This Article Abstract Full Text (PDF) CME: Take the course for this article: New Approaches to the Treatment of Myelodysplasia eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by List, A. F. Search for Related Content PubMed PubMed Citation Articles by List, A. F.

New Approaches to the Treatment of Myelodysplasia

Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA

Correspondence: Alan F. List, M.D., Associate Professor of Medicine, Director, Bone Marrow Transplant Program, University of Arizona, 1515 N. Campbell Avenue, Tucson, Arizona 85724, USA. Telephone: 520-626-2340; Fax: 520-626-2415; e-mail: Mhala{at}azcc.arizona.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
After taking all of the CME courses in this supplement the reader will be able to:

1. Describe the basic biology of various leukemias, multiple myeloma, and myelodysplastic syndrome (MDS).
   
2. Discuss new targeted treatment strategies for hematologic malignancies.
   
3. Understand the rationale for the use of nontraditional cytotoxic agents such as arsenic trioxide in the treatment of hematologic malignancies.
   
4. Examine the role of arsenic trioxide and other novel agents in early-versus accelerated-stage hematologic disease.
   
5. Discuss the preclinical and clinical efficacy of arsenic trioxide and various agents in treating acute promyelocytic leukemia, MDS, and multiple myeloma.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
The therapeutic dilemma that confronts the management of patients with myelodysplastic syndromes (MDS) is illustrated by the absence of a Food and Drug Administration-approved agent with an indication for this disease. Clinical heterogeneity and inadequate understanding of the disease pathobiology have limited progress in the development of novel therapeutics. Preclinical investigations indicate that reciprocal interaction between the malignant clone and the microenvironment serve to create a hostile milieu that reinforces ineffective blood cell production. Ineffective hematopoiesis, the hallmark of MDS, arises from impaired progenitor responsiveness to normal trophic signals and excess local generation of inhibitory cytokines, which promote accelerated apoptotic loss of progenitors and their progeny. Evidence to support this model derives from cytokine neutralization studies and the direct relationship between plasma tumor necrosis factor- concentration and DNA oxidation and glutathione depletion in malignant CD34⁺ progenitors. Recent investigations indicate that angiogenic molecules generated by malignant myelomonocytic precursors represent integral diffusable signals that reinforce leukemia progenitor self-renewal while promoting the generation of proapoptotic cytokines and medullary angiogenic response. The potential for leukemia evolution is compounded by epigenetic events including methylation silencing of the p15 proto-oncogene or activating ras point mutations. Delineation of such biologic features that are central to the pathobiology of MDS provides a reliable framework for the development of novel therapeutics.

Antiangiogenic agents in clinical testing include vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, thalidomide and related analogues, and the recombinant VEGF neutralizing antibody, bevacizumab. Agents whose actions may restore differentiation programs, such as the DNA methyltransferase inhibitors or histone deacetylase inhibitors, offer the prospect to promote effective hematopoiesis while impacting the potential for leukemia evolution. RAS farnesyl transferase inhibitors have shown encouraging preliminary results in acute myeloid leukemia and are currently under investigation in advanced MDS and chronic myelomonocytic leukemia. Arsenic trioxide (ATO) interacts with a spectrum of biologic targets that may be uniquely suited to MDS. ATO is a potent inducer of apoptosis in thiol-depleted malignant progenitors and neovascular endothelium, while promoting differentiation through histone acetylation and inactivation of transcriptional corepressors. The identification of relevant biologic targets in MDS has raised expectations for the development of disease-specific therapies for MDS in the years that follow.

Key Words. Acute myeloid leukemia • Investigational agents • Myelodysplasia

	INTRODUCTION

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
The myelodysplastic syndromes (MDS) have emerged as one of the most common hematologic malignancies affecting adults. The estimated crude incidence of MDS ranges from 3.5-12.6/100,000 per year in the U.S. However, the relative risk increases with age, reaching 15-50/100,000 per year in persons older than 70 years [1]. Although there is no national registry of patients with MDS, an estimated 15,000 to 20,000 new cases are diagnosed annually, primarily affecting individuals between 58 and 74 years of age [1]. These figures probably underestimate the true incidence of MDS, since patients with low-grade disease have a paucity of symptoms and display subtle bone marrow changes [1]. As the population of the industrialized world ages, and as physician awareness and diagnostic recognition of MDS increase, the incidence of MDS is expected to rise dramatically over the next few decades [2].

The major manifestations of MDS reflect the signature biologic feature, i.e., ineffective hematopoiesis, which arises from accelerated apoptotic death of affected multipotent hematopoietic progenitors and their progeny. Patients with MDS typically present with an unexplained anemia often accompanied by reticulocytopenia [3]. In a recent analysis, anemia was the presenting manifestation in 85% (99/117) of MDS patients [4].

No uniformly effective treatment exists for patients with MDS. Allogeneic stem cell transplantation and intensive induction chemotherapy have had limited success, particularly in the elderly, who are poor candidates for such aggressive procedures. Therefore, there is a tremendous need for novel approaches in the management of MDS. Advances in our knowledge of the pathobiology of MDS and insight into the molecular biology of the disease have led to innovative approaches to this hematologically diverse group of bone marrow malignancies. Among these treatments are DNA methylation inhibitors, aminothiols, clonal suppression with new classes of agents such as the topoisomerase I inhibitors and farnesyltransferase inhibitors (FTIs), angiogenesis inhibitors, and arsenic trioxide (ATO). This article provides a succinct overview of the pathobiology and classification of MDS and presents experimental and clinical experience to date with these new therapeutics.

