Myelodysplastic Syndromes
`
`Peter L. Greenberg, Neal S. Young, and Norbert Gattermann
`
`The myelodysplastic syndromes (MDS) are charac-
`terized by hemopoietic insufficiency associated
`with cytopenias leading to serious morbidity plus
`the additional risk of leukemic transformation.
`Therapeutic dilemmas exist in MDS because of the
`disease’s multifactorial pathogenetic features,
`heterogeneous stages, and the patients’ generally
`elderly ages. Underlying the cytopenias and evolu-
`tionary potential in MDS are innate stem cell
`lesions, cellular/cytokine-mediated stromal defects,
`and immunologic derangements. This article
`reviews the developing understanding of biologic
`and molecular lesions in MDS and recently avail-
`able biospecific drugs that are potentially capable
`of abrogating these abnormalities.
`Dr. Peter Greenberg’s discussion centers on
`decision-making approaches for these therapeutic
`options, considering the patient’s clinical factors
`and risk-based prognostic category.
`One mechanism underlying the marrow failure
`present in a portion of MDS patients is immuno-
`logic attack on the hemopoietic stem cells. Consid-
`erable overlap exists between aplastic anemia,
`paroxysmal nocturnal hemoglobinuria, and subsets
`of MDS. Common or intersecting pathophysiologic
`mechanisms appear to underlie hemopoietic cell
`
`I. CONTROVERSIES AND THERAPEUTIC OPTIONS
`IN MYELODYSPLASTIC SYNDROME:
`BIOLOGICALLY TARGETED APPROACHES
`
`Peter L. Greenberg, MD*
`
`Therapeutic dilemmas abound in myelodysplastic syn-
`drome (MDS) because of the disease’s multifactorial
`pathogenetic features and heterogeneous stages, and the
`patients’ generally elderly ages. Underlying the cyto-
`penias and evolutionary potential in MDS are innate stem
`cell lesions, cellular/cytokine-mediated stromal defects,
`and immunologic derangements. Given the developing
`understanding of biologic and molecular lesions in MDS
`and recently available biospecific drugs that are poten-
`tially capable of abrogating these abnormalities, specific
`
`destruction and genetic instability, which are
`characteristic of these diseases. Treatment results
`and new therapeutic strategies using immune
`modulation, as well as the role of the immune
`system in possible mechanisms responsible for
`genetic instability in MDS, will be the subject of
`discussion by Dr. Neal Young.
`A common morphological change found within
`MDS marrow cells, most sensitively demonstrated
`by electron microscopy, is the presence of ringed
`sideroblasts. Such assessment shows that this
`abnormal mitochondrial iron accumulation is not
`confined to the refractory anemia with ring
`sideroblast (RARS) subtype of MDS and may also
`contribute to numerous underlying MDS patho-
`physiological processes. Generation of abnormal
`sideroblast formation appears to be due to mal-
`function of the mitochondrial respiratory chain,
`attributable to mutations of mitochondrial DNA, to
`which aged individuals are most vulnerable. Such
`dysfunction leads to accumulation of toxic ferric
`iron in the mitochondrial matrix. Understanding the
`broad biologic consequences of these derange-
`ments is the focus of the discussion by Dr. Norbert
`Gattermann.
`
`targets are being evaluated for possible therapeutic in-
`tervention.
`Goals of therapy range from symptom management/
`hematologic improvement (using low-intensity treatment
`with biologically targeted agents) to attempts at chang-
`ing the natural history of the disease (generally using
`high-intensity treatment, including chemotherapy and
`hemopoietic stem cell transplantation). This review will
`
`* Professor of Medicine, Hematology Division, Room S161,
`Stanford University Medical Center, Stanford, CA 94305 and
`Head, Hematology Section, Palo Alto VA Health Care System,
`Palo Alto CA 94304.
`
`Dr. Greenberg has received research support from Amgen,
`Johnson & Johnson, Celgene, and Genentech.
`
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`center on decision-making approaches for these thera-
`peutic options, considering clinical factors such as the
`patient’s age, performance status, and risk-based prog-
`nostic category. The format for this review will be to
`attempt to respond to questions generally posed by pa-
`tients to their physicians regarding this problematic dis-
`ease, about which a great deal of uncertainty and con-
`troversy exist:
`• What is my disease?
