The myelodysplastic syndromes: biology and implications for management.

REVIEW ARTICLE

The Myelodysplastic Syndromes: Biology and Implications for Management By Alan F. List, Harinder S. Garewal, and Avery A. Sandberg Since the initial efforts to characterize the myelodysplastic syndromes in 1976, an extensive body of information has accumulated defining biologic features and the relation to clinical aspects of disease. While the pathogenesis of these disorders remains incompletely understood, laboratory investigations indicate that they are clonal disorders affecting hematopoietic stem cells characterized by a progressive imbalance between self-renewal and differentiation. Despite karyotypic resemblance to acute myeloid leukemia, fundamental biologic differences may underly the disappointing results achieved to date with inten-

M

ORE THAN a decade has passed since

the French-American-British (FAB) Cooperative Group first characterized the myelodysplastic syndromes and proposed diagnostic criteria for their recognition.' In 1982, the classification was expanded to include five disorders distinguishable by morphologic features: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), chronic myelomonocytic leukemia (CMML), refractory anemia with excess blasts (RAEB), and RAEB-in-transformation (RAEB-T).2 These disorders by definition share histologic features of hematopoietic dysplasia and display a varied propensity for leukemic transformation. The natural history of the myelodysplastic syndromes varies widely, ranging from chronic anemias with low propensity for leukemic conversion to disorders characterized by profound disturbance in blood-cell production with a high risk

From the Division of Hematology/Oncology, Department of Medicine, University of Arizona College of Medicine and the Tucson Veterans Administration Medical Center, Tucson; and the Genetics Center of the Southwest Biomedical Research Institute, Scottsdale, AZ. Submitted November 7, 1989; accepted April 2, 1990. Supported in part by United States Public Health Service Grant P01-CA 27502. Dr Garewal is a recipient of an American CancerSociety CareerDevelopment Award. Address reprintrequests to Alan F. List, MD, Section of Hematology/Oncology (111D), Veterans Administration Medical Center, 3601 S 6th Ave, Tucson, AZ 85723. © 1990 by American Society of ClinicalOncology. 0732-183X/90/0808-0016$3.00/0

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sive chemotherapy. The recent availability of recombinant hematopoietic growth factors for use in clinical trials has shown that the maturation defect in many instances can be overcome with administration of lineage-restricted recombinant hematopoietins. Routine use of these promising agents must await results of randomized clinical trials to determine the impact of prolonged treatment on leukemic evolution and disease-related morbidity. J Clin Oncol 8:1424-1441. @ 1990 by American Society of ClinicalOncology.

of progression to acute leukemia or bone marrow failure.3- 7 Recent investigations have demonstrated that the pathogenesis of cytopenias in these disorders is more heterogeneous than previously recognized. 8"" Advances in understanding the complexity of factors that govern the process of normal hematopoietic differentiation have furthered our understanding of the biologic abnormalities that underly the myelodysplastic syndromes, and provided new insight for therapeutic intervention.' 2'13 Herein we will briefly review the biology of hematopoiesis, corresponding disturbances detected in the myelodysplastic syndromes, and their relation to patient management. NORMAL HEMATOPOIESIS

An extensive body of information indicates the existence of a hierarchy of hematopoietic differentiation whereby mature blood cells derive from a small number of hematopoietic precursors with extensive capacity for self-renewal, termed hematopoietic stem cells.14 Pluripotent stem cells give rise to morphologically indistinguishable progeny committed to differentiation along one of two lineage pathways, ie, lymphoid colonyforming unit [CFU-L] or the multipotent CFU granulocyte, erythrocyte, monocyte, and megakaryocyte (CFU-GEMM). This balanced process of stem-cell replication and differentiation is regulated locally via a complex interplay with the hematopoietic microenvironment composed of stromal cells (fibroblasts, endothelial cells, and reticulum cells), accessory cells (T-lymphocytes,

Journalof Clinical Oncology, Vol 8, No 8 (August), 1990: pp 1424-1441

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MYELODYSPLASTIC SYNDROMES: A REVIEW

macrophages, and natural-killer [NK] cells), and extracellular matrix.1 5 17 Humoral factors liberated by stromal elements provide regulatory signals active at different stages of lineage development. 18"2 The biologic activity of hematopoietic growth factors is dependent on intimate contact between hematopoietic cells and specific components of the microenvironment. 21' 22 Glycosaminoglycans in the extracellular matrix selectively retain growth factors and present them in an active form to hematopoietic progenitors.23,24 Developing hematopoietic cells remain anchored to specific glycoproteins in the extracellular matrix via membrane adhesion antigens until ready for release into the general circulation. 252 7 This anchorage dependence is evidenced in vivo by segregation of immature forms along the endosteal surface.15,28 Release of mature cells into the circulating blood compartment is triggered by transient expression of specific carbohydrate moieties on the plasma 29 30 membrane. ,