	PATHOPHYSIOLOGY OF MYELODYSPLASIA

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
The Seed (Clone) and the Soil (Microenvironment)
MDS is characterized by refractory multilineage cytopenias that result in dependence on transfusion, excessive risk of infection or hemorrhage, and heightened potential for transformation to acute myeloid leukemia (AML). Ineffective hematopoiesis results from a complex interaction between hematopoietic progenitors and the microenvironment, resulting in premature apoptotic death of progenitors and their maturing progeny. Myelodysplastic bone marrow progenitors display deficient growth of multipotent and primitive erythroid progenitors, retarded maturation capacity, and impaired responsiveness to growth factors despite normal receptor display and ligand-binding capacity [5-9]. Chronic myelomonocytic leukemia (CMML) represents the sole exception, demonstrating myeloid progenitor hypersensitivity to GM-CSF associated with activated Ras point mutations. Erythroid progenitors display both impaired phosphorylation of the signal transduction factor STAT-5 and induction of the erythroid-specific factor GATA-1, in response to erythropoietin stimulation [10]. Although normal erythroid precursors constitutively express fas receptor (CD95), receptor density is low, thereby fostering a high level of resistance to fas ligand-induced apoptosis [11-13]. In contrast, in myelodysplastic CD34⁺ cells, both fas receptor and ligand display are increased, permitting autocrine and paracrine activation of the cell death program [14-17]. The intensity of CD95 expression on MDS CD34⁺ cells inversely correlates with blast percentage, whereas fas ligand density remains preserved, indicating that with disease progression, myeloblast populations emerge that are more resistant to fas ligand-induced cell death [16,18].

CD95 upregulation in hematopoietic progenitors is mediated in part by the actions of tumor necrosis factor- (TNF-) and other inflammatory cytokines [12]. Overproduction of inflammatory cytokines, such as TNF- and interleukin-1ß (IL-1ß), is demonstrable in both the bone marrow microenvironment and the plasma of patients with MDS [11,12,19-22]. These cytokines promote the apoptotic death of long-term initiating cells as well as of primitive and committed progenitors [12]. Indeed, in vitro neutralization of TNF- promotes the outgrowth of MDS bone marrow progenitors [23]. There is a direct correlation between the concentration of TNF- in the bone marrow plasma and both nucleotide pyrimidine oxidation and depletion of cellular glutathione in CD34⁺ bone marrow mononuclear cells, supporting an effector role for these cytokines in the impaired hematopoiesis of MDS [22].

VEGF and Medullary Angiogenesis in MDS
Delineation of biologic signals responsible for the induction of proapoptotic cytokines in MDS represents a focus of active investigation. Bone marrow microvessel density (MVD) is increased in trephine biopsies, and the density directly correlates with myeloblast percentage [24]. A critical factor contributing to neoplastic angiogenesis is vascular endothelial growth factor (VEGF), a potent homodimeric peptide with biologic actions that extend to the regulation of hematopoietic stem cell development, extracellular matrix remodeling, and the generation of inflammatory cytokines [25-32]. Transcriptional regulation of VEGF is influenced by numerous upstream signals, including Ras activation, which converge upon the oxygen-sensitive, hypoxia inducible factor, HIF1. We have shown that VEGF is overexpressed and secreted by myelomonocytic precursors in MDS and AML, which also display the high-affinity receptor, VEGFR-1 (Flt-1), whereas erythroid precursors are receptor naïve [33,34]. This pattern of VEGF and receptor coexpression is demonstrable in central myeloblast clusters (i.e., abnormal localized immature precursors) in MDS biopsy specimens, monocytic precursors of CMML, and AML myeloblasts.

Neutralization of VEGF inhibits leukemia colony formation (CFU-L) in advanced MDS and CMML, whereas recombinant human (rHu)-VEGF stimulates CFU-L formation in clinical specimens [33,34]. Indeed, using receptor-competent AML cell lines as an in vitro model, we have shown that rHu-VEGF exerts direct trophic effects leading to increases in colony size and number and leukemia self-renewal [34].

Although VEGF may impart a trophic signal for myeloid elements, excessive local elaboration of VEGF may accelerate apoptotic death of receptor-naïve erythroid progenitors. In vitro observations that antibody neutralization of VEGF suppressed the generation of TNF- and IL-1ß and promoted the formation of multipotent and erythroid progenitors from MDS bone marrow mononuclear cells support this notion [33,34]. Similarly, Broxmeyer et al. [35] showed that rHu-VEGF promotes in vitro expansion of myeloid progenitors while inhibiting the formation of erythroid bursts and multipotent progenitors. Prolonged in vivo administration of rHu-VEGF results in intense medullary hyperplasia of immature myeloid elements and arrest of erythroid maturation in animal models [36].

Cytogenetic Abnormalities
Clonal cytogenetic abnormalities are demonstrable in 40%-50% of patients with primary MDS and in up to 80% of patients with secondary or treatment-induced MDS [2,3]. The specific chromosome affected and the number of chromosomal abnormalities (i.e., complexity) offer powerful prognostic information. Evolution to AML, however, may be influenced by epigenetic events. For example, methylation silencing of the proto-oncogene p15^INK4b is detected in >70% of patients experiencing AML evolution [37,38].

Apoptosis Regulation
Accelerated apoptosis (programmed cell death) and abnormal apoptosis regulation in hematopoietic progenitors and their progeny represent important elements of the pathobiology of MDS. In low-risk MDS, characterized by refractory cytopenias and low leukemic burden, the apoptotic index and the proliferative fraction are markedly increased, resulting in ineffective hematopoiesis and bone marrow hypercellularity [1,18]. With progression to more advanced stages of the disease, the apoptotic index decreases, accompanied by further impairment in maturation potential with a corresponding elevation in blast percentage. A number of biologic events have been implicated in the seeming reversal in survival signal regulation; these include upregulation of the Bcl-2 and/or Bcl-X_L antiapoptotic proteins, methylation silencing of the p15^INK4b proto-oncogene, and downregulation of the Fas receptor. Mutations of p53 and other tumor suppressor genes are infrequent, but may contribute to leukemia clonal expansion.

