential genes are ongoing (Miyazato A, Ueno S, Ohmine K, et al: Blood 98:422-427, 2001).

Other abnormalities An increase in reticulin and collagen fibers in the bone marrow may be seen in some patients. Angiogenesis Recently, increased marrow vascularity and increased levels of angiogenic mitogens vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been described in patients with MDS.

Other laboratory findings Serum iron, transferrin, and ferritin levels may be elevated. As a result of ineffective hematopoiesis, lactic dehydrogenase (LDH) and uric acid concentrations are frequently increased.

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Monoclonal gammopathy, polyclonal hypergammaglobulinemia, or hypogamma-globulinemia are found occasionally.

Cytogenetic and molecular findings

Chromosomal abnormalities Clonal cytogenetic abnormalities are found at diagnosis in 50%-60% of patients with de novo MDS and 75%-85% of those with secondary MDS or AML. An interesting feature that distinguishes MDS from AML is the high incidence of complete or partial chromosomal loss or, less frequently, chromosomal gain and the relative rarity of translocations. Among the translocations, unbalanced translocations leading to a loss of chromosomal material are most frequent.
Common cytogenetic abnormalities are listed in Table 1. None of them is characteristic of MDS, since all can be found in other myeloid disorders. Some of the most frequent abnormalities are interstitial deletion of the long arm of chromosome 5 (5q-), monosomy of chromosome 7, trisomy of chromosome 8, 20q-, and loss of the Y chromosome. Complex cytogenetic abnormalities involving three or more chromosomes occur in approximately 15% of de novo MDS cases and 50% of secondary MDS cases. Therapy-related MDS Loss of chromosome 7 and/or 7q- has been reported in as many as 50% of patients previously exposed to chemotherapy for other malignancies, most frequently in association with prolonged use of alkylating agents. Other abnormalities commonly associated with prior exposure to alkylating agents include -5 and/or del(5q) in 25% of cases and involvement of chromosomes 17p and 21 in 10%-15%. Complex chromosomal abnormalities may be The role of VEGF and its receptor in CMML and MDS has been found in nearly 50% of patients. Previous exposure to the epipodophyllotoxins etoposide and teniposide has been associated with abnormalities of the long arm of chromosome 11 (11q23) or, less often, chromosome 21 (21q22). However, patients with these abnormalities most frequently develop a secondary leukemia in the absence of an antecedent myelodysplastic phase.
investigated by Bellamy et al. Coexpression of VEGF and at least one of its receptors was identified in neoplastic cells from patients with MDS or CMML. Furthermore, VEGF stimulated leukemia colony formation in 12 patients and neutralization with an anti-VEGF antibody inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML or RAEB-t patient specimens. These results suggest that VEGF may have an autocrine function in CMML and MDS promoting self-renewal of leukemic progenitors. Thus, therapeutic approaches targeting VEGF are of interest in MDS and are currently being pursued (Bellamy W, Richter L, Sirjani D, et al: Blood 97:1427-1434, 2001).

Cytogenetics and FAB classification RA and RARS Approximately 15%-30% of patients with RA and RARS have abnormal karyotypes. The most frequent abnormality in patients with RA is 5q, present in 70% of patients, whereas the most common abnormalities in patients with RARS are 5q-, +8, and 20q(each occurring in 20% of patients).
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791

RAEB and RAEB-t Nearly 60% of patients with RAEB and RAEB-t have cytogenetic abnormalities, with 5q-, -7, 7q-, and +8 being the most frequent. CMML Chromosomal abnormalities are found in 25%-30% of patients with CMML; the predominant abnormalities include -7, 7q-, +8, 12q-, and t(5;12). Interestingly, 5q- is seen in < 1% of cases of CMML. Monosomy 7 is found in up to 25% of children with MDS, most frequently as an isolated abnormality. In contrast, older patients most often have monosomy 7 associated with other chromosomal abnormalities.

