Recent advances in myelodysplastic syndromes

Experimental Hematology 35 (2007) 137–143

Recent advances in myelodysplastic syndromes Richard K. Shadduck, Joan M. Latsko, James M. Rossetti, Bushra Haq, and Haifaa Abdulhaq Western Pennsylvania Cancer Institute, Western Pennsylvania Hospital, Pittsburgh, Pa., USA

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by both bone marrow failure and a propensity for development of acute myeloid leukemia. The incidence of these conditions has risen sharply over the past several years, making them the most common malignant bone marrow disorders. While the majority of patients are diagnosed with low-grade disease, approximately two-thirds will succumb to complications of peripheral blood cytopenias or progression to acute leukemia. In recent years, there has been striking progress in our understanding of the pathogenesis of these disorders. For example, the recognition of the roles of angiogenesis and cytokine abnormalities in the development of these diseases led to clinical trials with agents such as thalidomide, which yielded encouraging erythroid responses. Subsequent work with the thalidomide derivative lenalidomide resulted in marked erythroid and cytogenetic responses in individuals with the 5qabnormality. Additionally, the identification of hypermethylation as an important aspect in the pathogenesis of these and other hematological diseases led to clinical trials utilizing the demethylating agents azacitidine and decitibine. These agents are now known to result in trilineage responses in 30% to 50% of patients with MDS with as many as 20% achieving partial or complete remissions. These results have altered the natural history of these diseases in a significant number of patients. Investigators anticipate that further studies with tyrosine kinase, histone deacetylase, and farnesyl transferase inhibitors will contribute to already promising attempts to reverse or block the pathogenesis of these diseases. Other novel agents are being evaluated as investigators continue to make progress for patients affected by these disorders. Ó 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

Over the last several decades, there has been major progress in the definition, diagnosis, and management of myelodysplastic syndromes (MDS). These conditions are characterized by varying degrees of cytopenias with ineffective hematopoiesis, leading to a frequent need for blood transfusions [1]. Over time, there is worsening bone marrow failure or progression to acute myelogenous leukemia. These conditions occur de novo or secondary to previous exposures to industrial solvents, such as benzene or irradiation, alkylating agents, or topoisomerase II inhibitors [2,3]. Physicians feel that the incidence of MDS is increasing with more frequent referrals and larger numbers of patients requiring chronic blood transfusions. Recent estimates suggest there are 15,000 to 20,000 new cases each year in the United States, with an overall incidence of approximately 55,000 cases [4].

Offprint requests to: Richard K. Shadduck, M.D., Western Pennsylvania Cancer Institute, 4800 Friendship Avenue, Pittsburgh, PA 15224; E-mail: [email protected]

Classification systems Prior to the development of an accepted classification system, by the French, American and British (FAB) group, there was little uniformity in the understanding or management of these disorders [5]. Certain older patients who were found to be anemic were thought to have refractory anemia with or without abnormal ringed sideroblasts in the marrow. Patients did not respond to the known hematinics and required blood transfusions until their ultimate demise, 3 to 4 years later from progressive cytopenias or the consequences of severe iron overload. Other patients had a similar presentation, but owing to increased numbers of myeloblasts in the marrow, their conditions were termed preleukemia. They, too, were managed with supportive care until they died 6 to 18 months later of progression to acute leukemia or the consequences of severe cytopenias. In order to clarify the situation, the FAB group, which also classified the types of acute leukemias, provided a series of criteria for establishing the diagnosis and for identifying the subtypes of MDS. All patients had to show evidence of dysplastic hematopoiesis. Peripheral blood smears revealed

0301-472X/07 $–see front matter. Copyright Ó 2007 International Society for Experimental Hematology. Published by Elsevier Inc. doi: 10.1016/j.exphem.2007.01.022

