Novel agents for the management of myelodysplastic syndromes

Novel agents for the management of myelodysplastic syndromes

John Meletis1, Nora Viniou1, Evangelos Terpos2

1 1st Department of Internal Medicine, University of Athens School of Medicine, Laikon General Hospital, Athens, Greece2 Department of Hematology, 251 General Airforce Hospital, Athens, Greece

Source of support: Self fi nancing

Summary

Therapeutic decisions in patients with myelodysplastic syndromes (MDS) are very complex. The dilemma that confronts the management of MDS is illustrated by the presence of only one agent (5-azacitidine), which has been approved by the USA Food and Drug Administration, with an indi-cation for all subtypes of this disease and another one (lenalidomide) for the management of a spe-cifi c MDS subgroup, the 5q- syndrome. Current classifi cations and prognostic systems do not take into account the considerable clinical heterogeneity of MDS or their diverse biology. Supportive care, low-intensity treatment, acute myeloid leukemia-type therapy, and stem cell transplantation (SCT) produce unsatisfactory results because patients continue to be exposed to the inherent complications of worsening cytopenias and leukemic transformation. Recent years have witnessed an evolution in our understanding of pathophysiology pathways in MDS. At the same time, many novel and targeted therapies are being investigated in clinical trials, offering patients the prospect of sustained benefi t and changing the natural course of the disease. Hypomethylating agents, im-munomodulatory drugs, and farnesyl-tranferase inhibitors have produced very promising results in terms of response and survival in MDS patients. This review summarizes all recent data on the role of novel agents and SCT in the treatment of patients with MDS in an attempt to better under-stand their possible therapeutic status in the management of these patients.

key words: myelodysplastic syndromes • 5-azacitidine • decitabine • lenalidomide • farnesyl-transferase inhibitors

Full-text PDF: http://www.medscimonit.com/fulltxt.php?IDMAN=9026

Word count: 6688 Tables: 2 Figures: 5 References: 109

Author’s address: John Meletis, 1st Department of Internal Medicine, University of Athens School of Medicine, Laikon General Hospital, 2 Agiou Thoma street, Goudi, GR-11527, Athens, Greece, e-mail: [email protected]

Received: 2006.04.03Accepted: 2006.06.20Published: 2006.09.01

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PMID: 16940944

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BACKGROUND

Treatment strategies for myelodysplastic syndromes include mainly supportive care, growth factors, low-intensity treat-ment, acute myeloid leukemia (AML)-type therapy, and stem cell transplantation (SCT) [1]. The decision about how to deal with the morbidity of the disease versus the potential benefi ts and toxicities of treatment is very complex. This decision is based on age, performance status, type of MDS, and available data on disease biology and prognostic fac-tors. Although the possibility of curing MDS has increased with improved transplant strategies, the majority of MDS pa-tients will die of their disease. Severe anemia leading to the need for chronic transfusions and markedly reduced qual-ity of life are often the major clinical problems for patients with low or intermediate-1 (Int-1) risk in the International Prognostic Scoring System (IPSS) [2,3]. Progressive cyto-penia, which is more common in the other MDS subtypes, may be predictive of transformation to AML but may also be a feature of refractory anemia with multilineage dyspla-sia (RCMD) without an increase of blasts. Severe pancyto-penia is linked to markedly increased morbidity and re-duced quality of life. The life expectancy of patients with high- and Int-2-risk MDS, according to IPSS, is very short (≤12 months), and approaches to prevent transformation from low- to high-risk disease are urgently needed. The bet-ter understanding of MDS pathophysiology has led to the development of novel agents that target both the MDS cell and its interactions with the abnormal marrow microenvi-ronment. Hypomethylating agents, immunomodulatory drugs, and farnesyl-transferase inhibitors have produced very promising results in MDS. This review summarizes all available data on these and other novel agents as well as recent data on the role of SCT in the management of pa-tients with MDS.