5q- Syndrome The interstitial deletion characteristic of the 5q- syndrome involves bands 5q13 to 5q33, regions known to contain genes coding for granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]), macrophage colony-stimulating factor (M-CSF), interleukin (IL)-3 , IL-4, IL-5, IL-9, IL-12, M-CSF receptor, platelet-derived growth factor receptor, interferon-regulatory factor-1 (IRF-1) endothelial cell growth factor, glucocorticoid receptor, and early growth response gene-1 (EGR-1).
Clinical features This syndrome has characteristic clinical features, including older age, female predominance, diagnosis of RA without excess (< 5%) of blasts in 75% of cases, macrocytosis with severe anemia, erythroblastopenia, normal leukocyte counts, normal or increased platelet counts, and hypolobulated megakaryocytes in the bone marrow. Progression to AML is rare, and prognosis is usually good. However, not every patient with a del(5q) has this syndrome and its associated good prognosis.

Molecular findings The ras family of genes is most frequently associated with MDS, although other abnormalities involving NF1, FMS, p53, TEL, EVI, AXL, TEC, HCK, c-mpl, and other genes have also been described.
Mutations in ras Mutations in the ras family occur in approximately 20%40% of patients with MDS but are most frequently found in those with CMML. Mutations in ras are more common in codons 12, 13, and 61. Mutations in N-ras are more common than those in K-ras or H-ras. A difference in the surface expression of phosphatidylserine (a marker of apoptosis) on cell membranes among de novo AML, MDS, and secondary AML and normal bone marrow cells has been found (increased in MDS and secondary AML). Epigenetic silencing of the p15 tumor-suppressor gene by promoter hypermethylation antedates AML transformation in > 70% of patients.

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Staging and prognosis

Prognostic factors FAB and WHO classifications The FAB classification has been used most frequently to evaluate survival and risk for AML transformation (Table 1). The WHO classification has similar prognostic implications.
Cytogenetics Patients with complex karyotypes and abnormalities in chromosome 7 have a poor prognosis, whereas those with a normal karyotype, -Y, 5q-, or 20q- have a better prognosis. Peripheral cytopenias (hemoglobin < 10 g/dL, absolute neutrophil count (ANC) < 1.5 109/L, and platelet count < 100 109/L) are associated with a poor prognosis. Other prognostic factors Other parameters associated with a poor outcome include CD34 cell expression, high serum LDH levels, expression of the c-mpl gene, ras mutations, p-glycoprotein expression, p15 inactivation, and p53 mutations. However it is unclear whether these factors have independent prognostic value.

International Prognostic Scoring System (IPSS) An International MDS Risk Analysis Workshop has proposed a system that combines clinical, morphologic, and cytogenetic data to generate a consensus prognostic system.

TABLE 2: International Prognostic Scoring System (IPSS) for MDS

Characteristic Bone marrow blasts (%) Value <5 5-10 11-20 21-30 Good Intermediate Poor 0-1 2-3 Sum of score 0 0.5-1.0 1.5-2.0 > 2.5 Score 0 0.5 1.5 2.0 0 0.5 1.0 0 0.5

Karyotypea

Cytopenias Risk group Low Intermediate 1 Intermediate 2 High

a

Good = diploid, -y, del(5q), del(20 q); Poor = chromosome 7 abnormalities or complex ( 3) abnormalities; Intermediate = all others. 793

MYELODYSPLASTIC SYNDROMES

By multivariate analysis, the most significant independent variables were percentage of bone marrow blasts, number of cytopenias, and cytogenetics (Table 2). It is important to keep in mind, however, that other variables (eg, age and prior therapy) not included in this system may alter prognosis and influence the results of therapy among patients in similar IPSS groups.

Treatment
The treatment of MDS is sometimes controversial. Suggested guidelines are outlined in Table 3 and discussed below.

Supportive care The use of transfusions affords temporary benefits and is an alternative that can be considered in patients with lower-risk MDS or that otherwise can be used in conjunction with more definitive therapy. Diff er entia tion ther ap Differ erentia entiation therap apy y Differentiation therapy includes the use of such agents as retinoids and hexamethylene bisacetamide (HMBA).