`• How long will I live with my disease? What prob-
`lems should I anticipate experiencing? What is my
`chance of developing leukemia?
`• What treatments are available for my disease? Which
`treatment(s) should I receive? When should I receive
`them?
`• How can I learn more about my illness? Are there
`clinical trials with which I can and should become
`involved? How do I find out about them?
`
`What is my disease?
`
`A. Diagnostic Classification
`MDS is characterized by hemopoietic insufficiency as-
`sociated with cytopenias leading to potentially serious
`morbidity (transfusion-dependent anemia, bleeding
`manifestations) and mortality (death from infection in
`the setting of neutropenia), plus the additional risk of
`leukemic transformation. The disease may arise de novo
`or may develop following treatment with mutagenizing
`agents after the patient has been treated with chemo-
`therapy or chemoradiotherapy for other diseases (usu-
`ally other malignancies). The latter variant is termed
`secondary or treatment-related MDS. MDS is generally
`relatively indolent, often with a pace of disease com-
`prising at least several months and with a rate of pro-
`gression related to a number of defined clinical features.
`The French-American-British (FAB) classification
`initially categorized patients morphologically for the di-
`agnostic evaluation of MDS.1 Of importance for diag-
`nosis is the morphologic finding of dysplastic changes
`in at least 2 of the 3 hemopoietic cell lines. These in-
`clude megaloblastoid erythropoiesis, nucleocytoplasmic
`asynchrony in the early myeloid and erythroid precur-
`sors, and dysmorphic megakaryocytes.2 MDS patients
`have been classified by FAB as having 1 of 5 subtypes
`of disease:
`• Refractory anemia (RA): < 5% marrow blasts;
`• RA with ringed sideroblasts (RARS): < 5% blasts
`plus ≥ 15% ringed sideroblasts;
`• RA with excess of blasts (RAEB): 5-20% marrow
`blasts;
`
`• RAEB in transformation (RAEB-T): 21-30% mar-
`row blasts; and
`• Chronic myelomonocytic leukemia (CMML): ≤ 20%
`marrow blasts plus monocytosis > 1000/mm3.
`CMML has been categorized as MDS, although it often
`has characteristics of a myeloproliferative disorder
`(MPD). Some groups have separated these patients into
`proliferative and nonproliferative/dysplastic subtypes,
`with prognosis being most dependent on the proportion
`of marrow blasts. Patients with the dysplastic form have
`been classified within the FAB subtypes based on their
`percentage of marrow blasts.
`Methods are needed to enhance our ability to stratify
`patients by their morphologic and biologic features. Such
`approaches could improve prognostication and treatment
`for these individuals. Regarding morphologic ap-
`proaches, a World Health Organization (WHO) panel
`has recently issued a report with proposals for reclassi-
`fying MDS,3,4 although it has not yet been universally
`accepted because of certain controversial issues.5 In this
`report, suggestions have been made to modify the FAB
`definitions of MDS. Although most prior data require at
`least 2-line dysplasia to diagnose MDS, the WHO guide-
`lines accept unilineage dysplasia for the diagnosis of RA
`and RARS, so long as other causes of the dysplasia are
`absent and the dysplasia persists for at least 6 months.
`Table 1 provides a comparison of the FAB and WHO
`classifications.
`
`Table 1. Classifications of myelodysplastic syndrome (MDS).
`
`FAB1
`RA
`
`RARS
`
`RAEB
`
`RAEB-T
`
`CMML
`
` —
`
`WHO3,4
`RA (unilineage)†
`5q– syndrome‡
`RCMD
`
`RARS† (unilineage)
`RCMD (with RS)
`
`RAEB-I
`RAEB-II
`
`AML
`
`MDS/MPD§
`
`Unclassified
`
`Abbreviations: MDS, myelodysplastic syndrome; FAB, French-
`American-British; WHO, World Health Organization; RA, refractory
`anemia; RCMD, refractory cytopenia with multilineage dysplasia;
`RARS, RA with ringed sideroblasts; RS, ringed sideroblasts; RAEB,
`RA with excess of blasts; RAEB-T, RAEB in transformation; AML,
`acute myeloid leukemia; CMML, chronic myelomonocytic leukemia;
`MPD, myeloproliferative disorder.