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dysmorphic, and often macrocytic, red cells; hypogranular and hypolobular neutrophils; and abnormal large platelets. Despite the cytopenias, bone marrow samples were normocellular or hypercellular with altered numbers of abnormal dysplastic megakaryocytes. These were often small unilobular cells or at times, larger megakaryocytes with hyperlobular nuclei. Myeloid precursors showed decreased granulation with abnormal mitoses. Erythroid hyperplasia was a common feature with megaloblastoid cell maturation. In addition, abnormal nuclear lobulation was seen leading to dumbbell or cloverleaf nuclei in the normoblasts. Based on the number of blasts in the marrow and the morphology, patients were characterized as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T) and chronic myelomonocytic leukemia (Table 1). RA and RARS were termed low-risk or low-grade forms of MDS, owing to a survival of 3 to 4 years, whereas the other three subtypes were termed high-risk or high-grade, owing to their more rapid progression and demise. Chronic myelomonocytic leukemia was considered a crossover condition between MDS and myeloproliferative disorders. However, for the purpose of classification, it was considered a form of MDS. Although the FAB classification provided a basis for understanding of MDS subtypes, there remained patients with single or bilineage cytopenias (who were not anemic) that could not be classified. Subsequently, the World Health Organization (WHO) established a more comprehensive approach to classification of these disorders [6] (Table 2). The low-grade subtypes were reclassified to reflect the varying degrees of marrow dysfunction. Those patients with bilineage cytopenias, were termed refractory cytopenia with multilineage dysplasia; those with either neutropenia or thrombocytopenia alone were designated MDS unclassified. A specific clinical entity with a more favorable prognosis, the 5q- syndrome, was recognized because of unique clinical features. The high-risk subtypes were redesignated RAEB I (5% to 9% blasts) and RAEB II (12% to

Table 1. French-American-British Classification

Type

Frequency (%)

Blasts %

Transformation to AML (%)

RA RARS RAEB CMML

10–40 10–20 25–30 10–20

!5 !5 5–20 #20

10–20 10 40–50 20

RAEB-T

10–30

21–30

50–60

Other

O15% RS O109 monocytes

AML 5 acute myelogenous leukemia; CMML 5 chronic myelomonocytic leukemia; RA 5 refractory anemia; RAEB 5 refractory anemia with excess blasts; RAEB-T 5 refractory anemia with excess blasts in transformation; RARS 5 refractory anemia with ringed sideroblasts; RS 5 ringed sideroblasts.

19% blasts) with the previous RAEB-T patients reclassified as acute myelogenous leukemia (AML). Despite these improvements, the WHO did not consider cytogenetic abnormalities, nor did the various subtypes provide detailed prognostic information. A growing number of classification systems were devised to evaluate other prognostic features, such as cytopenias and cytogenetic abnormalities. Ultimately, an MDS Risk Analysis Group utilized the data from 816 previously reported patients to develop a new system to assess the prognosis in MDS. The International Prognostic Scoring System (IPSS) utilized the percentage of blasts, the types of cytogenetic abnormalities, and the number of cytopenias to define four distinct categories [7] (Table 3). Low, intermediate I, intermediate II, and high-risk categories were established. These indicated median survivals ranging from 5.7 to 0. 4 years. Patient age was important with low and intermediate I disease, with a doubling of survival times in patients under age 60. There was no age-related difference in survival with intermediate II or high-risk MDS subtypes. It was thought that this more accurate estimation of prognosis could be used to decide upon appropriate therapy.