TABLE 3: Suggested approach to the treatment of MDS

Diagnosis RA, RARS Characteristics IPSS score low or intermediate 1 Treatment Observation Supportive care (transfusions, growth factors?) New approaches (amifostine, ATG, AZA, DAC, antiapoptotic therapy, thalidomide) Therapy with curative intent, eg, chemotherapy (topotecan or anthracycline + Ara-C), AZA, lowdose DAC, SCT(< 60 years old, HLA-identical sibling) Therapy with curative intent, eg, topotecan-based combinations, anthracyclines + Pgp-antagonist, oral camptothecins (topotecan, 9-NC), SCT AML-like chemotherapy, (anthracyclines + Pgp-antagonist), SCT

RA, RARS

IPSS score intermediate 2 or high

RAEB, RAEB-t CMML

All Chronic phase

Transformed

AML = acute myelogenous leukemia; Ara-C = cytarabine; ATG = antithymocyte globulin; AZA = azacytidine; CMML = chronic myelomonocytic leukemia; DAC = decitabine; IPSS = International Prognostic Scoring System; 9-NC = 9-nitrocamptothecin; Pgp = p-glycoprotein; RA = refractory anemia; RAEB = refractory anemia with excess of blasts; RAEB-t = refractory anemia with excess of blasts in transformation; RARS = refractory anemia with ringed sideroblasts; SCT = stem-cell transplantation

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In view of the evidence of

increased angiogenesis in MDS patients, thalidomide (Thalomid) has been investigated in clinical trials. Eighty-three patients with MDS (36 with RA, 24: RAEB, 6: RAEB-t, 13: RARS, and 4: CMML) were treated with thalidomide, starting with 100 mg daily and increasing to 400 mg daily. Thirtytwo (39%) of patients stopped therapy before 12 weeks. Although no complete or cytogenetic response was observed, 16 patients (19%) showed hematologic improvement (15: erythroid, 1: platelet), with 10 patients becoming transfusion independent. Responders had lower blast counts, shorter duration of pretreatment platelet transfusion requirements, and higher pretreatment platelet counts than nonresponders (Raza A, Meyer P, Dutt D, et al: Blood 98:958-965, 2001).

Retinoids The use of oral 13-cis-retinoic acid (CRA, isotretinoin [Accutane]) has produced some responses among low-risk patients. However, it has been associated with significant toxicity when used at a high dose (100 mg/m 2/d) and has failed to show an improvement in survival. The addition of tocopherol has been reported to improve response and survival.

Cytokines Recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) has been reported to decrease transfusion requirements in 15%-25% of patients with MDS, usually those with low plasma levels of EPO (< 100 mU /mL). The addition of granulocyte colony-stimulating factor (G- CS F [Neupogen]) or GM-CSF to rHuEPO may increase the response rate, mostly in patients with low transfusion requirements. The benefit is frequently transient. IL-11 (at low doses of 10 g/kg/d) has been used in patients with bone marrow failure disorders, including MDS. Among 11 patients with MDS, 4 (45%) had a platelet response and 1 had a multilineage response. The median platelet increase was 95 109/L. Thus, this approach may be beneficial for some patients.
IL-11 is a cytokine involved in thrombopoiesis currently used for management of postchemotherapy thrombocytopenia. Kurzrock et al treated 16 patients with MDS or other marrow failure disorders with low-dose IL-11 (10 g/kg/d). Six patients (38%) had a platelet response, and two had a multilineage response; among MDS patients, five responded (one multilineage). Among responders, the median peak increase in platelet counts was 95 109/L (range 55 to 130 109/L). The responses lasted 12, 13, 14+, 25, 30, and 30+ weeks. There were no grade 3 side effects. This study suggests that low-dose IL-11 may be beneficial for some patients with MDS. G-CSF and GM-CSF may improve neutropenia and decrease infections in up to 70% of MDS patients, but the effect is usually transient. No increase in the probability of developing AML has been demonstrated with extended use of these cytokines.

Other alternatives Antithymocyte globulin (ATG [Atgam]) has been associated with response (defined as independence from transfusions) in 34% of patients, which was sustained for a median of 36 months in 81% of them. Also, 48% had a sustained platelet improvement and 55% had an increase in neutrophils. Younger
MYELODYSPLASTIC SYNDROMES 795

Thalidomide has modest activity in MDS. New thalidomide analogs are being investigated. They include selective cytokine inhibitory drugs (SelCIDs) and immunomodulatory drugs (IMiDs).The clinical activity of CC5013, an IMiD, has recently been reported. Fifteen patients with MDS who were transfusion dependent or had symptomatic anemia were treated. Six of 9 evaluable patients had an erythroid response, including 4 who became transfusion independent. Three of 5 evaluable patients had a cytogenetic response.The treatment had minimal nonhematologic toxicity (List A, Kurtin S, Glinsmann-Gibson BJ, et al: Blood [abstract] 100:96a, 2002).