`†Requires ≥ 6 months of anemia unrelated to other causes.
`‡< 5% marrow blasts, micromegakaryocytes, thrombocytosis.
`§MDS: WBC ≤13,000/mm3; MPD: WBC >13,000/mm3.
`
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`Other categories within the WHO proposal include
`refractory cytopenia with multilineage dysplasia
`(RCMD), separating RAEB patients into those with < 10%
`versus > 10% marrow blasts, 5q– syndrome, and MDS
`Unclassified. MDS/MPD has been proposed for patients
`who previously had been classified as CMML.
`The WHO panel has also suggested excluding
`RAEB-T patients from MDS (proposing acute myeloid
`leukemia [AML] to now include patients with ≥ 20%
`marrow blasts, rather than the previously used 30% cut-
`off). However, as stated above, MDS is not only a dis-
`ease related to blast quantitation, but one that possesses
`a differing pace related to its distinctive biologic fea-
`tures, in contrast to de novo AML. Recent studies have
`provided conflicting evidence regarding the utility of the
`WHO proposals.6,7 Further studies will be needed to sub-
`stantiate the prognostic value of this system.
`Additional morphologic advances (e.g., degree of
`dysplasia, fibrosis) could provide additive information
`for characterizing MDS by building upon well-estab-
`lished forms of MDS categorization. Regarding biologic
`advances, as a new understanding of critical molecular,
`immunologic, immunophenotypic (using flow cytometry)
`and cytogenetic features of MDS emerges, these param-
`eters will also be added to currently accepted methods as a
`means to improve the characterization of MDS.
`
`How long will I live with my disease? What problems
`should I anticipate experiencing with my disease? What
`is my chance of developing leukemia?
`
`B. Disease Natural History
`
`1. Clinical features
`One of the major morbidities of MDS is symptomatic
`anemia, with associated fatigue, which occurs in the vast
`majority (~60-80%) of patients. Other cytopenias may
`also contribute to the patient’s symptom distress, includ-
`ing neutropenia (~50-60%) and dysfunctional neutro-
`phils leading to an increased incidence of infections.
`Thrombocytopenia (~40-60%) and thrombocytopathy
`ensue in more advanced forms of MDS, with associated
`bleeding. Of importance is being alert to the potential
`postoperative bleeding and infectious complications that
`may ensue in these patients who possess dysfunctional
`platelets and neutrophils. Proactive management of pa-
`tients’ perioperative periods with relevant transfusion and
`antibiotic support is quite important.
`With a moderate degree of variability, RAEB pa-
`tients and those with RAEB-T generally have a relatively
`poor prognosis, with a median survival ranging from 5
`to 12 months (reviewed in Greenberg8). In contrast, RA
`patients or RARS patients have median survivals of ap-
`
`proximately 3 to 6 years. The proportion of these indi-
`viduals who transform to AML varies similarly, ranging
`from 40% to 50% in the relatively high-risk RAEB/
`RAEB-T patients, and from 5% to 15% in the low-risk
`RA/RARS group. Regarding time-to-disease evolution,
`25% of patients with RAEB and 55% of patients with
`RAEB-T underwent transformation to AML at 1 year;
`35% of patients with RAEB and 65% with RAEB-T
`underwent transformation to AML at 2 years. RAEB
`patients with ≥ 10% blasts have poorer prognoses than
`do those with <10% blasts. In contrast, for patients with
`RA the incidence of transformation was 5% at 1 year
`and 10% at 2 years, and none of the RARS patients un-
`derwent leukemic transformation within 2 years.