Changes in the rate of production of mature blood cells in response to systemic demands are achieved by shifting cells from progenitor to differentiating compartments under the selective influence of hematopoietic growth factors.1 9 Interleukin- 1-alpha (hematopoietin-1) in cooperation with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (multiCSF), and interleukin-6 play important roles in the recruitment of primitive marrow progenitors from a quiescent to a proliferative state.3 1' 32 Although these hematopoietins promote colony formation of multilineage progenitors, differentiation along specific lineage pathways is potentiated by interaction with growth factors possessing more restricted lineage specificity, ie, erythropoietin, granulocyte (G)-CSF, and macrophage (M)-CSF. The cellular events responsible for transmission of the CSF signal are incompletely understood. Growth-factor binding to surface receptors initiates a cascade of events that generally culminates in translocation of cytosolic protein kinase C to the plasma and nuclear membranes. 333- 5 The proliferative capability of progenitor cells ultimately derives from expression of specific growth-promoting genes. Transcripts of c-myc, c-myb, and c-fos proto-oncogenes are detected in actively dividing normal and leuke-

mic progenitors. 36-38 Induction of terminal differentiation is preceded by down-regulation of these genes, arrest of cell growth, and expression of lineage-specific CSF receptors. 37-40 Selective manipulations of cellular oncogenes indicate that down-regulation of c-myb is an essential early event in this sequence.4 1 BIOLOGIC FEATURES OF MYELODYSPLASIA Impairment of differentiation capacity is the fundamental abnormality shared by the myelodysplastic syndromes. Results of bone marrow culture studies,42 X-chromosome inactivation studies, and cytogenetic analysis 43"45 indicate that the defect arises at the level of the multi- or pluripotent stem cell. Varied lineage penetrance of the maturation abnormality appears to underly the diverse hematologic manifestations that may involve one or all major cell lines. Blood cells produced by the abnormal clone may be functionally deficient and have shortened survival in the marrow and peripheral blood. In the majority of cases, the defect is unstable resulting in progressive loss of differentiation competence, worsening cytopenias, and/or evolution to acute myeloid leukemia. Bone marrow culture studies from patients with myelodysplasia show reduced or absent colony formation of multipotent progenitors (CFU-GEMM), irrespective of FAB type.46-48 The maturation defect is not uniformly apparent in unipotent progenitors, but may be restricted to certain lineages, whereas others retain maturation competence. Growth of CFU-GM and other committed progenitors generally corresponds to peripheral blood abnormalities. Patients with sideroblastic anemia for example, whose disease is often characterized by isolated anemia, typically exhibit single lineage defects in colony assays. 47,49-51 The notable exception is CMML, distinguished by excessively increased growth of CFU-GM in the absence of exogenous colonystimulating activity (CSA) supplementation, 52 a feature shared with the myeloproliferative syndromes. Recent observations that GM-CSF is produced by CMML cells suggest that this hematopoietin may participate in the spontaneous in vitro proliferation of CMML by autocrine stimulation.5 3 Investigations of GM-CSF, multi-CSF, and G-CSF production by marrow stromal and acces-


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LIST, GAREWAL, AND SANDBERG

sory cells have described normal or elevated activity. 47 ,54 ,55 While myelodysplastic progenitors

generally remain dependent on CSA for in vitro growth, CFU-GEMM growth is noticeably deficient and poorly supported by supplementation with recombinant growth factors. 48,56,57 Recombi-

nant GM-CSF, G-CSF, and erythropoietin partially restore growth of committed progenitors, indicating a blunted response to regulatory signals that is most apparent at the level of multipotent progenitors. 48,58 ,59 The nature of this abnor-

mality may be heterogeneous, involving defects affecting receptor-signal transduction as well as extracellular abnormalities. Luikart et al and others 60,61 have reported aberrant production of

glycosaminoglycans in myelodysplasia and myeloid leukemia. Changes in the marrow matrix may alter local processing of growth factors and anchorage-dependent cellular interactions influencing progenitor cell differentiation. Excess production of certain matrix components may restrict developing hematopoietic elements to an extended period of residency within the marrow and limit entry into the circulating blood compartment. Two patterns of myeloid colony growth are distinguishable that have prognostic significance, designated as leukemic and nonleukemic.47,62-65

The latter is marked by persistent colony formation accompanied by small clusters with modest maturation impairment. Leukemic growth, in contrast, is characterized by absent or reduced colony growth and micro- or macrocluster formation. In patients studied serially, evolution from a nonleukemic to a leukemic pattern is demonstrable with disease progression.66 6' 7 This pattern is

associated with abnormal marrow cytogenetics, a high propensity for leukemic transformation, and considerably shortened median survival. 62 Histologic features of leukemic-type growth are identifiable on trephine marrow biopsies by abnormal central clustering of myeloid precursors, which often precedes clinical evidence of leukemic transformation.6 8 Studies examining the molecular basis of the maturation defect are limited, but preliminary evidence suggests fundamental abnormalities in proto-oncogene expression. P-75, the peptide product of c-myb, is found in high concentration in myelodysplastic cells of all lineages at each stage of maturation. 38 Although oncoprotein con-

tent declines with differentiation, it remains disproportionately elevated relative to normal hematopoietic elements at equivalent stages of maturation, reflecting an imbalance between selfrenewal and differentiation. Whether such changes represent a primary disturbance in protooncogene regulation or reflect other defects in cell control is as yet undetermined. The recent identification of hematopoietic-specific, transcription regulatory genes that may function as primary regulators of differentiation, warrants study in myelodysplasia.6 9 Differences in genetic stability of neoplastic stem cells may govern the rate and type of hematologic progression. Two principal patterns of evolution have been identified in prospective studies. 4,70 The first is characterized by gradual accumulation of marrow blasts with eventual termination in acute leukemia or progressive hematopoietic failure. Serial culture studies have shown a succession of karyotypically distinct subclones with incremental impairment in maturation potential.71'72 The second pattern is distinguished by an abrupt transformation to acute leukemia with high blast-cell proliferative capacity following a variable period of apparent hematologic stability. Acquisition of collaborative proliferation signals may be a critical factor in this sequence. Point mutations resulting in transcriptional activation of N-ras proto-oncogene alleles, collaborative activators of protein kinase C,73 are detected in 30% to 40% of cases of myelodysplasia.74' 77 The major body of evidence indicates preferential expression in CMML, and other subtypes with leukemic progression. The precise chronology of acquisition of ras mutations and the relation to leukemia conversion is currently being evaluated in a prospective study by the Cancer and Leukemia Group B (CALGB). The ras gene products are homologous to the guanine-nucleotide-binding G-proteins that couple membrane receptors to phospholipase C. 78 The growth-promoting effect of ras oncoproteins appears to derive at least in part from their ability to augment growth factor-dependent proliferation. 79 Data implicating the development of autocrine growth characteristics in leukemic transformation are conflicting. Autonomous blast proliferation in vitro, including leukemias evolving from a myelodysplastic syndrome, is associated with production of autostimulatory