patients and those with low platelet counts are more likely to respond than older patients and those with higher platelet counts. Cyclosporine (Neoral, Sandimmune) significantly increases cell colony growth in laboratory studies of hypoplastic RA. Responses have been reported in a limited number of patients. Amifostine (Ethyol) is a phosphorylated thiol amine first used as a cytoprotective agent for cisplatin (Platinol)-based chemotherapy. In vitro and clinical studies showed that amifostine stimulates normal hematopoiesis, with an increase in reticulocytes, hemoglobin levels, and platelet and WBC counts. Used as a single agent, it has been associated with a single- or multi-lineage hematologic improvement in 42% of patients with MDS.

Azacytidine and 5-Aza-2-deoxycytidine (DAC, decitabine) are hypomethylating agents that have shown activity in MDS. In a randomized trial, 191 patients with MDS (63% RAEB or RAEB-t) were treated with azacytidine or supportive care. Responses were observed in 60% of those treated with azacytidine (CR: 6%; PR: 10%; improvement: 47%) compared with 5% with supportive care. There was a significant improvement in probability of transformation to AML and overall survival when the confounding effect of early crossover to azacytidine was eliminated. In a multicenter phase II study, 66 patients (73% RAEB or RAEB-t) were treated with decitabine. The overall response rate was 49% (CR: 20%; PR: 4%; imArsenic trioxide (ATO) has provement: 24%). The actuarial median re- significant activity against acute sponse duration was 31 weeks and median sur- promyelocytic leukemia. In vitro, it vival was 22 months. In addition, 31% of pa- induces apoptosis in MDS. A phase tients with cytogenetic abnormalities pre- II trial is currently evaluating the sented before treatment achieved a cytoge- clinical activity of ATO in MDS. Thirty-two patients received ATO netic response. Cytogenetic response con- (0.25 mg/kg IV 5 d/wk for 2 weeks ferred a survival advantage to these patients. every 4 weeks). Six of 25 (24%) These agents continue to be evaluated in clini- patients responded, including 1 cal trials. Further evaluation of these drugs, patient (CMML) who achieved a PR, 3 patients with major erythroid alone or in combination, is needed. hematologic improvement (HI) (2 Steroids, androgens, and pyridoxine are rarely effective, although they are often used clinically.
with a decrease in blast count to < 5%), 1 with a major platelet HI, and 1 with a minor HI in neutrophils (List A, Schiller G, Mason J, etal: Blood [abstract] 100:790a, 2002).

Chemotherapy The rationale for this strategy stems from the concepts that MDS is a clonal disorder and that MDS and AML are overlapping illnesses with an arbitrary delineation resulting from the FAB classification (ie, a 30% blast threshold).
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The Cancer and Leukemia Group B (CALGB) treated 874 AML and 33 MDS patients with AML-like chemotherapy. The CR rate was 79% for MDS patients vs 68% for AML patients (P = .37, median CR duration was 11 vs 15 months (P = .28), and median survival was 13 vs 16 months. The authors concluded that the FAB distinction between MDS (RAEB and RAEB-t) and AML has minimal therapeutic implications. Estey et al treated 372 patients with AML, 52 with RAEB, and 106 with RAEB-t with AML-type chemotherapy. CR rates were 62% for patients with RAEB, 66% for those with RAEB-t, and 66% for those with AML (P = .79). Event-free survival was significantly better for patients with AML/RAEB-t than for patients with RAEB. However, when cytogenetics and other prognostic variables were considered in a multivariate analysis, no difference in outcome could be identified among FAB subgroups. These findings suggest that the prognosis is determined more by cytogenetics and other prognostic features than by the percentage of blasts or FAB classification. However, this finding does not necessarily mean that MDS and AML are biologically equivalent entities. Combination regimens Different combination chemotherapy regimens have been investigated. The combination of Ara-C and anthracycline is the cornerstone of intensive chemotherapy, leading to CRs in 40%-60% of patients. However, despite the fact that cytogenetic remissions generally accompany CRs, median remission duration and survival times are brief, rarely exceeding 1 year. The death rate during induction therapy is 5%-20%. Myeloblasts in RAEB-t and secondary AML commonly express the multidrug exporter pglycoprotein (Pgp), which extrudes anthracyclines and limits their activity. A recent randomized, controlled trial performed by the Southwest Oncology Group (SWOG) reported a twofold improvement in survival for patients treated with an anthracycline- and Ara-C-containing induction and consolidation regimens with the Pgp antagonist cyclosporine added. It is possible that certain drugs can be more specific for use in MDS. Topotecan (Hycamtin), a topoisomerase I inhibitor, has shown significant activity as a single agent in the treatment of MDS, with a CR rate of 37% in previously treated patients
MYELODYSPLASTIC SYNDROMES