	CLASSIFICATION AND PROGNOSIS OF MYELODYSPLASIA

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
For a classification scheme to be useful, it must be easily applied, reproducible, and clinically relevant. Since 1976, MDS has been categorized by the French, American, and British (FAB) morphologic scheme into five subgroups based upon the number of ringed sideroblasts, degree of monocytosis, and the percentage of myeloblasts (Table 1) [39,40]. While this classification has prognostic utility, owing primarily to the discrimination in blast percentage, some aspects remain controversial. These include the validity of defining CMML as a myelodysplastic disorder despite its myeloproliferative features, the wide range in survival among patients with refractory anemia with excess blasts (RAEB), and the failure to recognize a form of MDS characterized by dysplasia confined to a single cell lineage. The World Health Organization (WHO) proposed changes to the classification of neoplastic diseases of the hematopoietic system [41,42]. The WHO reclassified proliferative CMML (i.e., leukocyte count >13,000/µl) as a disorder with mixed myelodysplastic and myeloproliferative features, and divided RAEB into two categories using a myeloblast threshold of 10%: RAEB-I, with 5%-10% blasts, and RAEB-II, with 11%-20% blasts (Table 2) [41,42]. The category of RAEB in transformation (RAEB-t), with 21%-30% myeloblasts, was eliminated in favor of a lower blast threshold for AML. Although this classification is not universally endorsed, it offers a more refined prognostic discrimination, as demonstrated in a recent retrospective analysis of 1,600 patients [43,44].

	STANDARD CARE OF THE PATIENT WITH MYELODYSPLASIA

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

The only curative therapy demonstrated to date for patients with MDS is high-dose chemotherapy with stem cell transplantation. Younger patients with low-grade MDS (e.g., IPSS Intermediate-I), favorable cytogenetics, and an appropriately matched sibling or unrelated donor can be treated with allogeneic transplantation with expectations for cure ranging from 40%-60% [46,47]. However, allogeneic transplantation is associated with high morbidity and mortality (30%-50%), which increases with age. An alternative investigational therapy is high-dose chemotherapy followed by autologous stem cell transplantation [46]. Although this procedure decreases the period of posttransplantation cytopenias and eliminates the risk of graft-versus-host disease, which complicates allogeneic stem cell transplantation, the risk of relapse from graft contamination by clonal progenitor cells is pronounced.

Chemotherapy as applied in AML, with cytarabine and an anthracycline, alone or in combination with other chemotherapeutic agents or hematopoietic growth factors, has been employed as a less toxic, moderately effective treatment for patients with MDS [50,51]. Although generally not curative, this approach can suppress leukemia burden and improve cytopenias, and it may induce complete remissions in some patients [46,50]. Patients with the greatest potential for sustained remission are young individuals with normal or more favorable cytogenetic patterns.

	NOVEL THERAPEUTIC INTERVENTIONS

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
Since few treatments, other than stem cell transplantation, offer the prospect to alter the natural history of MDS, a number of novel interventions have been and remain under investigation. Promising agents include DNA methylation inhibitors, aminothiols, and agents intended to suppress the MDS clone such as topoisomerase I inhibitors and FTIs, angiogenesis inhibitors, and ATO.

DNA Methylation Inhibitors
DNA methylation allows mammalian cells to modify gene expression epigenetically. Methylation occurs when DNA methyltransferase covalently links a methyl group to the 5-position of cytosine residues [52]. Promoter hypermethylation is the most common type of epigenetic DNA modification in human malignancies that silences gene transcription. In normal physiology, DNA methylation also serves to recruit methyl-binding proteins, promote X chromosome inactivation, facilitate imprinting, and provide nuclear protection against viral DNA insertion [53]. An increase in DNA methyltransferase activity appears universal in neoplastic cells, contributing to inactivation of tumor suppressor genes by transcriptional repression [52].

DNA methyltransferase inhibitors, such as 5-azacytidine, promote hypomethylation of DNA, leading to expression of previously silenced genes. The Cancer and Leukemia Group B reported the results of a randomized controlled trial of 5-azacytidine versus observation in 191 patients with MDS [54]. The majority of patients were elderly (median age 68 years), male (69%), and transfusion dependent (71%). Patients of all FAB subtypes with significant hematologic deficits were randomly assigned to a 16-week course of treatment with 5-azacytidine 75 mg/m²/day s.c. for 7 days in 28-day cycles x 4 (n = 99) or observation (n = 92). Patients in the observation arm were permitted to cross over to the 5-azacytidine arm after 16 weeks or if disease progression occurred.

5-azacytidine therapy produced responses in 63% of patients (47% hematologic improvement, 10% partial remission, and 6% complete response), while only 7% of patients receiving supportive measures experienced improvement (p < 0.0001). 5-azacytidine prolonged the median time to progression to AML by 10 months (12 months versus 22 months; p = 0.0034) and decreased the probability of leukemia transformation (31% versus 11%) (p = 0.003). Quality of life was significantly improved with 5-azacytidine treatment [54,55], including symptoms such as fatigue (p = 0.001), dyspnea (p = 0.0014), physical functioning (p = 0.0002), positive affect (p = 0.0077), and psychological distress (p = 0.015) [55].

The effects of 5-azacytidine on both hematologic response and AML evolution indicate that it may have an impact on relevant methylation targets in MDS, thus emerging as the first of a new class of agents with tangible therapeutic benefit in these patients. At present, 5-azacytidine is available only for compassionate release by the National Cancer Institute, but it is being considered for orphan drug approval by the Food and Drug Administration (FDA).

Aminothiols
Organic thiols can neutralize both the free radicals generated in tissues exposed to cytotoxic drugs as well as the reactive metabolites of those drugs [56]. Amifostine is a phosphorylated aminothiol that was developed as a radioprotective agent at the Walter Reed Army Medical Institute [57]. Following systemic administration, the prodrug is dephosphorylated by tissue alkaline phosphatase [56]. Because the activity of alkaline phosphatase is much greater in normal tissue than in tumor tissue, active free thiol accumulates to a greater degree in nontumor tissue. These properties have allowed amifostine to be administered as a selective radioprotective and a cytoprotective agent in solid tumors [58].