activity that is neutralized by antibodies to GMCSF.80 Some, but not all investigators, have found constitutive expression of CSF-genes in acute myeloid leukemias 81'8 2; however, the inclusion of cases studied following short-term culture introduces potential bias that may not reflect physiologic events in vivo. Indeed, one study has found CSF gene transcription to be uncommon in unprocessed leukemia specimens, and frequently induced as an artifact of in vitro processing.83 It is likely that CSF gene overexpression is uncommon in AML; however, autocrine mechanisms may participate in blast proliferation via posttranscriptional events stabilizing CSF gene message. 84 Whatever mechanisms are involved, host factors appear to influence this sequence since not all patients with leukemic growth in clonogenic assay ultimately demonstrate clinical progression.85 Murine preleukemia models induced by radiation have shown that these cells but not their leukemic counterparts are immunogenic, and intact NK-cell activity is central to preventing emergence of leukemia.86 8s 7 Whether immune response influences leukemic progression in human myelodysplasia is uncertain. NK-cell number and function have been studied in patients with myelodysplasia and are commonly deficient. 79 '85 1 9 It is unclear whether this represents expression of a pluripotent stem-cell defect, or a host feature with pathogenetic significance. Although some investigators have noted a correlation between marrow blast count and degree of NK functional impairment, 92 this has not been a consistent finding. 88' 90 CYTOGENETICS

Clonal cytogenetic abnormalities are detected in more than 50% of patients with myelodysplasia at initial presentation. 9 "98 The frequency with which such abnormalities are found varies with morphologic category, ranging from 30% to 50% in RA, RARS, and CMML to 60% to 90% in remaining subtypes. The number or complexity of defects follows a similar pattern and is highest among more malignant phenotypes and therapyrelated myelodysplasia. 964'00 Abnormalities affecting three chromosomes occur with sufficient frequency to indicate a nonrandom association; these include numerical or long-arm deletions of chromosomes 5 and 7, and trisomy 8. These abnormalities account for fewer than a third of

1427 the karyotypic abnormalities detected in patients with de novo acute myeloid leukemia (AML), but as many as 80% of those found in therapyrelated AML. 98 10 ' o This cytogenetically defined subset of myeloid leukemia shares clinical and biologic features in common with the myelodysplastic syndromes, occurring predominantly in older individuals and often preceded by a "preleukemic" phase.°0 2 Results of a recent epidemiologic survey performed by Farrow et al10 3 have shown that, like their karyotypically related leukemic counterparts, patients with myelodysplastic disorders have an inordinately high incidence of exposure to petrochemicals and other potential mutagens. Chromosome translocations and inversions specifically associated with de novo AML such as t[8;21], t[15;17] and invl6 are rare in myelodysplasia. The detection of clonal chromosomal abnormalities in patients with myelodysplasia is associated with a heightened risk of hematologic progression and shortened survival independent of FAB type.62,93-95,98,100,104-106 However, the perceived risk

varies with the number of abnormal metaphases and specific aberrations permitting segregation into cytogenetically defined prognostic groups (Table 1). Patients with an interstitial deletion of the long arm of chromosome 5 (5q-) as an isolated defect characteristically have a stable clinical course and low risk of leukemic conversion comparable to that seen in patients with a normal karyotype. Monosomy 7 and complex chromosomal defects identify patients with a shortened survival due to leukemia or progressive cytopenias. Within each cytogenetic category, the detection of residual normal metaphases exerts a moderating effect on survival.62 1" Analysis of DNA content provides similar prognostic information with poorer survival among patients with hypodiploid marrow cells compared with patients with hyperploidy or normal DNA content.' 40 07 Table 1. Cytogenetically Defined Prognostic Groups Prognostic category Favorable Intermediate Unfavorable

Karyotype Normal del 5q +8 del 7q, -7 Complex defects

Adapted with permission.9


Median Survival (months) > 24 18 < 12

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Despite their prognostic significance, mounting evidence indicates that chromosome aberrations per se are not the initiating pathogenic event. Unique point mutations may precede appearance of structural chromosome abnormalities or may be identified in karyotypically discordant clones. 74, 75 '10 8"10 9 In addition, in up to two thirds of patients experiencing leukemic progression cytogenetic abnormalities are not demonstrable or appear late in the clinical course.4'94'105'110 Raskind et al"' proposed that alterations in karyotype occur after a step that leads to expansion of a genetically unstable clone of hematopoietic stem cells. Accordingly, chromosome aberrations may be considered markers of a broader disturbance in genomic stability, associated in most instances with a higher incidence of genetic events that impart more malignant growth characteristics. This appears especially true for patients with monosomy 7 or complex defects, and is supported by the high frequency of emergence of additional aberrations in patients with an abnormal karyotype compared with cytogeneti5 112 4 93 94 0 cally normal individuals. , , ,1 '