Farnesyl transferase inhibitors

(FTIs) have been investigated in MDS with promising results. R115777 was used in a phase I study to treat 18 patients with MDS with a starting dose of 300 mg twice daily for 21 days every 28 days. Six patients (33%) had an objective response (Kurzrock R, Sebti S, Kantarjian H, et al: Blood [abstract] 98:623a, 2001). In a phase II study, 23 patients with high-risk MDS were treated with R11577 (600 mg twice daily for 28 days every 42 days). Two of 16 (13%) evaluable patients responded (Kurzrock R, Cortes J, Ryback ME, et al: Blood [abstract] 98:848a, 2001). SCH66336 (lonafarnib), another FTI, was investigated in a phase I study; its starting dose was 200 mg twice daily. Six of 16 (38%) evaluable patients had clinical activity (List A, DeAngelo D, OBrien S, et al: Blood [abstract] 100:789a, 2002). In a phase II study, 3 of 15 patients with MDS treated with SCH66336 (200 mg twice daily) had a hematologic improvement, and 6 of 12 patients with CMML had normalization of monocytes (Cortes J, Holyoake T, Silver R, et al: Blood [abstract] 100:793a, 2002).

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with RAEB/RAEB-t and 27% in patients with CMML. Median CR duration was 7.5 months and survival was 10.5 months. Topotecan is well tolerated, with a death rate during induction therapy of < 5%. Combinations of topotecan with Ara-C resulted in a 56% CR rate (66% in previously untreated patients). Similar CR rates were observed despite the risk category. This regimen is well tolerated, with an induction mortality of 7%. A randomized trial of topotecan and Ara-C vs A small fraction of patients with idarubicin (Idamycin) and Ara-C showed that CMML have rearrangements the topotecan combination was an equivalent involving the platelet-derived growth factor receptor regimen, possibly with lower toxicity.
(PDGFR). Several PDGFR fusion genes have been identified, involving at least four known genes:TEL(ETV6), HIP1, H4(D10S170), and Rabaptin-5; they have been identified by translocations involving chromosome 5q33. These fusion genes lead to intrinsic activation of the tyrosine kinase activity PDGFR. This process can be inhibited by imatinib, and clinical activity has been reported in patients with these abnormalities. Three patients with a t(5;12)(q33;p13) and the TEL(ETV6)/PDGFR fusion gene and one with t(5;12)(q33;q13) with an unknown partner for PDGFR were treated with imatinib. All achieved rapid hematologic and cytogenetic responses, and in all cases, the levels of the transcript decreased significantly (Apperley JF, Gardembas M, Melo JV, et al: N Engl J Med 347:481-487, 2002). One patient with CMML and a t(5;17)(q33;p13.3) and the RAB5EP/PDGFR fusion gene also responded dramatically to imatinib (Magnusson MK, Meade KE, Nakamura R, et al: Blood 100:10881091, 2002). In contrast, patients with CMML or MDS without these fusion genes did not respond to imatinib (Cortes J, Giles F, OBrien S, et al: Blood [abstract] 100:800a, 2002).

SCT Allogeneic SCT can be of benefit in a subset of MDS patients. However, most series have concentrated on younger patients, who constitute a minority of patients with MDS and frequently have favorable cytogenetics and therefore a better prognosis. The best results to date have been reported in patients with a better prognosis (ie, those with RA/RARS). In most series, allogeneic SCT is associated with a long-term remission rate of approximately 40%, a 30% relapse rate, and a 30% rate of transplant-related deaths.
The timing of transplantation remains controversial. Runde et al reported on a group of 131 patients (median age, 33 years; range, 2-55 years) who underwent allogeneic SCT as front-line therapy without prior induction chemotherapy. The 5-year disease-free survival rate was 34%, overall survival rate was 41%, and transplant-related mortality was 38%. The actuarial probability of relapse at 5 years was 39%, with better results observed in the RA/RARS subgroup.