In preclinical models and in vitro studies, amifostine protects primitive hematopoietic progenitors from chemotherapy-induced toxicity and stimulates hematopoiesis by promoting the formation of hematopoietic progenitors [57,58]. In a canine model, a single dose of i.v. amifostine produced reticulocytosis and thrombocytosis, accompanied by an increase in white blood cell count and hematocrit [57]. In vitro, amifostine stimulates the formation of primitive hematopoietic progenitors up to sevenfold [57]. The greatest activity is apparent in multipotential and erythroid progenitors, as revealed by in vitro assays for colony-forming unit-granulocyte, erythrocyte, megakaryocyte, macrophage, and BFU-E. The stimulatory effects of amifostine remain erythropoietin dependent [57].

In a phase I/II study in patients with MDS, i.v. amifostine was administered to four cohorts of patients at doses of 100, 200, or 400 mg/m² three times per week, or 740 mg/m² once weekly, for three consecutive weeks, followed by an observation period of 2 weeks [59]. Single-lineage or multilineage responses were observed in 83% of patients (15/18) treated with the three-times-per-week dose schedule. Of these patients, 78% (14/18) demonstrated a 50% increase in neutrophil count, and 43% (6/14) of patients with thrombocytopenia experienced a similar increment in platelet counts. One third (5/15) of the transfusion-dependent patients had decreased transfusion needs [59]. Although amifostine treatment improved blood counts in the treated population, abnormal karyotypes persisted. The number of blasts increased in three patients who enrolled with excess blasts, and evolution to AML occurred in two treated patients and persisted after withdrawal of amifostine. Patients treated with amifostine doses >200 mg/m², three times weekly, experienced dose-limiting toxicities of grade 2 nausea, vomiting, and fatigue [59]. Results of phase II trials using more stringent response criteria suggest that response rates are somewhat lower when amifostine is used as a single agent.

Recent studies investigating the potential for added benefit when used in combinations appear promising [60-63]. Amifostine has been applied in combination with other antiapoptotic strategies using pentoxifylline, ciprofloxacin, and dexamethasone for the treatment of patients with MDS [63]. Pentoxifylline is a xanthine derivative that interferes with lipid-signaling pathways used by proapoptotic cytokines (e.g., IL-1ß, TNF-, transforming growth factor-ß [TGF-ß]) to reduce their activity. Ciprofloxacin was added as a pharmacologic inhibitor of the hepatic metabolism of pentoxifylline, whereas dexamethasone was added to downregulate mRNA translation of TNF-. Amifostine was administered intravenously at doses of 200, 300, and 400 mg/m², three times weekly, to cohorts of 10 patients each [63]. Twenty-nine patients completed at least 12 weeks of treatment. Patients were elderly (median age 67 years) and were classified as having refractory anemia (n = 20), refractory anemia with ringed sideroblasts (n = 3), RAEB (n = 5), or CMML (n = 1). A correlation between amifostine dose and response rate was not apparent. However, an improvement in cytopenias was observed in 76% (22/29) of the patients. In addition, 86% (19/22) of the patients showed improvements in neutrophil counts, 32% (7/22) had improvement in thrombocytopenia, and 50% (11/22) had a >50% decrease in transfusion requirements [63]. These results suggest that the combination of cytoprotection and hematopoietic stimulation with amifostine to decrease apoptosis is a fertile avenue for continued investigation in the treatment of MDS.

Clonal Suppression

Topoisomerase Inhibitors
Topotecan is an agent that stabilizes the topoisomerase I (Topo I)-DNA complex, thereby inhibiting cell growth and triggering apoptosis [64]. Topotecan has demonstrated activity in patients with acute leukemia [58]. Since patients with high-grade MDS have excess blasts that may approach the numbers seen in patients with AML, single-agent therapy with topotecan has been investigated in patients with RAEB, RAEB-t, and CMML [64]. Topotecan 2 mg/m² was administered by continuous infusion over 24 hours daily for 5 days every 4-6 weeks for two courses. This was followed by administration of a maximum tolerated dose of 1-2 mg/m² by continuous infusion over 24 hours daily for 5 days once every 4-8 weeks, for a maximum of 12 courses. Complete responses occurred in 31% (19/60) of patients. These responses were often accompanied by disappearance of clonal cytogenetic abnormalities.

Encouraging response rates with single-agent topotecan have fostered combination trials with other antineoplastics active in AML. Topotecan 1.25 mg/m²/day administered by continuous i.v. infusion daily for 5 days was combined with cytarabine 1.0 g/m²/day by infusion over 2 hours for 5 days. This treatment produced complete responses in 51% of evaluable patients (30/59) [65]. The benefit of this therapy was significantly greater in patients with RAEB or RAEB-t than in those with CMML (p 0.05). The benefit was equally pronounced in patients with poor prognostic features, such as adverse karyotypes and secondary MDS. Combination therapy with topotecan, fludarabine, cytarabine, and G-CSF has also produced responses in patients with high-grade MDS [66]. Although the activity of the topotecan combination appears encouraging, a recent retrospective comparison with anthracycline/cytarabine combinations in patients with advanced MDS or AML shows that the topotecan combination yields inferior response rates and remission durations [67].

FTIs
Another class of agents that may offer selective application in MDS is the FTI class. By targeting the Ras mitogen-activated protein kinase pathway, FTIs retard neoplastic cell proliferation [68,69]. Evidence shows that the antineoplastic properties of FTIs additionally result from their ability to inhibit the farnesylation of signal transduction proteins other than Ras. FTIs target proteins that contain the CAAX amino acid consensus sequence motif requisite for plasma membrane insertion and activation, including Rho B and Lamins A and B [70].