`In addition to having symptoms related to their
`cytopenias and need for multiple transfusions, MDS pa-
`tients have major concerns about the potential for their
`illness to evolve into acute leukemia. Emotional stress
`and life-planning issues need to be addressed. All of these
`features lead to difficulties patients have with their quality
`of life (QOL).9,10 Assessment of and engagement in the
`patients’ relevant QOL domains—physical, functional,
`emotional, social, spiritual—are important for determin-
`ing and potentially improving the clinical status of these
`individuals. Several recent studies have demonstrated the
`positive effects of effective therapy for MDS on patients’
`QOL.11,12
`
`2. Prognostic stratification
`Despite its value for diagnostic categorization of MDS
`patients, the prognostic limitations of the FAB classifi-
`cation have become apparent, with quite variable clini-
`cal outcomes within the FAB subgroups. The morpho-
`logic features contributing to this variability include the
`wide range of marrow blast percentages for patients with
`RAEB (5-20%) and CMML (1-20%); lack of inclusion
`of critical biologic determinants, such as marrow cyto-
`genetics; and the degree and number of morbidity-asso-
`ciated cytopenias. These well-perceived problems for
`categorizing MDS patients have led to the development
`of additional risk-based stratification systems.13,14
`The International MDS Risk Analysis Workshop
`developed a consensus risk-based International Prognos-
`tic Scoring System (IPSS) for primary MDS (Table 2).14
`Compared with prior systems, the IPSS has markedly
`improved prognostic stratification of MDS patients. In
`the workshop, cytogenetic, morphologic, and clinical
`data were combined and collated from a relatively large
`group of patients who had been included in previously
`reported studies that relied on independent risk-based
`prognostic systems. FAB morphologic criteria were used
`to establish the diagnosis of MDS.
`Patients with CMML were subdivided into ‘prolif-
`
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`Table 2. International Prognostic Scoring System (IPSS) for
`myelodysplastic syndrome (MDS).*
`
`Prognostic
`Variable
`Marrow blasts (%)
`Karyotype†
`Cytopenias‡
`
`Survival and AML Evolution Score Value
`0
`0.5
`1.0
`1.5
`2.0
`< 5
`5-10
`—
`11-20
`21-30
`Good Intermediate Poor
`0-1
`2-3
`
`Risk Category
`Low
`Int-1
`Int-2
`High
`
`Combined Score
`0
`0.5-1.0
`1.5-2.0
`> 2.5
`
`Abbreviations: AML, acute myeloid leukemia.
`* Modified from Greenberg P, Cox C, Le Beau MM, et al. Interna-
`tional scoring system for evaluating prognosis in myelodysplastic
`syndromes. Blood. 1997;89:2079-2088.
`† Good = normal, –Y, del(5q), del(20q); Poor = complex
`(≥ 3 abnormalities) or chromosome 7 anomalies;
`Intermediate = other abnormalities.
`‡ Neutrophils < 1800/µL, hemoglobin < 10 g/dL, platelets
`< 100,000/µL.
`
`Table 3. Age-related survival and acute myeloid leukemia (AML) evolution in
`myelodysplastic syndrome (MDS) patients within International Prognostic Scoring
`System (IPSS) subgroups.*
`
`erative’ and ‘nonproliferative-dysplastic’ subtypes. Pro-
`liferative type CMML patients (those with white blood
`cell counts > 12,000/mm3) were excluded from this
`analysis, since these individuals predominantly repre-
`sented MPD rather than MDS.15 Nonproliferative CMML
`patients had white blood cell counts ≤ 12,000/mm3 as
`well as other features of MDS, and were included.
`The most significant independent variables for de-
`termining outcome for both survival and AML evolu-
`tion were found to be marrow blast percentage, number
`of cytopenias, and cytogenetics subgroup (Good, Inter-
`mediate, Poor) (Table 2).14 Patients with normal marrow
`karyotypes, del (5q), del (20q), and −Y (70%), had rela-
`tively good prognoses, whereas patients with complex
`abnormalities (i.e., ≥ 3 anomalies) or chromosome 7
`anomalies (16%) had relatively poor prognoses. The re-
`maining patients (14%) were intermediate in outcome.
`Of the patients in the complex category, the vast major-
`ity had chromosome 5 and/or 7 abnormalities in addi-
`tion to other anomalies.
`When the risk scores for the 3 major variables were
`combined, patients were stratified into 4 distinctive risk
`groups in terms of both survival and AML evolution.
`These risk groups are Low, Intermediate-1 (Int-1), In-
`termediate-2 (Int-2), and High (Table 2). Median sur-
`vivals and risk of MDS evolution
`were determined, and survival was
`shown to also be related to age
`(Table 3 and Figures 1 and 2).14
`Much less precise discrimination
`between the 4 subgroups occurred
`when either cytopenias or cytoge-
`netic subtypes were omitted from
`the classification. This system
`separated patients into relatively
`low-risk (IPSS Low, Intermediate-
`1 [Int-1]) and high/poor-risk (In-
`termediate-2 [Int-2] and High)
`prognostic groups.