Certain clinical phenotypes in myelodysplasia have been linked to specific, recurring genetic defects. Monosomy 7 or partial deletion of the long arm of chromosome 7 is associated with loss of a major surface glycoprotein, impairment of granulocyte, and monocyte chemotaxis, and in113 114 creased susceptibility to bacterial infection. , The best characterized of the genetic defects, however, is the long-arm deletion of chromosome 5 or the so-called 5q- syndrome. This abnormality, when present as an isolated defect in patients with refractory anemia, is associated with a clinically distinct hematologic syndrome characterized by profound dyserythropoiesis, macrocytic anemia, and normal or increased platelet number accompanied by dysplastic megakaryocytes.s'1,"' Although the precise breakpoint may vary, the chromosome segment most often deleted involves an interstitial segment localized to 5ql 3-33. Among the genes mapped to this region are those encoding five hematopoietic growth factors (GM-CSF, IL-3, IL-4, IL-5, and M-CSF) and the M-CSF receptor (c-fms). 116-120 The bio-

logic significance of their deletion is uncertain since in vitro abnormalities of progenitor cell growth are generally limited to the erythroid series."116 Huebner et al

21

have proposed that

rearrangement of this and related gene clusters may represent normal events in commitment to myeloid differentiation, analogous to the recombinatorial events known to precede lymphocyte lineage commitment. Such rearrangements and ensuing deletions would normally go undetected because of restriction to postmitotic cells. However, when occurring in neoplastic clones with self-renewal capacity, such deletions may be conserved. Nevertheless, hemizygosity for the 5q growth factor gene cluster may afford some degree of protection from leukemic transformation in view of the remarkably low frequency of leukemic conversion that appears unique to this cytogenetic defect. IMMUNE ABNORMALITIES A variety of abnormalities affecting cellular and humoral immunity has been identified in patients with myelodysplasia. Decreased circulating NK-cell number is accompanied by absolute lymphopenia in the majority of patients. Immunophenotyping has shown pronounced deficits in CD4+ T-lymphocytes and normal or increased numbers of CD8 + T cells. 89'122' 123 Clonal involvement of T-lymphocytes may underlie these abnormalities in some cases. 43' 108 However, Hokland et al123 found a close correlation between helper-cell loss and total number of transfusions administered, implying acquisition of these defects via immunosuppressive effects of blood component therapy. T-lymphocyte function is similarly affected; proliferative response to mitogens is depressed and gamma-interferon production is significantly impaired.

12 4 12 6

In contrast to studies of

NK cells, suppressor T-lymphocyte number at presentation in patients with RA or RARS, and changes observed during the course of disease may be inversely predictive of hematologic progression.'27 T-cell mediated suppression of hematopoiesis is demonstrable in 15% of patients, analogous to that seen in aplastic anemia. 8'128 Monocyte production of interleukin- 1 (IL-1) has been reported to be normal in the limited number of patients studied.129 Immunoglobulin production in myelodysplasia is generally intact. One third of patients exhibit polyclonal elevations in serum immunoglobulins, and a monoclonal gammopathy is evident in an additional 12% of patients. 130 Autoantibody production appears to be particularly common in


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patients with CMML. Solal-Celigny et al"'3 detected erythrocyte autoantibodies directed against the I-antigen in 13 (46%) of 28 patients. A variety of polyspecific autoantibodies are demonstrable in over half of CMML patients.' 30 Why such humoral abnormalities are overrepresented in CMML is uncertain, but may relate to clonal expansion of B-lymphocytes or excessive stimulation by cytokines elaborated by neoplastic monocytes (eg, IL-6).53 In a recent study of thrombocytopenia in myelodysplasia, Stadtmauer et a1' 32 detected increased amounts of platelet-bound immunoglobulin and circulating antiplatelet antibody in 55% of patients at presentation, irrespective of FAB type. The monocyte Fc-receptor number was similarly increased to levels comparable to that seen in idiopathic thrombocytopenic purpura. PATHOGENESIS

If the multihit theory of carcinogenesis holds true for the myelodysplastic syndromes, then at least two steps are necessary for disease expression: an initial, potentially silent genomic alteration, that promotes a state from which a second insult can initiate neoplastic transformation. Abundant evidence from marrow culture, cytogenetic, and chromosome inactivation studies indicates that these changes must occur at the level of a primitive hematopoietic stem cell, the result of which is expansion of a single multipotent stem-cell clone. As indicated earlier, somatic mutations leading to exaggerated or abnormal expression of cellular oncogenes have been implicated in this sequence. Point mutations resulting in transcriptional activation of N-ras alleles are detected in 30% to 40% of cases of myelodysplasia.7477 Recognition that such mutations may be detected late in the clinical course indicate that other cellular oncogenes may be involved in initiation of tumorigenesis. Indeed, using tumorigenicity assays, oncogene expression can be detected in an additional 28% of cases that lack N-ras mutations by polymerase chain reaction.133 These findings indicate the presence of activating mutations affecting other members of the ras gene family or expression of additional, unrecognized cellular oncogenes. Jacobs et al recently identified point mutations in codon 301 of the c-fms proto-oncogene in 13% of cases of myelodysplasia AML.'3 4 Investigations by Roussel et