Patients with adverse cytogenetics have a poor outcome with other treatment modalities, and SCT can be considered for such patients during first CR. However, the long-term outcome for these patients after SCT has not proved to be superior to that after any other approach, although the procedure appears curative in a small percentage of patients. Therefore, SCT should be considered in the setting of a research program. New applications for allogeneic SCT (eg, nonmyeloablative) to make this option available to the typical MDS patient (who is frequently older and has

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other associated medical problems), as well as matched-unrelated donor SCT, should be investigated further. Autologous SCT In the majority of MDS patients, lymphocytes do not appear to be part of the clone, suggesting the presence of normal nonclonal stem cells. De Witte et al described 79 patients with MDS or secondary AML who underwent autologous SCT during first CR. The 2-year survival, disease-free survival, and relapse rates were 39%, 34%, and 64%, respectively. The 2-year survival rate for the MDS group was 40% and treatment-related mortality was 9%. The best BMT is an option for patients with CMML. A recent report on 50 outcome was seen among patients with RA/ adult patients with CMML RARS. included patients receiving graft

Treatment recommendations Treatment of patients with MDS is an evolving and controversial issue, and enrollment in a clinical trial should be encouraged. Treatment can probably be designed according to the IPSS.

Patients with RA and RARS, particularly those with low- or intermediate-risk scores, can be treated with supportive measures, although the use of hematopoietic-promoting agents such as erythropoietin, amifostine, ATG, and thalidomide alone or in combination should be explored. Demethylating agents (azacytidine and decitabine) are promising alternatives. Patients with RA or RARS who have intermediate-2 or high-risk disease should probably be treated in the same manner as patients with RAEB and RAEB-t. Patients with RAEB or RAEB-t are usually in the intermediate-2 and highrisk groups, with significant risk of mortality from cytopenias or AML evolution. They should be considered for treatment options with the intention to cure. Chemotherapy should be considered. SCT is an alternative for younger patients in complete remission with an HLAidentical sibling, particularly patients with adverse cytogenetic abnormalities. However, the best results to date have been reported in patients with a better prognosis (ie, those with RA/RARS). Therefore, allogeneic transplantation and other transplant alternatives should be considered in a research setting (eg, mixed-unrelated donor, minitransplants, etc.).

from identical sibling (n = 38), related-matched (n = 1), relatedmismatched (n = 5), or unrelated (n = 7) donors. The estimated 5year probability of relapse was 49%, and disease-free survival was 18%. Patients who received T-cell depleted grafts (n = 11) tended to have an increased probability of relapse (62%) compared with those who had no T-cell depletion (45%); patients who developed graft-versus-host disease (GVHD) had a 29% probability of relapse compared with 51% among those without GVHD (Kroger N, Zabelina T, Guardiola P, et al: Br J Haematol 118:67-73, 2002).

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Aguayo A, Kantarjian H, Manshouri T, et al: Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:22402245, 2000. Bellamy WT, Richter L, Sirjani D, et al: Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 97:14271434, 2001. Cheson BD, Bennett JM, Kantarjian HM, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671 3674, 2000. Deeg JH, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188 1194, 2000. Kroger N, Zabelina T, Guardiola P, et al: Allogeneic stem-cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 118:6773, 2002. Kurzrock R, Cortes J,Thomas DA, et al: Pilot study of low-dose interleukin-11 in patients with bone marrow failure. J Clin Oncol 19:41654172, 2001. List A, Kopecky K, Willman C, et al: Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: A Southwest Oncology Group Study. Blood 98: 32123220, 2001. Lubbert M, Wijermans P, Kunzmann R, et al: Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2-deoxycytidine. Br J Haematol 114:349357, 2001. Molldrem JJ, Leifer E, Bahceci E, et al: Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 137:156 163, 2002. Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958965, 2001. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol 20:24292440, 2002. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:22922302, 2002. Wijermans P, Lubbert M,Verhoef G, et al: Low dose 5-Aza 2-deoxycytidine, a DNA hypomethylating agent for the treatment of high-risk myelodysplastic syndrome: A multicenter phase II study in elderly patients. J Clin Oncol 18:956962, 2000.

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