Several FTIs are currently at various stages of preclinical and clinical development. Phase I and II trials are under way, testing the antineoplastic activity of several FTIs, both alone and in combination with other agents [71]. The most intensive clinical investigations involve the FTIs SCH66336 (Schering-Plough Corporation; Kenilworth, NJ) and R115777 (Janssen Pharmaceutical Products, LP; Titusville, NJ).

A dose-escalation phase I trial is being conducted with R115777 in 19 MDS patients representing all FAB subtypes who had failed 2 prior therapies. Preliminary results have shown either hematologic improvement or partial remission in 6 of 18 (33%) evaluable patients, only two of whom harbored mutations in the ras genes [72]. Dose-limiting toxicities were observed at 900 mg administered twice daily, and included myelosuppression, fatigue, and gastrointestinal toxicity. Interim results from phase II trials evaluating the efficacy of R115777 in MDS demonstrated complete remissions in 2 of 16 evaluable patients (13%) (RAEB, n = 1; RAEB-t, n = 1) following 8 weeks of therapy at 600 mg twice daily. These results suggest that FTIs have substantial antineoplastic activity in MDS and CMML and merit further investigation [73].

Angiogenesis Inhibitors
As in solid tumors, angiogenic factors may contribute to the pathobiology of hematologic malignancies [34]. The effect of angiogenic factors on tumor neovascularization can be assessed by estimating MVD. This can be done using immunohistochemical staining for blood vessel antigens such as CD31 and factor VIII antigen or by the expression profile of angiogenic factors such as VEGF [34,74]. Analysis of bone marrow MVD in 81 patients with MDS demonstrated significantly higher MVD in these patients than in controls (p < 0.001) [74]. MVD was higher in patients with RAEB-t and CMML, and the density correlated with blast percentage, but MVD remained significantly lower in patients with MDS than in those with AML. In normal bone marrow, immunohistochemical staining for VEGF is demonstrable in macrophages, megakaryocytes, and erythroblast islands at low intensity [34]. In patients with MDS, intense expression is demonstrable in myelomonocytic precursors, particularly in areas of abnormal localization of immature precursors. Both VEGF and its receptors (VEGFR-1 and VEGFR-2) are detected in MDS myelomonocytic precursors. This suggests that neoangiogenesis in MDS is accompanied by autocrine cytokine stimulation of the leukemic clone. A pathogenic role for VEGF in high-grade MDS is supported by the finding that antibody neutralization of VEGF inhibits CFU-L formation in specimens from patients with CMML and RAEB-t, whereas rHu-VEGF promotes CFU-L [34].

SU5416 and SU6668
Following ligation of VEGF receptors, receptor dimerization activates tyrosine kinases on the receptor's cytoplasmic tail [75]. SU5416 and SU6668 are potent, small-molecule inhibitors of receptor tyrosine kinases whose spectrum of activity extends to receptors for stem cell factor (c-kit), platelet-derived growth factor, and other so-called type III receptors [75,76]. Administration of SU5416 to an elderly woman in second relapse of AML restored remission after 12 weeks of therapy. With the exception of persistent moderate thrombocytopenia, peripheral blood findings were also restored to normal [75]. This response continued for more than 4 months. The remission was accompanied by restoration of the elevated MVD into the normal range over a 2-month period [75]. Phase II studies with SU5416 are nearing completion in a broad range of bone marrow malignancies.

Thalidomide and Thalidomide Analogues
Thalidomide represents the antiangiogenic agent with the broadest investigation in hematopoietic malignancies to date. Thalidomide displays both antiangiogenic and anti-TNF- properties [77]. In a phase II trial of thalidomide in MDS, in which 100 mg of thalidomide was given at bedtime escalating to a maximum dose of 400 mg, 15 of 51 evaluable patients (29%) who completed 12 weeks of treatment achieved red blood cell transfusion independence or a >50% decrease in red blood cell transfusion requirements. Responses in other lineages were less frequent [77]. The potential clinical benefit of thalidomide on erythropoiesis in MDS is currently under investigation in a national randomized, placebo-controlled trial.

Novel orally bioavailable thalidomide analogues have demonstrated 10- to 1,000-fold greater activity than the parent compound in TNF- inhibition assays and a more potent antiangiogenic effect [78,79]. These analogues are divided into two classes: selective cytokine inhibitory drugs, which inhibit TNF- but do not enhance T-cell activation, and immunomodulatory drugs (IMiDs), which stimulate T-cell proliferation as well as IL-2 and interferon- production. Preclinical studies indicate that treatment of multiple myeloma cells with IMiDs inhibits DNA synthesis and promotes growth arrest [80]. Given the greater potency of the thalidomide analogue, the IMiDs may provide a potent and less toxic alternative to thalidomide in MDS [77].

Arsenic Trioxide
Arsenicals have a long history as chemotherapeutic agents for treatment of patients with hematologic diseases. In the 1900s, arsenic in the formulation of Fowler's solution was demonstrated to have efficacy in patients with chronic myelogenous leukemia (CML) [58]. Until supplanted by radiation and modern chemotherapy, Fowler's solution remained a first-line drug for CML. Recently, a resurgence in the use of arsenicals followed FDA approval of ATO for use in the treatment of patients with relapsed and refractory acute promyelocytic leukemia (APL). This novel agent has diverse mechanisms of action that vary by tumor type. These actions include degradation of the APL PML/RAR protein product and wild-type PML transcripts, downregulation of Bcl-2, alterations in mitochondrial membrane permeability, caspase activation, enzyme inactivation by binding to protein sulfhydryl groups, and disruption of microtubules of the mitotic spindle [58]. These activities of ATO appear to contribute to the high rate of complete responses, including molecular remissions, that are observed in patients with APL after treatment with this drug [81].