al and others'135,'136 have shown that mutations at this site produce a confirmation change in the M-CSF receptor that results in sustained kinase activity and neoplastic transformation in susceptible cells. As expected, the incidence of c-fms mutations is greatest in CMML (six of 30), with activating mutations of either ras orfms detected in 80% of CMML cases overall (R. Padua, personal communication, May 1990). Transfection studies describing induction of M-CSF responsiveness and commitment to monocytic differentiation with introduction of c-fms CDNA into primitive myeloid progenitors provide convincing support for a role of activating c-fms mutations in dictating ligand-independent, monocyte lineage commitment in myelodysplasia. 241 Factors responsible for these specific genetic insults may be heterogeneous. A constitutional predisposition may occasionally be identified in young individuals; however, with few exceptions, this does not apply to the majority of adults with myelodysplastic syndromes. Since the incidence of these disorders increases with age, senescence itself with attendant acquisition of spontaneous mutations has been proposed as a potentially important predisposing factor. Increasing evidence indicates that environmental factors may contribute to this process. The type of ras mutations detected in the myelodysplastic syndromes are characteristic of those produced by alkylating agents and other chemical mutagens.138-140 Epidemiologic studies have implicated exposure to benzene,141-143 radiation,144 chemotherapeutics, and alkylating agents in particular 45",146 as initiating factors in the development of myelodysplasia. Indeed, among hematologically normal individuals previously treated with chemotherapy for non-Hodgkin's lymphoma, mutant ras alleles are demonstrable by polymerase chain reaction in blood cells of up to 13% of individuals.' 37 Although a history of such exposure can be elicited in only a fraction of patients, a recent case-control survey has shown a consistently higher frequency and intensity of exposure to petrochemicals and other potential environmental mutagens in persons with primary myelodysplasia.' 03 The implications of these findings are that the cumulative effect of exposure to generally unrecognized environmental toxins may be an important contributor in the development of myelodysplasia. In support of this, investiga-


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tions in our laboratories and others1 47,148 have

shown expression of the multidrug resistance gene (MDR1) or its glycoprotein product in marrow specimens from up to 40% of patients with primary myelodysplastic syndromes. In vitro investigations and murine models have shown that MDR is induced following exposure to xenobiotics and certain chemical carcinogens, and thereby has been implicated as a potential 49pheno50 typic marker of chemical carcinogenesis.1 ,1

Experience from laboratory studies has shown that adaptive genetic changes alone may be insufficient to confer tumorigenicity in the absence of collaborative changes in the microenvironment. The age-related decline in number and proliferative capacity of hematopoietic progenitors and impaired stromal-cell responsiveness limits normal hematopoiesis with advancing age.151-153 Excessive production of proteoglycans

by myelodysplastic progenitors may alter local processing of growth factors and provide a favor60 6 able milieu for outgrowth of malignant clones. ' 1 The relative contribution of these changes remains speculative; however, future investigations will provide insight into the importance of these interactions. MANAGEMENT

Treatment decisions for patients with myelodysplasia are complicated by the variable natural history of the disorders, the advanced age of affected patients, and paucity of controlled clinical trials. Empiric treatment with androgens or pyridoxine seldom results in sustained hematologic improvement.154 -156 Transfusion therapy

may ameliorate symptoms, but is unlikely to positively influence the natural history of disease. Therapeutic strategies designed to restore effective hematopoiesis may be divided into three major categories based upon the presumed mechanism of action: immune modulation, cytotoxic therapy, and differentiating agents. Immune Modulation In the only prospective trial evaluating the activity of glucocorticoids in myelodysplasia, patients treated with prednisone were compared with a concurrent cohort managed with supportive care alone.128 Clinical response was correlated with the ability of cortisol to enhance granulocyte colony growth in vitro. Hematologic

improvement was noted in only three patients, whereas eight (24%) experienced undue toxicity. Interestingly, clinical response to prednisone was limited to three of five in vitro responders with cortisol-sensitive, hematopoietic-inhibitory Tlymphocytes. 8 The basis for this aberrant immune response is uncertain, but may relate to allo- or neoantigen expression by neoplastic hematopoietic progenitors. 57,158 Although an empiric trial of prednisone cannot be justified for the majority of patients, the recognition of immune regulation of blood-cell production in a subset of patients with myelodysplasia has stimulated further study of immune manipulation in selected individuals. Patients with hypoplastic myelodysplasia in particular, because of histologic resemblance to aplastic anemia, were included in recent trials using antithymocyte globulin or cyclosporine.11,159-161 Among 10 patients treated, seven failed prior treatment with corticosteroids. Effective hematopoiesis was partially restored in six patients, with remission durations ranging from 2 to 36+ months. The achievement of hematologic remissions in this histologic subset implies a pathophysiologic relation between hypoplastic myelodysplasia and aplastic anemia. 162 This is supported by observations of an increasing late risk for development of myelodysplasia or AML in long-term survivors of aplastic anemia treated with antithymocyte globulin.' 63 ,164 At present, the effect of such treatment, if any, on the evolution to leukemia is unknown. Investigators at the University of Pennsylvania have used danazol, an attenuated synthetic androgen with established activity in immune thrombocytopenia, to ameliorate the severity of thrombocytopenia in selected patients with elevated platelet-bound immunoglobulin. 9, 0° Among 28 patients treated for a minimum of 3 months, eight (28%) benefited with a mean rise in platelet count of 63%. Response to danazol was limited to patients with moderate thrombocytopenia and fewer than 20% marrow blasts, and was associated with a decrease in monocyte Fc-receptor number. Changes in platelet-bindable immunoglobulin were not detected. Although thrombocytopenia primarily results from ineffective thrombopoiesis, danazol may ameliorate thrombocytopenia in selected individuals with accelerated platelet clearance. However, its clinical use-