`Extension of this system was
`planned to subsequently include
`certain immunologic, morpho-
`logic, and molecular anomalies
`that would also be shown to have
`an impact on clinical outcomes.
`Flow cytometric analysis of blasts
`from MDS patients has provided a
`valuable additive prognostic tool,
`as demonstrated by a recent study
`from Japan.16 These investigators
`showed that marrow blasts from
`most MDS patients possess a spe-
`cific immunophenotypic signature
`
`No. of Pts
`
`Low
`
` Median Survival (yr)
`Int-1
`Int-2
`
`Total pts.: No. (%)
`
`816
`
`Age ≤ 60 yr
` > 60 yr
` ≤ 70 yr
` > 70 yr
`
`206 (25%)
`611
`445 (54%)
`371
`
`267 (33%)
`5.7
`11.8
`4.8
`9.0
`3.9
`
`314 (38%)
`3.5
`5.2
`2.7
`4.4
`2.4
`
`176 22%)
`1.2
`1.8
`1.1
`1.3
`1.2
`
`No. of Pts
`
`Low
`
`25% AML Evolution (yr)
`Int-1
`Int-2
`
`Total pts.: No. (%)
`
`759
`
`Age ≤ 60 yr
` > 60 yr
` ≤ 70 yr
` > 70 yr
`
`187 (25%)
`572
`414 (55%)
`345
`
`235 (31%)
`9.4
`> 9.4 (NR)
`9.4
`> 9.4 (NR)
`> 5.8 (NR)
`
`295 (39%)
`3.3
`6.9
`2.7
`5.5
`2.2
`
`171 (22%)
`1.1
`0.7
`1.3
`1.0
`1.4
`
`High
`
`59 (7%)
`0.4
`0.3
`0.5
`0.4
`0.4
`
`High
`
`58 (8%)
`0.2
`0.2
`0.2
`0.2
`0.4
`
`Abbreviations: AML, acute myeloid leukemia; pts., patients; NR, not reached.
`* Modified from Greenberg P, Cox C, Le Beau MM, et al. International scoring system for
`evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079-2088.
`
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`Figure 1. Survival (left) and freedom from AML evolution (right) of myelodysplastic syndrome (MDS) patients related to their
`classification by the International Prognostic Scoring System (IPSS) for MDS: Low, Int-1, Int-2, High (Kaplan-Meier curves). AML
`indicates acute myeloid leukemia.
`Reprinted with permission from Greenberg P, Cox C, Le Beau MM, et al. International scoring system for evaluating prognosis in
`myelodysplastic syndromes. Blood. 1997;89:2079-2088.
`
`Figure 2. Survival, based on ages ≤≤≤≤≤ 60 years old (left) versus > 60 years old (right), of myelodysplastic syndrome (MDS) patients
`related to their classification by the International Prognostic Scoring System (IPSS) for MDS: Low, Int-1, Int-2, High (Kaplan-Meier
`curves).
`Reprinted with permission from Greenberg P, Cox C, Le Beau MM, et al. International scoring system for evaluating prognosis in
`myelodysplastic syndromes. Blood. 1997;89:2079-2088.
`
`that is distinct from AML and normal blasts.16 These
`investigators showed that a high percentage of enriched
`MDS blast cells had an immunophenotype descriptive
`of committed progenitor cells (i.e., were positive for
`CD34, 33, 13, 38, HLA-DR). In addition, differential
`expression of other surface markers on these blasts cor-
`related with stage of disease and prognosis. Thus, the
`immature-type CD7 marker was generally positive on
`blasts from late-stage MDS patients who had poor clini-
`
`cal outcomes, whereas the more mature CD15 marker
`was generally positive on blasts from MDS patients with
`earlier stage disease and better prognoses. A shift oc-
`curred to a more immature phenotype accompanying
`disease progression. These investigators also demon-
`strated that RAEB-T blasts possessed immunophenotypic
`markers more closely related to MDS than to de novo
`AML, indicating that there are biologic differences be-
`tween these entities.16 Incorporation of such analyses into
`
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`the IPSS system should further refine the ability to pro-
`vide useful prognostic information in MDS.