In vitro studies have shown that exposure of MDS bone marrow mononuclear cells to micromolar concentrations of ATO promotes apoptosis in short-term cultures. An apoptotic response was demonstrated in 7 of 11 patients (64%) with advanced MDS (RAEB-t, CMML, and AML-MDS), whereas pretreatment with GM-CSF increased the apoptotic index [82]. Administration of ATO to a 56-year-old woman with RAEB-t restored neutrophil counts to normal and eliminated the need for red blood cell and platelet transfusions [83]. Bone marrow examination performed at completion of the ATO treatment showed improved maturation of myeloid, erythroid, and megakaryocytic elements and a return to a normal blast percentage (<5%). Eight months after therapy was initiated, the patient remained in remission and transfusion independent. The only complication of therapy was a peripheral neuropathy that improved over time [83].

ATO has now received orphan drug designation from the FDA for the treatment of MDS. At this time, a phase II multicenter trial is ongoing to evaluate its full potential in this patient population [3]. The trial is an open-label, two-stage study in adults representing all FAB subtypes. Patients are treated in 4-week cycles consisting of ATO 0.25 mg/kg/day for 5 days per week in weeks 1 and 2 of each cycle and a treatment hiatus in weeks 3 and 4. The International Working Group Response Criteria proposed for trials in MDS will be applied to characterize responses [84]. Response analyses will be segregated into two cohorts according to risk score as calculated by the IPSS criteria. For lower-risk patients, the primary efficacy measure is the proportion of patients with hematologic improvement, whereas in higher-risk patients (IPSS Intermediate-2, High), the primary end point is the proportion of patients with partial or complete response. Among the 11 evaluable patients enrolled to date, a partial response was achieved in one high-risk patient, and stable disease has been achieved in four high-risk and seven low-risk patients. The drug has been well tolerated, and most patients, including the elderly, are continuing in the study, having received between one and six cycles of therapy. These preliminary results provide evidence for the clinical activity of ATO in patients with advanced transfusion-dependent MDS that merits further investigation.

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
Over the last several decades, the number of patients diagnosed with MDS has steadily increased. With the exception of allogeneic transplantation, none of the current therapeutic interventions are curative. Rather, treatment has remained primarily supportive, involving transfusions, hematologic growth factors, and antibiotics. More effective treatment options are urgently needed to prevent or delay the progression to AML and to prolong survival and improve patients' quality of life. New and investigational agents that may help meet these goals include DNA methyltransferase inhibitors, aminothiols, topoisomerase I inhibitors (alone and in combination with other agents), FTIs, angiogenesis inhibitors, and ATO. The prospect that one or more of these agents will benefit patients with MDS is greater now than at any time in the past.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 
A.F.L. is a member of the Speakers' Bureau for Celgene and Cell Therapeutics, Inc. At the time of publication, this paper discusses an unlabeled usage of arsenic trioxide and the investigational usage of thalidomide.

	References

Top Learning Objectives Abstract Introduction Pathophysiology of... Classification and Prognosis of... Standard Care of the... Novel Therapeutic Interventions Conclusions References

 