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fulness is limited since people with severe thrombocytopenia generally do not benefit from such therapy. Empiric treatment in unselected patients has yielded less encouraging results.'6 5'16 7

Table 3. Results of Intensive Chemotherapy in Primary Myelodysplastic Syndromes

Cytotoxic Therapy

No. of Patients Median Less Than Median No. of Age CR + PR 50 Years CR Duration Patients (year) (%) of Age (months)

Reference 7

Mertelsman et al1 Armitage et a117 76 Tricot et al Fenaux et al'" Martiat et 0al' Gajewski et al79

The subacute nature of the myelodysplastic syndromes and advanced age of affected patients have relegated use of cytotoxic therapy to individuals with leukemic conversion or poor-prognostic subtypes (eg, RAEB, RAEB-T). Among younger patients with a compatible marrow donor, however, bone marrow transplantation has proved to be a potentially curative mode of therapy in 40% to 50% of cases (Table 2). Results to date are comparable for patients with either primary or therapy-related myelodysplastic syndromes. An initial report of a higher risk of graft failure in patients with increased marrow-fibrosis16 8 was not confirmed in subsequent studies. 6 9 ' 170,'

17 3

45 20 15 29 25 44

53 70 59 47 50 59

22 (49) 3 (15) 8(53) 14(48) 8 (32) 18(41)

NR 2 6 6 4 8

7 22+ 12 8.5 7 9

Abbreviations: CR, complete remission; PR, partial remission; NR, not reported.

prolonged survival in de novo AML, this may not be the case in myelodysplasia. Nevertheless, available data suggest that the majority of patients do not benefit from intensive cytotoxic therapy. In the only study in which causes of treatment failure were compared with a concurrently treated patient cohort with de novo AML, patients with myelodysplasia or leukemia following antecedent hematologic disorder had a significantly longer interval to granulocyte recovery and a higher frequency of regeneration failure, which significantly increased treatment-related morbidity.1 79 Additionally, drug resistance evidenced by failure to achieve remission, requirement for two or more treatment courses to achieve remission, and short remission duration was significantly more common among the myelodysplastic group. Importantly, these differences persisted after adjustment for age, indicating that the limited efficacy of conventional leukemia therapy in myelodysplasia may relate in part to intrinsic biologic differences between the disorders. Neoplastic involvement of a primitive, genetically unstable stem

As

might be anticipated, age, higher pretreatment leukemic burden, and longer duration of disease adversely influence outcome, 173 indicating younger patients should be considered for transplantation relatively early in the disease course. Treatment with conventional cytarabineanthracycline combinations has yielded results inferior to that achieved in de novo adult AML with an average rate of complete remission approaching 30% (Table 3). Differences in age distribution and attendant higher treatmentrelated morbidity contribute to the disparity in outcome. Indeed, patients less than 50 years of age may have a higher remission rate and perhaps a survival advantage, although comparative trials have not been conducted and the number of patients in each series is small. While achievement of complete remission is necessary for

Table 2. Results of Bone Marrow Transplantation in Patients With Myelodysplastic Syndromes Reference 8

Appelbaum et al1s 69

O'Donnell et al' 7

Guinan et al' Bunin et al"'7 Belanger et a1172

Median Age (year)

Preparative Regimen

No. of Patients

Treatment-Related Deaths

No. of Relapses

24

CT CT + TBI CT CT + TBI CT + TBI CT + TBI CT CT + TBI

3 27 5 15 8 6 4 4

12 3 6 4 2 1 1

3 2 4 1 1

36 12 10 34

Abbreviations: CT, chemotherapy; TBI, total body irradiation. *Range, 4 to 85 months.


Event-Free Survival*(%) 13(48) 2 (40) 5 (33) 4 (50) 3 (50) 3 (75) 2 (50)

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cell in the myelodysplastic disorders may itself limit the ability to successfully reestablish nonclonal hematopoiesis, a notion supported by the higher rate of induction failure observed in acute myeloid leukemias exhibiting trilineage dysplasia.'8 0 Alternatively, myelodysplastic progenitors may by nature exhibit a higher degree of intrinsic drug resistance. These features may be inherently inseparable. However, cytogenetic studies in AML have consistently identified patients with abnormalities of chromosomes 5 and 7 as a group with poor response to standard induction chemotherapy.!81-184 The biologic basis for this may derive at least in part from expression of the multidrug resistance (MDR) phenotype. The multigene family encoding the surface glycoprotein associated with MDR has been mapped to the long-arm of chromosome 7.185 Sato et a1' 86 recently demonstrated expression of the MDR1 gene in leukemic blasts of patients with monosomy 7 and patients whose disease evolved from a myelodysplastic syndrome; MDR I overexpression was associated with clinical resistance to chemotherapy as evidenced by failure to achieve a complete remission or short remission duration. Investigations in our laboratory and others have shown a high prevalence of expression of the MDR phenotype in primary myelodysplastic disorders and associated acute leukemias.147,148 These findings have important therapeutic implications. A variety of agents including calcium channel blockers, calmodulin inhibitors, and cyclosporine restore sensitivity to 8 7 88 chemotherapy in resistant tumor cell lines' , and have demonstrated encouraging results in 18 9 91 preliminary clinical trials," providing a framework for future trials in high-risk subsets of myelodysplasia and associated acute leukemia. DifferentiatingAgents The progressive impairment in blood-cell maturation that characterizes the myelodysplastic syndromes makes them attractive targets for treatment with differentiation promoting agents. In vitro observations that continuous exposure of HL-60 cell lines to low concentrations of cytarabine could induce terminal differentiation192 triggered numerous clinical trials in patients with myelodysplasia.'5 5 '93 -98 In a review of 170 assessable patients treated with low-dose (5-25 mg/ m2/d) cytarabine regimens, 63 (37%) were re-