`The separation of CMML patients into proliferative
`and non-proliferative/dysplastic subgroups was sup-
`ported by a recent study of their clinical outcomes.17 An
`extensive review of CMML patients has also indicated
`that CMML patients could be subdivided into 4 prog-
`nostic risk groups based on a combination of indepen-
`dent predictive factors: level of marrow blasts and de-
`grees of anemia, peripheral blood immature mononuclear
`cells, and lymphocytes.18 In these patients, the presence
`of ras mutations, high LDH, and high β2 microglobulin
`levels were associated with poorer prognoses.
`
`What treatments are available for my disease?
`Which treatment(s) should I receive?
`When should I receive them?
`
`C. Therapeutic Options
`Data suggest that pathogenetic lesions in MDS relate to
`ineffective hemopoiesis due to enhanced apoptosis of
`hemopoietic cells within MDS marrow, particularly in
`low-risk patients.19-22 This intramedullary hemolysis is
`contributed to by increased marrow production of in-
`hibitory cytokines such as tumor necrosis factor-alpha
`(TNF-α), occurring in part through enhanced angiogen-
`esis.19,22-24 During disease progression, decreased apop-
`tosis of the hemopoietic precursors occurs with associ-
`ated expansion of the abnormal clone. Biospecific agents
`aimed at countering some of these lesions in MDS, which
`currently are being evaluated in experimental trials, in-
`clude stimulatory growth factors, antiapoptotic agents,
`blockers of inhibitory cytokines, antiangiogenesis com-
`pounds (mainly for low-risk disease), and ras inhibitors
`and arsenicals (mainly for higher-risk disease; see below).
`The therapeutic options for MDS include support-
`ive care, low-intensity therapy, and high-intensity
`therapy. The main goal of low-intensity therapy gener-
`ally is to cause hematologic improvement and is used
`mainly in low-risk disease, whereas high-intensity
`therapy generally aims to alter the disease’s natural his-
`tory (i.e., improve survival, decrease AML evolution)
`and is used mainly in higher-risk disease.25 Concomi-
`tant with both aims is the desire to improve patients’
`QOL. Cytogenetic responses are surrogate markers of
`response that will likely have an impact on disease out-
`come similar to that found in treatment of other myeloid
`malignancies.
`
`1. Supportive care
`Currently, the standard of care in the community for MDS
`is ‘supportive care.’ This type of care entails red blood
`cell transfusions, generally leukocyte reduced, as needed
`
`for symptomatic anemia or platelet transfusions for se-
`vere thrombocytopenia or thrombocytopenic bleeding.
`For patients with excessive iron accumulation due to the
`number of red blood cell transfusions received (gener-
`ally > 40 units), iron chelation therapy should be insti-
`tuted, generally with subcutaneous nightly desferriox-
`amine.26 For this parameter, serum ferritin levels and
`associated organ dysfunction (e.g., heart, liver, pancreas)
`should be monitored.
`
`2. Low-intensity therapy
`Low-intensity therapy includes use of biologic response
`modifiers or low-intensity chemotherapy, agents that
`generally can be administered to outpatients, in addition
`to supportive care. These agents [except for erythropoi-
`etin (Epo), for which much data regarding its efficacy
`exist] should be administered in the context of clinical
`trials, because for most of these agents limited informa-
`tion is available regarding their general efficacy, opti-
`mal doses, toxicity, or the appropriate selection of pa-
`tients.
`a. Treatment of the anemia of MDS: Epo±G-CSF.