1. Aul C, Germing U, Gattermann N et al. Increasing incidence of myelodysplastic syndromes: real or fictitious? Leuk Res 1998;22:93–100.[CrossRef][Medline]
2. Dansey R. Myelodysplasia. Curr Opin Oncol 2000;12:13–21.[CrossRef][Medline]
3. Saba HI. Myelodysplastic syndromes in the elderly. Cancer Control 2001;8:79–102.[Medline]
4. Intragumtornchai T, Prayoonwiwat W, Swasdikul D et al. Myelodysplastic syndromes in Thailand: a retrospective pathologic and clinical analysis of 117 cases. Leuk Res 1998;22:453–460.[CrossRef][Medline]
5. List AF, Garewal HS, Sandberg AA. The myelodysplastic syndromes: biology and implications for management. J Clin Oncol 1990;8:1424–1441.[Abstract]
6. Merchav S, Wagemaker G, Souza LM et al. Impaired response of myelodysplastic marrow progenitors to stimulation with recombinant haemopoietic growth factors. Leukemia 1991;5:340–346.[Medline]
7. May SJ, Smith SA, Jacobs A et al. The myelodysplastic syndrome: analysis of laboratory characteristics in relation to the FAB classification. Br J Haematol 1985;59:311–319.[Medline]
8. Everson MP, Brown CB, Lilly MB. Interleukin-6 and granulocyte-macrophage colony-stimulating factor are candidate growth factors for chronic myelomonocytic leukemia cells. Blood 1989;74:1472–1476.[Abstract/Free Full Text]
9. Backx B, Broeders L, Hoefsloot LH et al. Erythropoiesis in myelodysplastic syndrome: expression of receptors for erythropoietin and kit ligand. Leukemia 1996;10:466–472.[Medline]
10. Hoefsloot LH, van Amelsvoort MP, Broeders LCAM et al. Erythropoietin-induced activation of STAT5 is impaired in the myelodysplastic syndrome. Blood 1997;89:1690–1700.[Abstract/Free Full Text]
11. Dai C-H, Price JO, Brunner T et al. Fas ligand is present in human erythroid colony-forming cells and interacts with Fas induced by interferon to produce erythroid cell apoptosis. Blood 1998;91:1235–1242.[Abstract/Free Full Text]
12. Maciejewski J, Selleri C, Anderson S et al. Fas antigen expression on CD34⁺ human marrow cells is induced by interferon and tumor necrosis factor and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995;85:3183–3190.[Abstract/Free Full Text]
13. Hockenbery DM, Zutter M, Hickey W et al. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci USA 1991;88:6961–6965.[Abstract/Free Full Text]
14. Gersuk GM, Lee JW, Beckham CA et al. Fas (CD95) receptor and Fas-ligand expression in bone marrow cells from patients with myelodysplastic syndrome. Blood 1996;88:1122–1123.[Free Full Text]
15. Kitagawa M, Yamaguchi S, Takahashi M et al. Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia 1998;12:486–492.[CrossRef][Medline]
16. Gupta P, Niehans GA, LeRoy SC et al. Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival. Leukemia 1999;13:44–53.[CrossRef][Medline]
17. Fontenay-Roupie M, Bouscary D, Guesnu M et al. Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br J Haematol 1999;106:464–473.[CrossRef][Medline]
18. Bouscary D, De Vos J, Guesnu M et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia 1997;11:839–845.[CrossRef][Medline]
19. Raza A, Mundle S, Shetty V et al. Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines. Int J Hematol 1996;63:265–278.[CrossRef][Medline]
20. Kitagawa M, Saito I, Kuwata T et al. Overexpression of tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma by bone marrow cells from patients with myelodysplastic syndromes. Leukemia 1997;11:2049–2054.[CrossRef][Medline]
21. Raza A, Gezer S, Mundle S et al. Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 1995;86:268–276.[Abstract/Free Full Text]
22. Peddie CM, Wolf CR, McLellan LI et al. Oxidative DNA damage in CD34⁺ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor- concentration. Br J Haematol 1997;99:625–631.[CrossRef][Medline]
23. Gersuk GM, Beckham C, Loken MR et al. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998;103:176–188.[CrossRef][Medline]
24. Pruneri G, Bertolini F, Soligo D et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999;81:1398–1401.[CrossRef][Medline]
25. Leung DW, Cachianes G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989;246:1306–1309.[Abstract/Free Full Text]
26. Dvorak HF, Brown LF, Detmar M et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146:1029–1039.[Abstract]
27. Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol 1995;7:728–735.[CrossRef][Medline]
28. Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–66.[CrossRef][Medline]
29. Ziegler BL, Valtieri M, Porada GA et al. KDR receptor: a key marker defining hematopoietic stem cells. Science 1999;285:1553–1558.[Abstract/Free Full Text]
30. Gearing AJ, Beckett P, Christodoulou M et al. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature 1994;370:555–557.[CrossRef][Medline]
31. Black RA, Rauch CT, Kozlosky CJ et al. A metalloproteinase disintegrin that releases tumour-necrosis factor- from cells. Nature 1997;385:729–733.[CrossRef][Medline]
32. Kayagaki N, Kawasaki A, Ebata T et al. Metalloproteinase-mediated release of human Fas ligand. J Exp Med 1995;182:1777–1783.[Abstract/Free Full Text]
33. List AF, Holmes H, Vempaty H et al. Phase II study of amifostine in patients with myelodysplastic syndromes (MDS): impact on hematopoiesis. J Clin Oncol 1999;18:51a.
34. 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 2001;97:1427–1434.[Abstract/Free Full Text]
35. Broxmeyer HE, Cooper S, Li ZH et al. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Int J Hematol 1995;62:203–215.[CrossRef][Medline]
36. Gabrilovich D, Ishida T, Oyama T et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92:4150–4166.[Abstract/Free Full Text]
37. Uchida T, Kinoshita T, Nagai H et al. Hypermethylation of the p15^INK4b gene in myelodysplastic syndromes. Blood 1997;90:1403–1409.[Abstract/Free Full Text]
38. Quesnel B, Guillerm G, Vereecque R et al. Methylation of the p15^INK4b gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood 1998;91:2985–2990.[Abstract/Free Full Text]
39. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–199.[Medline]
40. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976;33:451–458.[Medline]
41. Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999;17:3835–3849.[Abstract/Free Full Text]
42. Brunnig R, Bennett JM, Flandrin G et al. Myelodysplastic syndromes: introduction. In: Jaffe ES, Harris NL, Stein H et al., eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001:63-73.
43. Greenberg P, Anderson J, de Witte T et al. Problematic WHO reclassification of myelodysplastic syndromes [comment]. Members of the International MDS Study Group. J Clin Oncol 2000;18:3447–3452.[Free Full Text]
44. Germing U, Gattermann N, Strupp C et al. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000;24:983–992.[CrossRef][Medline]
45. Greenberg P, Cox C, LeBeau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079–2088.[Abstract/Free Full Text]
46. Hellström-Lindberg E. Treatment of adult myelodysplastic syndromes. Int J Hematol 1999;70:141–154.[Medline]
47. Gordon MS. Advances in supportive care of myelodysplastic syndromes. Semin Hematol 1999;36:21–24.