NOVEL AGENTS FOR MDS

MDS is a clonal disorder of hematopoietic stem cells that results in excessive apoptosis, as refl ected by the degree of dysplasia and proliferation and loss of differentiation of hematopoietic progenitors [4]. There is strong evidence supporting the view that MDS arises from an intrinsic or acquired genetic defect in stem cells leading to clonal ex-pansion of the abnormal population. It is also clear that ab-errant cytokine production, including tumor necrosis fac-tor-alpha (TNFa), transforming growth factor-beta (TGFb), interleukin-1beta (IL-1b), and vascular endothelial growth factor (VEGF), altered stem cell adhesion, and an abnor-mal marrow microenvironment contribute to the biology of the disease and may provide important therapeutic targets (Figure 1) [5]. As the numerous pathophysiological path-ways involved in MDS are being unraveled, new molecular targets are being identifi ed. Novel and targeted therapeu-tic agents, including inhibitors of farnesyl-transferases and receptor tyrosine kinases, more potent thalidomide analogs and epigenetic therapies, have produced encouraging re-sults and might offer durable benefi ts to patients with MDS. These novel agents are depicted in Table 1.

Angiogenesis inhibitors

Angiogenesis has emerged as a key biological process, the deregulation of which has been established as a prognostic

factor not only in patients with solid tumors, but also in pa-tients with hematological malignancies [6]. Increased micro-vascular density of the bone marrow and overproduction of angiogenic cytokines have been described in MDS patients [7,8]. VEGF is an important diffusible angiogenic effector in MDS, while a complex network of other cytokines, such as basic fi broblast growth factor (b-FGF), hepatocytic growth factor (HGF), TNFa, and TGFb, also modulates neo-ang-iogenesis in myelodysplasia [9,10]. VEGF is overexpressed and elaborated in concordance with its high-affi nity type III receptor tyrosine kinases VEGFR-1 (Flt-1) and/or VEGFR-2 (Flk/Kdr) by myeloblasts and monocytes derived from the malignant clone [11,12]. Indeed, laboratory studies have established an autocrine role for VEGF as a mitogenic cy-tokine supporting myeloblast self-renewal in primary MDS [13]. Based on this biological background, the potential therapeutic capacity of anti-angiogenic factors has been explored in MDS.

Thalidomide

Thalidomide (Thalomid™) has signifi cant antitumor activ-ity in patients who have hematological malignancies with increased bone marrow angiogenesis and has been shown to inhibit bFGF and VEGF-induced angiogenesis [14,15]. Thalidomide may exert immunomodulating activities, in-cluding suppression of cell adhesion molecules on endothe-lial cells, enhancement of the capacity of type-2 T-helper cells to secrete interferon-gamma and IL-2 with concom-itant inhibition of Th1 cytokines, and stimulation of pro-liferation, cytokine production, and cytotoxic response in the CD8(+) lymphocyte subset [16]. Since angiogenesis has been found to be increased in MDS and immunological derangement has been suggested as a possible initial step for the development of at least some cases of MDS, thalid-omide has been considered of potential activity in this set-ting. Furthermore, thalidomide seems to reduce apoptosis levels in bone marrow cells derived from MDS patients [17]. Therefore, thalidomide has been tested in several phase II studies (Table 2) [18].

In the largest phase II study published to date, 83 patients with MDS (36 patients with RA, 13 patients with RARS, 24 pa-tients with RAEB, 6 patients with RAEB-t, and 4 patients with CMML) received oral thalidomide at doses between 100 mg and 400 mg daily. Among 51 evaluable patients, the majori-ty took thalidomide at doses of between 150 mg and 200 mg daily. Doses of up to 400 mg were tolerated poorly and were maintained for only a short time. In an intent-to-treat anal-ysis, 16 patients (19%), including 9 patients with RA, 5 pa-tients with RARS, and 2 patients with RAEB, demonstrated hematological improvement, according to response crite-ria by Cheson et al. [19] (Figure 2). Ten previously transfu-sion-dependent patients became transfusion independent. No leukocyte or cytogenetic responses were observed in this trial. Responders had lower pre-therapy blast counts, high-er pre-therapy platelet counts, and a lower duration of pre-therapy platelet transfusions. The median response duration was approximately 10 months, while the interval to erythroid response was 16 weeks. Thirty-two patients (38%) stopped early due to side effects (fatigue, constipation, shortness of breath, fl uid retention, dizziness, rash, numbness and tin-gling in fi ngers and/or toes, fever, headache, nausea; 14 pa-tients), leukemic evolution (6 patients), or other medical