`Hemopoietic stimulatory cytokine support should be
`considered for treating refractory symptomatic
`cytopenias, particularly the anemia occurring in MDS.27
`Much progress has been made in improving the man-
`agement of the anemia in MDS, with its associated fa-
`tigue. The general presentation of the anemia related to
`MDS is a hypoproductive macrocytic anemia, often as-
`sociated with suboptimal elevation of serum erythropoi-
`etin (Epo) levels.8 Morphologic examination of a bone
`marrow aspiration is important to determine FAB sub-
`type, iron status, and the presence or absence of ringed
`sideroblasts. The potentially beneficial use of recombi-
`nant human Epo to treat symptomatic anemia in MDS
`has been well established. Data indicate that Epo given
`daily or 3 times a week subcutaneously in relatively high
`doses may be efficacious, generally in doses of 10,000-
`20,000 units daily, with response rates of 20-30%.28 For
`responders, drug doses and their frequency may be re-
`duced as tolerated. For patients not responding after 4-6
`weeks, the drug could be given in combination with
`granulocyte colony-stimulating factor (G-CSF), 1 µg/kg/
`day (or with granulocyte-macrophage colony-stimulat-
`ing factor [GM-CSF]), which will generally double the
`response rate (i.e., to 40%-60%).29 This response pat-
`tern is particularly true for MDS patients with serum
`Epo levels < 500 mU/mL and for those with ringed
`sideroblasts.30,31 Evidence has indicated that G-CSF (and
`to a lesser extent GM-CSF) has synergistic erythropoi-
`etic activity when used in combination with Epo and
`markedly enhances the erythroid response rates.29-31 This
`is particularly evident for patients with ringed sidero-
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`blasts or with serum Epo levels < 500 mU/mL.
`Iron repletion needs to be verified prior to institut-
`ing Epo therapy. Often, despite adequate iron stores, poor
`utilization of storage iron in many of these patients may
`make oral iron supplementation helpful. Erythroid re-
`sponse generally occurs within 2 to 3 months of treat-
`ment. If no response occurs by that time, this treatment
`should be considered a failure and discontinued and al-
`ternative therapies considered (generally within a clini-
`cal trial). These therapies to consider (indicated below)
`include specific attempts at altering biologic lesions in
`MDS: anti-angiogenic compounds (anti-vascular endot-
`helial growth factor [VEGF] drugs), anti-tumor necro-
`sis factor (TNF) agents (e.g., Enbrel), thalidomide, 5-
`azacytidine (AzaC), immunosuppressive type therapies
`(e.g., antithymocyte globuline [ATG], cyclosporin), sin-
`gly or in combination. As multiple biologic abnormali-
`ties contribute to the cytopenias of MDS, it is likely that
`combination therapy will be needed to sustain hemato-
`logic responses in these patients.
`A recent report indicated the presence of neutraliz-
`ing anti-erythropoietin antibodies associated with pure
`red cell aplasia and Epo resistance in a small number of
`patients with renal failure who had received chronic Epo
`treatment.32 Virtually all such cases have been reported
`from Europe and may relate to differing Epo prepara-
`tions or manufacturing processes which differ from those
`employed elsewhere. Morphologic marrow examination
`and Epo antibody assays will aid in diagnosis of this
`iatrogenic problem.
`For attempting to enhance erythropoiesis in MDS
`by using less frequent dosing, a modified form of eryth-
`ropoietin (darbepoetin) with a 3-fold longer biologic half-
`life than standard Epo has shown good efficacy with less
`frequent dosing for patients with anemias induced by
`renal failure or chemotherapy.33 Trials are ongoing to
`assess the role of this agent in MDS.
`b. Treatment of neutropenia. Although low neutro-
`phil levels have been demonstrated to be improved with
`either recombinant human G-CSF or GM-CSF, data have
`not shown decreased infections or improved infection
`management with these agents in MDS. A Phase III ran-
`domized trial in high-risk MDS that compared chronic
`administration of G-CSF to observation and demon-
`strated no difference in the incidence or pace of devel-
`opment of AML or of infections in the 2 study arms.34
`For those patients with RAEB, a shortened survival was
`noted in the G-CSF arm. Thus, this agent is not recom-
`mended for chronic prophylactic use alone in MDS.
`Rather, a suggested approach is to employ these cyto-
`kines in neutropenic MDS patients with recurrent or
`antibiotic-refractory infections.
`c. Treatment of thrombocytopenia. For treating
`
`thrombocytopenia in MDS, relatively low doses (10 µg/
`kg/d) of IL-11 have recently been shown in a Phase I/II
`trial to be more effective than higher doses of the drug.35
`Further studies are ongoing with this agent. Occasional
`efficacy of danazol has also been reported in such pa-
`tients. Studies are warranted to determine the potential
`efficacy of thrombopoietin for the thrombocytopenia
`present in MDS.