Pathophysiology A unique aspect of MDS is the notion that both bone marrow failure and the propensity toward development of acute leukemia coexist. While both properties contribute to peripheral blood cytopenias and the natural history of the disease, it is thought that proliferative advantages lend themselves more to leukemic transformation, while initially accelerated apoptosis is responsible for the cytopenias. The typical cellular appearance of the dysplastic marrow is consistent with the fact that proliferation rates tend to be high in these disorders. Vascular endothelial growth factor (VEGF) receptors are known to be overexpressed more so on blast cells in the dysplastic marrow than on maturing elements [8]. This overexpression is thought to result in proliferation of the blast population as the disease progresses. It also seems likely that while these mutated cells confer some proliferative advantage, second mutations may be needed to induce progression to acute leukemia. Despite the proliferative advantage of these clonally derived cells, the cytopenias that develop appear to be explained by accelerated apoptosis [9]. Programmed cell death seems to be less prominent in the high-grade dysplastic syndromes and more so in those with lower blast counts. This may be due, in part, to a complex interaction of cytokines with the cellular components of the marrow. Some of the useful therapies for MDS, such as lenalidomide and thalidomide, seem to inhibit cytokine-related apoptosis, thus resulting in increased peripheral blood counts. Chromosomal abnormalities are a common finding in patients with MDS either at the time of diagnosis or during

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Table 2. World Health Organization Classification Type RA RARS RCMD RCMD-RS RAEB-1 RAEB-2 MDS-U MDS, 5q-

Blood findings

Bone marrow findings

Anemia No or rare blasts Anemia No blasts Cytopenias (23) Cytopenias (2–3) Cytopenias !5% Blasts Cytopenias 5% to 19% Blasts Cytopenias (1)/Rare blasts Anemia !5% Blasts

Erythroid dysplasia Erythroid dysplasia $15% ringed sideroblasts Dysplasia in $2 lineages Dysplasia in $2 lineages and $15% ringed sideroblasts Unilineage or multilineage dysplasia 5% to 9% Blasts Dysplasia 10% to 19% Blasts Unilineage dysplasia in granulocytes or megakaryocytes Normal to increased megakaryocytes with hypolobated nuclei

MDS 5 myelodysplastic syndromes; MDS-U 5 myelodysplastic syndromes, unclassified; RA 5 refractory anemia; RAEB 5 refractory anemia with excess blasts; RARS 5 refractory anemia with ringed sideroblasts; RCMD 5 refractory cytopenia with multilineage dysplasia; RCMD-RS 5 refractory cytopenia with multilineage dysplasia with ringed sideroblasts.

disease evolution [10]. Cytogenetic abnormalities are of particular importance, as they are closely linked to prognosis. Such abnormalities are present in 60% or more of patients with MDS at some point in their illness. The most common favorable cytogenetic abnormalities include isolated 5q-, -Y, and 20q-. Intermediate risk abnormalities include trisomy 8. Poor-risk karyotypes include either a partial or complete deletion of chromosome 7, as well as complex karyotypes, where three or more abnormalities are present. The incidence of chromosomal abnormalities in secondary MDS is quite high. Complete or partial deletions of chromosomes 5 and 7 are commonly associated with alkylating agent exposure, while 11q23 abnormalities are associated with topoisomerase inhibitors. While various genetic abnormalities are important in determining prognosis, many of these abnormalities have furthered our understanding of the pathogenesis of MDS. For example, the typically deleted portions of chromosome 5 contain genes for hematopoietic growth factors and their receptors [11]. Trisomy 8 abnormalities, on the other hand, are associated with overexpression of fas in clonal cells, making them susceptible to immune-mediated apoptosis [12]. Clonal cells lacking chromosome 7 appear to have a proliferation advantage due to overexpression of the short isoform of the granulocyte colony-stimulating factor (G-CSF) receptor

Table 3. International Prognostic Scoring System for MDS

[13]. Ras mutations may also be associated with monosomy 7 and could potentially respond to farnesyl transferase inhibition [14]. FLT3 tyrosine kinase mutations are also seen in some cases of MDS, thus driving the clinical investigation of FLT3 inhibitors. The potential roles of VEGF overexpression and epigenetic changes within DNA will be discussed further during a review of therapeutic modalities targeting these processes.