ported to have a major response.99 However, remission durations were generally short, and myelotoxicity was common with a reported fatal complication rate of 15%. The impact of such therapy on survival was addressed in a recently completed randomized trial performed by the Eastern Cooperative and Southwest Oncology Groups. 200 Eligible patients received either a 21-day course of low-dose cytarabine (20 mg/ m2/d) or supportive care. Of 51 patients in the treatment arm, only 12 (23%) had a major hematologic response lasting a median of 8 months. Although treated patients had a significantly longer interval to disease progression, there was no discernable difference in overall survival between the treatment and control groups. Comparison of results by FAB type showed the highest response in patients with RAEB-T (50%), whereas treatment negatively influenced survival in patients with RA or RARS. Moreover, the probability of achieving a favorable response correlated with the percentage cytoreduction at day 14 and conversion to a normal karyotype, implying the therapeutic effect is due principally to cytotoxicity rather than cell differentiation. It is clear from this study that low-dose cytarabine does not have a role in the management of patients with RA or RARS. Although hematologic remissions can often be achieved in patients with RAEB-T, a favorable impact on survival has not been demonstrated, and alternative treatment strategies should be considered. A variety of other agents including thioguanine, heme arginate, calcitriol, interferons, retinoids, and certain bisacetamides have significant activity in vitro as inducers of leukemic cell differentiation, but have demonstrated limited success in uncontrolled clinical trials in myelodysplasia.92'20 12"0 7 Retinoic acid analogs have been the most extensively studied. 13-cis retinoic acid (CRA), a stereoisomer of the native 13-trans compound, suppresses competence gene expression, inhibits cell proliferation, and promotes differentiation of marrow progenitors from patients with myelodysplastic syndromes.208-211 Phase I-II trials involving 100 patients with myelodysplasia demonstrated partial responses defined by improvement in at least one hematologic parameter in 27.211-216 Denmatologic and

hepatic toxicity were significant at the doses used


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in these studies (20 to 125 mg/m 2/d) and limited patient compliance. In a randomized trial limited to patients with RA or RARS,2 17 treatment with a daily dose of 20 mg was well tolerated and yielded a marked improvement in 1-year survival that was limited to the RA subgroup. Accompanying improvements in peripheral blood counts were not observed. A notable deficiency of this study, however, was the remarkably poor 1-year survival in the untreated cohort raising the likelihood that the difference in outcome is related to patient selection rather than the treatment per se. A recent double-blind trial comparing CRA (100 mg/m 2/d) to placebo in 68 patients with varied FAB types showed no difference in progression-free or overall survival. 218 Although this study does not exclude a possible beneficial effect in patients with early-stage disease since so few of the participants (< 15%) had indolent FAB types, it is clear that the majority of patients do not benefit from such treatment. The recent availability of recombinant human colony-stimulating factors (rhCSFs) has enabled clinical application of these physiologic regulators of hematopoiesis in varied states of bone marrow failure. Hematopoietins derived from one of two sources, ie, yeast or bacteria, have been evaluated and show comparable activity and toxicity profiles. Phase I-II trials using

rhGM-CSF have demonstrated potent stimulation of hematopoiesis in all FAB types (Table 4). Prolonged intravenous infusion or subcutaneous administration of the growth factor elicits doserelated increments in neutrophil, eosinophil, and monocyte counts in most patients. Whether intravenous administration offers any advantage over the more convenient subcutaneous route is as yet undetermined, but is the focus of an ongoing randomized trial using the yeast-derived product. Importantly, toxicity is mild and dosedependent, and neither tachyphylaxis nor neutralizing antibodies have been detected with repeated administration. Side effects encountered reflect the broad biologic activity of GM-CSF and secondary cytokine elaboration. At lower doses, fever, lethargy, thrombophlebitis, and bone pain may be noted, whereas pericarditis and edema appear as dose-limiting toxicities. Although GMCSF exhibits multipotent effects in vitro, amelioration of RBC or platelet transfusion requirements is observed in fewer than 15% of patients. Persistence of clonal cytogenetic abnormalities and premature chromosome condensation analysis of maturing granulocytes indicates that the beneficial effect of treatment is due principally to differentiation of neoplastic progenitors rather than selective stimulation of residual normal progenitors.226,227 The ability of GM-CSF to

Table 4. Phase I-I Trials of Recombinant GM- and G-CSF Myelodysplastic Syndromes

Reference 21

Vadhan-Raj et a1 ' Antin et a122' 22

Ganser et a1l

Thompson et ol

2

1

3

Rifkin et a12"

Herrmann et a1232

Kobayashi et a122 Negrin et a122l

4

Duration and Route

No. of Patients

Lineage Response (Range)

Hematopoietin (source)

Dose and Schedule

GM-CSF (yeast) GM-CSF (yeast) GM-CSF (yeast)

30-500 gg/m /d x 14, every 4 wks 2 15-480 Ag/m /d x7-14 d; every 4 wks 2 15-150 sg/m /d x7-14 d, every 4 wks

8-32 wks, CI

8

4-28 wks, IV (1-12 h) 44 wks, IV (8 h)

7 11

GM-CSF (E coli) GM-CSF (yeast) GM-CSF (E coli)