`d. 5-azacytidine. As a form of low-intensity chemo-
`therapy, recent encouraging data in MDS have been re-
`ported with the hypomethylating agent AzaC.36 In a ran-
`domized Phase III trial, AzaC decreased the risk of leu-
`kemic transformation; it also improved the survival of a
`portion of the patients.36 This trial evaluated 171 MDS
`patients, comparing AzaC (75 mg/m2/d subcutaneously
`for 7 days every 28 days, predominantly as an outpa-
`tient) with supportive care. Patients in the supportive care
`arm whose disease worsened were permitted to cross
`over to AzaC. Responses occurred in 60% of patients
`on the AzaC arm (7% complete response, 16% partial
`response, 37% improved) compared with 5% (improved)
`receiving supportive care. Median time to leukemic trans-
`formation or death was 21 months for AzaC versus 13
`months for supportive care. Transformation to AML
`occurred in 15% of patients on the AzaC arm and in
`38% receiving supportive care. Eliminating the con-
`founding effect of early crossover to AzaC, a landmark
`analysis after 6 months showed median survival of an
`additional 18 months for AzaC and 11 months for sup-
`portive care. QOL assessment found significant major
`advantages in physical function, symptoms, and psycho-
`logical state for patients initially randomized to AzaC.12
`Thus, AzaC treatment resulted in significantly higher
`response rates, improved QOL, reduced risk of leuke-
`mic transformation, and improved survival compared
`with supportive care. This agent appears to provide a
`new treatment option that is superior to supportive care for
`patients with MDS. Further trials with this agent are ongo-
`ing to attempt to confirm and extend these findings.
`e. Immunosuppressive therapy. The biologic re-
`sponse modifiers potentially capable of altering immune
`medicated subtypes of MDS which are now available
`include ATG and cyclosporine37-40 and will be discussed
`in detail by Dr. Neal Young in Section II. However, these
`data, though encouraging for specific subtypes of MDS
`(mainly hypoplastic MDS patients with normal cytoge-
`netics and evidence of a paroxysmal nocturnal hemo-
`globinuria [PNH] clone and HLA-DR2 subtype), require
`further evaluation in more extended clinical trials.
`f. Anti-TNF, anti-angiogenesis agents.Numerous
`Phase I/II clinical trials evaluating the roles of specific
`biologic response modifiers have been used to treat MDS.
`Relatively small pilot trials with anti-TNF fusion pro-
`
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`tein (etanercept, Enbrel) indicated erythroid responses
`in about 30% of patients in one trial, and lower levels of
`responses in another.41,42
`Clinical trials assessing the role of antiangiogenesis
`compounds [e.g., thalidomide, anti-VEGF agents] are
`ongoing. Although thalidomide has multiple mechanisms
`of action, its role as an antiangiogenic or anti-TNF agent
`may be important in its therapeutic effects. Results of
`treatment with thalidomide have been reported in 2 sepa-
`rate trials, with a 19% response rate in one and 56% in
`the other, including erythroid and trilineage responses.43,44
`In the latter trial, relatively high doses of thalidomide
`(i.e. > 300 mg/day) were tolerated, an unusual finding
`for this elderly population. Additional studies, includ-
`ing those with less toxic metabolites of thalidomide, are
`ongoing to better define the role of these agents in MDS.
`Use of a number of biologic response modifiers
`(amifostine, pentoxyphylline, interferon, low-dose AraC,
`retinoids, vitamin D analogues, butyrates) has previously
`been shown to have quite limited efficacy in Phase I-II
`trials with MDS patients.8,45 Other ongoing clinical tri-
`als include the use of agents capable of inhibiting neo-
`plastic growth, such as anti-ras type compounds [farnesyl
`transferase inhibitors (FTIs)] and arsenic trioxide. Re-
`cent preliminary studies have shown efficacy of FTIs in
`treating poor-risk AML, CMML, and MPDs.46,47
`
`3. High-intensity therapy
`High-intensity therapy includes intensive induction che-
`motherapy or hemopoietic (marrow or peripheral blood)
`stem cell transplantation (HSCT).8,48 Although these ap-
`proaches have a greater chance of changing the natural
`history of the disea