48. Scalzulli PR, Coscarella A, DeSantis R et al. Effects of three new recombinant, human GM-CSF/erythropoietin (EPO) hybrid molecules on in vitro growth of hemopoietic progenitors in myelodysplastic syndromes (MDS). Leuk Res 1997;21(suppl 1):S23a.
49. Gordon MS, Nemunaitis J, Hoffman R et al. A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Blood 1995;85:3066–3076.[Abstract/Free Full Text]
50. Cheson BD. Standard and low-dose chemotherapy for the treatment of myelodysplastic syndromes. Leuk Res 1998;22(suppl 1):S17–S21.
51. Gerhartz HH, Walther J, Neuwirtova R et al. Randomized 3-armed phase III study of interleukin 3 (IL-3), or granulocyte/macrophage colony-stimulating factor (GM-CSF) as an adjuvant to low doses of cytosine arabinoside (LD-ARAC) for the treatment of high-risk myelodysplastic syndromes (HR-MDS). Blood 1996;88:580a.
52. Singal R, Ginder GD. DNA methylation. Blood 1999;93:4059–4070.[Free Full Text]
53. Robertson KD, Jones PA. DNA methylation: past, present and future directions. Carcinogenesis 2000;21:461–467.[Abstract/Free Full Text]
54. Silverman LR, Demakos EP, Peterson B et al. A randomized controlled trial of subcutaneous azacitidine (AZA C) in patients with the myelodysplastic syndrome (MDS): a study of the cancer and leukemia group B (CALGB). J Clin Oncol 1998;17:14a.
55. Kornblith AB, Herndon JE, Silverman LR et al. The impact of 5-azacytidine on the quality of life of patients with the myelodysplastic syndrome (MDS) treated in a randomized phase III trial of the cancer and leukemia group B (CALGB). J Clin Oncol 1998;17:49a.
56. Santini V, Giles FJ. The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica 1999;84:1035–1042.[Abstract/Free Full Text]
57. List AF, Heaton R, Glinsmann-Gibson B et al. Amifostine protects primitive hematopoietic progenitors against chemotherapy cytotoxicity. Semin Oncol 1996;23(4 suppl 8):58–63.[Medline]
58. Cheson BD, Zwiebel JA, Dancey J et al. Novel therapeutic agents for the treatment of myelodysplastic syndromes. Semin Oncol 2000;27:560–577.[Medline]
59. List AF, Brasfield F, Heaton R et al. Stimulation of hematopoiesis by amifostine in patients with myelodysplastic syndrome. Blood 1997;90:3364–3369.[Abstract/Free Full Text]
60. Hofmann WK, Seipelt G, Ottmann OG et al. Effect of treatment with amifostine used as a single agent in patients with refractory anemia on clinical outcome and serum tumor necrosis factor alpha levels. Ann Hematol 2000;79:255–258.[CrossRef][Medline]
61. Bowen DT, Denzlinger C, Brugger W et al. Poor response rate to a continuous schedule of Amifostine therapy for ‘low/ intermediate risk' myelodysplastic patients. Br J Haematol 1998;103:785–787.[CrossRef][Medline]
62. Galanopoulos A, Kritikou-Griva E, Gligori J et al. Treatment of patients with myelodysplastic syndrome with amifostine. Leuk Res 2001;25:665–671.[CrossRef][Medline]
63. Raza A, Qawi H, Lisak L et al. Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone. Blood 2000;95:1580–1587.[Abstract/Free Full Text]
64. Beran M, Estey E, O'Brien SM et al. Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 1998;31:521–531.[Medline]
65. Beran M, Kantarjian H. Results of topotecan-based combination therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Semin Hematol 1999;36(suppl 8):3–10.[Medline]
66. Besa EC. A new combination chemotherapy using topotecan, fludarabine, ARA-C and G-CSF for aggressive myelodysplastic syndromes and acute myelogenous leukemia in the elderly: dose finding for topotecan study. Blood 1999;94:307a.
67. Estey EH, Thall PF, Cortes JE et al. Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 2001;98:3575–3583.[Abstract/Free Full Text]
68. Reuter CW, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies? Blood 2000;96:1655–1669.[Abstract/Free Full Text]
69. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 1999;17:3631–3652.[Abstract/Free Full Text]
70. Karp JE. Farnesyl protein transferase inhibitors as targeted therapies for hematologic malignancies. Semin Hematol 2001;38(3 suppl 7):16–23.[CrossRef][Medline]
71. Karp JE, Kaufmann SH, Adjei AA et al. Current status of clinical trials of farnesyltransferase inhibitors. Curr Opin Oncol 2001;13:470–476.[CrossRef][Medline]
72. Kurzrock R, Sebti SM, Kantarjian HM et al. Phase I study of a farnesyl transferase inhibitor, R115777, in patients with myelodysplastic syndrome. Blood 2001;98:623a.
73. Kurzrock R, Cortes J, Rybak ME et al. Phase II study of R115777, a farnesyltransferase inhibitor, in myelodysplastic syndrome. Blood 2001;98:848a.
74. Deliliers GL, Pruneri GC, Cortelezzi A et al. Angiogenesis in myelodysplastic syndromes. Leuk Res 1999;23(suppl 1):S24a.
75. Mesters RM, Padró T, Bieker R et al. Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood 2001;98:241–243.[Abstract/Free Full Text]
76. Smolich BD, Yuen HA, West KA et al. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Blood 2001;97:1413–1421.[Abstract/Free Full Text]
77. Raza A, Meyer P, Dutt D et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001;98:958–965.[Abstract/Free Full Text]
78. Corral LG, Haslett PA, Muller GW et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-. J Immunol 1999;163:380–386.[Abstract/Free Full Text]
79. Davies FE, Raje N, Hideshima T et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210–216.[Abstract/Free Full Text]
80. Hideshima T, Chauhan D, Shima Y et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000;96:2943–2950.[Abstract/Free Full Text]
81. Soignet S, Frankel S, Tallman M et al. U.S. multicenter trial of arsenic trioxide (AT) in acute promyelocytic leukemia (APL). Blood 1999;94(suppl 1, pt 1 of 2):698a.
82. Donelli A, Chiodino C, Panissidi T et al. Might arsenic trioxide be useful in the treatment of advanced myelodysplastic syndromes? Haematologica 2000;85:1002–1003.[Free Full Text]
83. Dutcher JP, Wiernik PH, Garl S et al. Major hematologic response in a patient with myelodysplasia (MDS) to arsenic trioxide (ATO). Blood 2000;96:260b.
84. Cheson BD, Bennett JM, Kantarjian H et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000;96:3671–3674.[Abstract/Free Full Text]
85. Gallagher A, Darley RL, Padua R. The molecular basis of myelodysplastic syndromes. Haematologica 1997;82:191–204.[Abstract/Free Full Text]

This article has been cited by other articles:

				D. Haase, U. Germing, J. Schanz, M. Pfeilstocker, T. Nosslinger, B. Hildebrandt, A. Kundgen, M. Lubbert, R. Kunzmann, A. A. N. Giagounidis, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients Blood, December 15, 2007; 110(13): 4385 - 4395. [Abstract] [Full Text] [PDF]

				J. L. Liesveld, C. T. Jordan, and G. L. Phillips II The Hematopoietic Stem Cell in Myelodysplasia Stem Cells, July 1, 2004; 22(4): 590 - 599. [Abstract] [Full Text] [PDF]

				J. L. Slack, S. Waxman, G. Tricot, M. S. Tallman, and C. D. Bloomfield Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide Oncologist, April 1, 2002; 7(90001): 1 - 13. [Abstract] [Full Text] [PDF]

				F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]

This Article Abstract