Treatment The only known curative therapy for MDS is allogeneic stem cell transplantation. By using less-toxic nonmyeloablative conditioning therapy, it is possible to extend the age criteria for transplantation, however, only 30% of patients with MDS are under age 70 and only 20% to 30% may have a human leukocyte antigenmatched sibling. Thus, #10% of patients with MDS can be considered for stem cell transplants. Timing is important, as low-grade MDS responds more favorably than high-grade disease, however, because of the morbidity and mortality of transplantation, it has been suggested that patients with highrisk disease undergo transplantation immediately, whereas those with low-risk disease be observed until there is some evidence of progression [15]. Although measures to downgrade the risk characteristics with chemotherapy or hypomethylating agents are appealing, it is unclear whether these approaches will improve outcomes.

Score value Prognostic variable BM blasts (%) Karyotypea Cytopeniasb

0 !5 Good 0/1

0.5 5–10 Intermediate 2/3

1.0

1.5 11–20

2.0 21–30

Poor

Scores for risk groups are as follows: Low 5 0; Int-1 5 0.5-1.0; Int-2 5 1.5-2.0; High $2.5. BM 5 bone marrow. a Good 5 normal, -Y, del(5q), del(20q); Intermediate 5 other abnormalities; Poor 5 complex ($3 abnormalities) or chromosome 7 abnormalities. b Hemoglobin ! 10 g/dL; absolute neutrophil count ! 1800/mL; platelet count 100,000/mL.

Hematopoietic growth factors Although MDS is not characterized by a deficiency of erythropoietin (EPO), many investigators have used high doses of EPO in order to overcome the maturation defect. Overall, 15% to 20% of patients have responded to 40,000 units once or twice weekly [16]. Patients with lower levels of EPO respond better than those with high serum levels [17]. The myeloid growth factors, G-CSF and granulocyte macrophage colony-stimulating factor (GM-CSF), have

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also been used alone or in combination with EPO. G-CSF and GM-CSF lead to rapid increases in neutrophil counts, but only on occasion lead to improvement in red cell production [18]. When used in combination with EPO, response rates range from approximately 25% to 70%, with most studies indicating approximately 40% major response rates [19–21]. Patients with RARS that rarely respond to EPO alone, have an excellent response to combined EPO and G-CSF. Therapy usually requires 3 months to show a response, and this often persists through 2 years of continued treatment. Figure 1 shows the excellent sustained response to combination therapy in a patient with RARS that was previously resistant to EPO alone. A scoring system was devised by Hellstrom-Lindberg [22] to predict those patients likely to respond to combined use of growth factors. This system incorporates the previous transfusion requirement and the serum EPO level to predict three groups of patients with 74%, 21%, and 7% chances of response to combination therapy. Individuals most likely to respond to such therapy have a transfusion requirement of !2 U packed red blood cells per month and a serum EPO level !500 U/L. With this information, other forms of therapy should be employed for patients unlikely to improve their transfusion requirements with EPO and G-CSF.

Thalidomide and lenalidomide Overproduction of VEGF is thought to be an important factor that mediates the interaction of dysplastic precursor cells with the microenvironment [23]. In addition, there is increased production of tumor necrosis factor and a cascade of inflammatory cytokines that may down regulate receptors for cell maturation [24]. Thalidomide, which is an inhibitor of angiogenesis, and a modulator of tumor necrosis factor and other cytokines, has been employed in patients with transfusion dependent MDS. In a Phase II trial