0.3-10 g/kg/d

2-9 wks, SQ

16

>_4wks, SQ

11

every 10 d x 11 IV (every 5 h)

4

IV (every 5 h)

4

4

6-8 wks, SQ

12

10 (2-10 x)

G-CSF G-CSF (E coli)

2

30-480

pg/m 2 /d 2

5-750 gg/m /d x 5

2

50-1,600 Ag/m /d x6d 0.1-3.0 Mg/kg/d

Multilineage Response

8 (5-70 x) 6 (1.6-6.4x) 10 (1.3-18x)

Hgb:3 Plat:3 -

12 (2-194x) 10 (Ž2x) 4 (1.8-3.5x)

Plat:3

-

Plat:1 -

Hgb:2

Leukemia Progression (FAB Type) 4 (RAEB:3; CMML:1) 1 (RAEB-T) 2 (RAEB; RAEB-T) 4 (RAEB ± T:2; CMML:2) -

Abbreviations: E coli, Escherichiacoli; d, days; CI, continuous intraveneous infusion; IV, intravenous; SQ, subcutaneous, h, hours; Hgb, hemoglobin; Plat, platelets.


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support in vitro growth of leukemic blasts has raised important concerns regarding the effect of prolonged treatment on the risk of leukemic evolution.228,229 Preliminary observations suggest that treatment with rhGM-CSF may indeed accelerate progression to AML in patients with a higher initial leukemic burden (ie, > 15% marrow blasts) (Table 4). Patients with CMML, which by nature exhibits augmented proliferative capability, may also be at increased risk. Nevertheless, rhGM-CSF has important therapeutic potential, and the impact of such treatment on the natural history of disease and related morbidity is currently being evaluated in a multicenter randomized trial. rG-CSF has been less extensively studied, but has demonstrated comparatively minor toxicity attributable to its narrow lineage specificity. Bone pain and hyperuricemia may occur with prolonged administration, but symptoms infrequently limit achievement of effective doses. The results of two phase I-II trials in patients with myelodysplastic syndromes are summarized in Table 4. A dose-dependent response that is limited to granulocytes is achieved in the majority of patients; an improvement in hemoglobin was noted in only two of 14 patients. Persistent normalization of granulocyte counts was achieved in eight of 10 neutropenic patients receiving maintenance treatment for 4 to 16 months. 230 An apparent advantage of G-CSF is its ability to partially restore granulocyte function in patients with myelodysplasia 225,231 which may not be the case with rhGM-CSF administration.23 3 Its preferential specificity for late myeloid progenitors suggests it may have comparatively less stimulatory effect on existing leukemia clones. Whether it has any clinical advantage over GM-CSF will need to be addressed in carefully designed phase III trials. Multipotent hematopoietins such as IL-3 and IL-1 may have broader application in myelodysplasia. Phase I trials with IL-3 are in progress, and a preliminary report indicates it may effect substantial, multilineage hematologic changes. Among 13 patients with varied forms of bone marrow failure treated by Kurzrock et a1234 with daily intravenous infusions, four experienced improvements in platelet, granulocyte, and reticulocyte number at the dosage levels evaluated. Interestingly, hematologic improvements per-

sisted up to 12 weeks following cessation of treatment. Side effects resembled those reported with GM-CSF and included fever, headache, and pleural effusions. The synergy observed between IL-3 and other growth factors both in vitro and in primates suggests that IL-3 alone or in combination with other hematopoietins may have important therapeutic applications in myelodysplasia. 23 5 FUTURE DIRECTIONS Advances in the past decade in understanding the biologic disturbances in the myelodysplastic syndromes have provided important insights into potentially useful avenues of treatment. Because these disorders differ with respect to prognosis and biologic features, no standard therapy can be recommended. Supportive care remains the mainstay of therapy for most patients. Although an occasional patient may benefit from the judicious use of drugs such as danazol or isotretinoin, empiric therapeutic trials cannot be generally recommended. Clearly, enrollment in clinical trials testing new therapeutic approaches must be given high priority. Results of treatment with the recombinant hematopoietins GM-CSF and G-CSF indicate that this class of agents has enormous therapeutic potential. Combinations of multipotent or lineage restricted hematopoietins offer the potential to alleviate cytopenias and minimize morbidity due to infection and hemorrhage. Future clinical trials should incorporate recombinant growth factors with agents that preferentially suppress the malignant clone and thereby halt progression of the neoplastic process. In vitro observations that GM-CSF preferentially stimulates uptake of cytarabine by malignant blasts23 6237 , have triggered clinical trials combining this hematopoietin with low-dose cytarabine. 238 Inhibitory cytokines such as gammainterferon 239 and new retinoids or vitamin D analogs with improved therapeutic index merit investigation. Despite elevated levels of immunoreactive erythropoietin, 240 high doses of the recombinant hormone alone or in combination with other hematopoietins may ameliorate the anemia of myelodysplasia. Phase II trials are currently underway to address this question. Elimination of the abnormal clone remains a possibility, particularly for young individuals with a higher


1435


leukemic burden who may better tolerate aggressive cytotoxic therapy or who are candidates for bone marrow transplantation. Recognition of biologic features contributing to drug resistance may permit pharmacologic manipulations to exploit such factors and improve chemotherapy effectiveness. Treatment strategies combining recombinant growth factors with cytotoxic ther-

apy may improve response by recruitment of kinetically resistant cells and reduce morbidity by shortening the interval to hematologic recovery. Major advances in the treatment of the myelodysplastic syndromes await application of these concepts and further investigations to elucidate the basic cellular disturbance that underlies these disorders.

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