[25], 83 patients were treated with doses up to 400 mg daily. Many were unable to tolerate such doses, because of severe sedation, constipation, and neuropathy. Overall, 18% of the 83 patients became transfusion independent, or had a significant reduction in their red cell transfusion requirement. The response rate was nearly 30% in those able to tolerate at least 12 weeks of therapy. Although red cell responses were seen in this study, thalidomide had certain drawbacks, namely poor tolerance and the lack of response in the other cell lines. A derivative of thalidomide, termed lenalidomide, has shown greater activity and has been more successful in clinical trials. In the initial study, List reported a 56% response rate in 43 patients with symptomatic anemia [26]. At doses of 10 mg daily or 10 mg for 21 days a month, 24 patients became transfusion independent, had a major hematologic improvement or a reduction in transfusion requirement. This effect was more pronounced in patients with a deletion of chromosome 5q, where an 83% response rate was observed. The response was 57% in those with normal cytogenetics, but only 12% in patients with other cytogenetic abnormalities. Although well tolerated, the drug did cause major neutropenia and thrombocytopenia in the initial phases of therapy that required dose reduction or cessation. This encouraging result led to more expanded trials of lenalidomide in both 5q- and non-5q- patients. The most recent update was presented at the American Society of Clinical Oncology Meeting in 2005 [27]. Sixty-six percent of patients with a 5q- abnormality with or without other cytogenetic changes responded favorably within the first few months of treatment. There was recovery of erythropoiesis with a mean increase in hemoglobin of 5.3 g/dL. Responses continued for intervals of longer than 1 year. The reported mortality rate was 10%, but according to the investigators, the drug-related mortality due to neutropenic infections was !2%. In our experience, three patients with a 5q- abnormality continue to respond for longer than 2 years and

15 14

Bimonthly PRBC Transfusions

Hemoglobin (G/dL)

13 12 11 10 9 8 7 6

Epo

Epo + G-CSF

Ju l-9 4 Ja n95 Ju l-9 5 Ja n96 Ju l-9 6 Ja n97 Ju l-9 7 Ja n98 Ju l-9 8 Ja n99 Ju l-9 9 Ja n00 Ju l-0 0 Ja n01 Ju l-0 1 Ja n02 Ju l-0 2 Ja n03 Ju l-0 3 Ja n04

5

Figure 1. Response to combined erythropoietin (Epo) and granulocyte colony-stimulating factor (G-CSF) in an 81-year-old female with refractory anemia with ringed sideroblasts that was previously unresponsive to erythropoietin alone. With the continued therapy, response has persisted through March 2006. PRBC 5 packed red blood cells.

R.K. Shadduck et al./ Experimental Hematology 35 (2007) 137–143

are undergoing bimonthly phlebotomies to reduce the transfusion-induced iron overload. In the large series presented at American Society of Clinical Oncology, the response rate was even greater in patients without other cytogenetic abnormalities. Seventy-five percent of patients with a pure 5q- syndrome had recovery of erythropoiesis with amelioration of their transfusion requirement. All patients developed varying degrees of neutropenia and thrombocytopenia that was often severe within the first 8 weeks of therapy. The use of this drug requires frequent blood counts, often once or twice weekly in the early phases of therapy, with cessation of the drug or dose reduction as necessary, until adequate white cell and platelet recovery ensues. A larger group of patients with non-5q- MDS received a similar treatment regimen [28]. Of 215 patients, nearly one third showed improvement in erythropoiesis and a reduction in transfusion requirements. The average increase in hemoglobin value was 3.2 g/dL. The degrees of neutropenia and thrombocytopenia seemed less severe in this group of patients, however, the improvement in the hemoglobin was less robust than seen in the 5q- syndrome. Moreover, the duration of improvement appeared to be somewhat less than 1 year. Thus, lenalidomide seems to be a very successful drug for treatment of patients with the 5q- syndrome, but its role in the management of other MDS patients remains to be clarified.

Epigenetic modification Epigenetic changes in DNA, which are acquired alterations in structure without a change in nucleotide sequence, seem important in the expression and evolution of malignant disorders. MDS is characterized by several epigenetic changes, such as hypermethylation of cytosine residues and subsequent histone deacetylation, both of which are initiated by DNA methyltransferases. These changes silence tumor suppressor genes, which impairs normal cell differentiation and augments leukemic cell transformation [29]. Reversal of DNA methylation by azacitidine or decitabine can restore function and allow normal cell differentiation. Azacitidine was originally used as an antileukemic agent in the 1970s. Its use was curtailed because of excess mucosal toxicity and only limited benefit in patients with resistant AML. Subsequently, in a Cancer and Leukemia Group B [CALGB] trial lower doses were used by continuous daily intravenous (IV) infusions in patients with highrisk MDS. The drug did cause nausea and vomiting, but was well-tolerated at a dose of 75 mg/M2/day for 7 days. As judged by CALGB criteria, responses were observed in 49% of 43 evaluable patients. There were 12% in complete remission (CR), 25% in partial remission (PR), and another 12% showed hematologic improvement. The median duration of response was nearly 15 months [30]. These encouraging results led to a subsequent Phase II trial in 70 patients in which the same dose of azacitidine was given

141

subcutaneously. The overall response rate was similar, with 53% of evaluable patients in CR, PR, or with hematologic improvement [31]. In order to confirm effectiveness of the drug, a randomized Phase III trial was conducted by CALGB [32]. Ninetynine patients were randomized to azacitidine and 92 to a supportive-care arm. Five percent of patients in the supportive-care arm had improvement in neutrophils or platelets, however, this proved to be secondary to evolution into AML. In contrast, the azacitidine treatment group had 7% CR, 16% PR, and 37% improved, for an overall response rate of 60%. The azacitidine group had red cell responses in 51% of patients, white cell responses in 47%, and improvement in platelets in 40% of patients. Trilineage responses were seen in 25% of patients. The responses were independent of FAB subtype, with an overall response rate of 59% and 61% in the low-risk and high-risk group, respectively. Median time to initial response was 64 days and median duration of response was 15 months. Major side effects were nausea and vomiting, neutropenia, thrombocytopenia, and, in some patients, nodules at the site of injection. The time from treatment to death or development of AML was calculated based on the original assignment group. The median time for these events was 12 months in the supportive-care arm and 21 months in the azacitidine group (p 5 0.007). Median survival was 20 months in the azacitidine group and 14 months in the supportive-care arm. After completion of entry into the CALGB study, 5azacitidine became available on a compassionate-use basis from the National Cancer Institute. We treated 48 patients on this program between 1996 and 2001 [33]. Transfusion independence was achieved in 34% of patients receiving red cells, 71% of those receiving platelets, and in 30% of those requiring both red cells and platelets. Using the more stringent International Working Group response criteria, major red cell responses were seen in 31%, platelet responses in 48%, and neutrophil responses in 40%. Cytogenetic studies were available from 43 patients. They were normal in 21 and abnormal in 22 (51%). Four showed improvement in chromosome abnormalities of which three had disappearance of complex clonal abnormalities. Ninety-four percent of responses were seen after three cycles of treatment. Two additional responders were observed after a 4th and 5th cycle of therapy. Responses lasted a median of 7þ months (2 to O45 months). Subsequently, we have treated a total of 95 patients. Responses were seen in all FAB subtypes (Fig. 2). Chronic myelomonocytic leukemia, that is generally refractory to conventional therapy, responded well to 5-azacitidine. Two of 6 patients with white counts !12,000 (dysplastic subtype) had a complete response after one cycle of therapy. This persisted through 13 months of continued treatment. Complete and partial remissions were observed in 55% of 18 patients with white counts O12,000 (myeloproliferative variety). Despite the

R.K. Shadduck et al./ Experimental Hematology 35 (2007) 137–143

142 60 55 50

Response (%)

45 40 35 30 25 20 15 10 5 0 RA

RARS

RAEB

Response

CMML CR

RAEB-T

Total

PR

Figure 2. Hematologic responses to azacitidine by French-AmericanBritish type. Complete remissions, partial remissions, and hematologic improvement (response) were determined using International Working Group criteria. CR 5 complete remission ; CMML 5 chronic myelomonocytic leukemia; PR 5 partial remission ; RA 5 refractory anemia; RAEB 5 refractory anemia with excess blasts; RAEB-T 5 refractory anemia with excess blasts in transformation; RARS 5 refractory anemia with ringed sideroblasts.

greater response rate, responses were of shorter duration, i.e., 6.8 months. Another demethylating agent, decitabine, has been used more widely in Europe. In an early trial this agent was given for MDS as a continuous IV infusion using 45 mg/ M2/day for 3 days [34]. In 29 patients with high-risk MDS, there was a 28% CR and 26% PR with a median survival of 46 weeks. The major toxicity was severe myelosuppression, with 17% mortality from infections. Decitabine was employed in a larger Phase II trial in 66 patients [35]. The dose was changed to a 4-hour infusion of 15 mg/M2 every 8 hours for 3 days. Patients who achieved a CR were given two additional courses as consolidation therapy. Those with lesser responses received a total of six courses of therapy. The overall response rate was 42%, with a median survival of 14 months in high-risk patients. Subsequently, Wijermans et al. [36] reported the combined results of four Phase II studies that included 177 patients [36]. They were reclassified by IPSS Scores; results were analyzed using International Working Group (IWG) criteria. Seventy-two percent of patients were high risk with intermediate I and high-risk scores by IPSS. Although various treatment schedules were employed, most were given 15 mg/M2 over 3- to 4-hour infusions every 8 hours for 3 days. Treatment was repeated every 6 weeks with occasional delays for cytopenias, but no dose reductions. A maximum of four to eight cycles of treatment were employed. There was an overall response rate of 49%, with

25% of patients in CR. An additional 20% manifested stable disease, indicating a potential benefit in up to 69% of patients. The median duration of response was 36 weeks. A Phase III randomized trial was recently conducted in the United States [37]. Of 170 patients, 81 were randomized to supportive care and 89 to decitabine. However, six withdrew from the latter group prior to treatment. Moreover, 43 patients in the treatment arm received two or less cycles because of disease progression, death, persistent cytopenias, and adverse events. Despite these problems, decitabine therapy led to a 9% CR and 8% PR and an additional 13% showed hematologic improvement. Median time to first response was 3.3 months and median duration of response was 10.3 months. The treatment group had a delay in time to AML or death, but this was of only 3 to 6 months duration in various subgroup analyzed. The Houston group has recently explored alternative dosing schedules, wherein 100 mg/M2 is administered IV or subcutaneously over 5 to 10 days [38]. It would appear that 20 mg/M2 IV over 1-hour daily infusions for 5 days can be given every 4 weeks rather than every 6 weeks. This resulted in a rather high 40% CR rate. It will be important to confirm this finding in further trials. Although there are no comparative trials using decitabine and 5-azacitidine, it would appear that the responses in the Phase III trials are roughly equivalent, however, the duration of response appears less with decitabine. This may be explained by the earlier discontinuation of treatment in the decitabine trials, namely a median of three, as compared to nine, cycles of treatment with 5-azacitidine. In one retrospective study, treatment was continued to progression, to assure a maximal response [33]. The last few decades have led to striking progress in our understanding of MDS, and application of therapies that attempt to reverse or block the pathogenesis of the disease. It is anticipated that the future will prove more rewarding as we explore the use of tyrosine kinase, histone deacetylase, and farnesyl transferase inhibitors, and other unique compounds in these difficult disorders. References 1. Greenberg P. The myelodysplastic syndromes. In: Hoffman R, Benz E, Shattil S, et al, eds. Hematology: Basic Principles & Practice. 3rd ed. New York: Churchill Livingstone; 2000. p. 1106–1129. 2. Cazzola M, Malcovati L. Myelodysplastic syndromes-coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–538. 3. Steensma DP, Bennett JM. The myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2006;81:104–130. 4. Silverman RL. Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes. Oncologist. 2001; 6(Suppl 5):8–14. 5. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51: 189–199. 6. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasm. Blood. 2002; 100:2292–2302.

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