Med Sci Monit, 2006; 12(9): RA194-206 Meletis J et al – Novel agents for the management of myelodysplastic syndromes

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reasons (12 patients) [20]. In a multicenter trial, currently available in an abstract form, thalidomide was given to 73 pa-tients with MDS (43 patients with IPSS scores ≤Int-1 and 30 patients with IPSS scores ≥Int-2) at an initial dose of 200 mg that was increased by 50 mg/week to a targeted maximum daily dose of 1000 mg. Six patients achieved hematological improvement and 1 patient achieved a PR, for an overall response rate of 10% in 69 evaluable patients. Only 32 pa-tients could receive at least three courses, and most patients had to be taken off the study because of toxicities (thalid-omide-related toxicity grade III and IV, mainly fatigue and neuropathy, was observed in about 15% of patients) [21]. The results of these and other smaller trials that are depict-ed in Table 2 have shown that response to thalidomide is near 23%, while 45% of patients cannot tolerate the doses that have been used in these studies.

The combination of thalidomide with other agents has been also tested in MDS. Thalidomide does not seem to have any synergistic effect with erythropoietin in low-risk MDS [22], while in combination with topotecan it produces a hema-tologic improvement rate of 24% in high-risk MDS (RAEB, RAEB-t, and CMML) [23]. Further studies are required to evaluate the role of thalidomide in MDS.

Immunomodulatory agents

Thalidomide analogs have been designed to increase ef-fi cacy and reduce toxicity of thalidomide. Lenalidomide (Revlimid™), a 4-amino-glutarimide thalidomide analogue, is currently being tested in MDS. It inhibits TNFa with a 10,000-fold increased potency compared with thalidomide, while it resembles thalidomide in its ability to inhibit other cytokines, including IL-1b, IL-6, and IL-12 [24]. It has been also shown that lenalidomide enhances costimulation of T cells, increases heterotypic adhesion of hematopoietic pro-genitors to bone marrow stroma, sensitizes cells to receptor-induced apoptosis, and inhibits trophic signals to angiogenic factors, such as VEGF, in both hematopoietic and stromal cells [25]. Furthermore, lenalidomide inhibits the proliferation of chromosome 5 deleted hematopoietic tumor cell lines in vitro, whether from the B-cell, T-cell, or myeloid lineage [26].

T-lymphocytes

Endothelial cells

BONE MARROWStem cells

Stromal cells

DNA damageAPOPTOSIS

ANGIOGENESIS

VEGF, bFGF VEGF, bFGFSCF, CSF-1, G-CSF, IL-6

TNFa, TGFb, IL1b

Altered adhesive interaction

Figure 1. The microenvironment in myelodysplastic syndromes: The fi gure illustrates components that contribute to the development of MDS and their relationships. Mutations in critical growth-regulating genes in the hematopoietic progenitor cells block the cells’ normal diff erentiation and maturation. Cytokine imbalances and aberrant signal transduction that result from these mutations in the aff ected myeloid cells lead to accelerated apoptosis and altered adhesive interactions with marrow stromal cells. Increased production of angiogenic factors leads to neo-angiogenesis [adapted from Hellstrom-Lindberg, Curr Hematol Rep, 2003 (5)].

Class of drug Name of drug

Angiogenesis inhibitorsIMiDsanti-VEGF monoclonal antibodiesVEGFR tyrosine kinase inhibitors

MMPs

ThalidomideLenalidomide (Revlimid™)Bevacizumab (Avastin™)

AG013736, SU11248, SU5416, PTK787

AG3340 (Prinomastat™)

Hypomethylating agents 5-azacitidine (Vidaza™)decitabine (Dacogen™)

Histone deacetylase inhibitors valproic acid, sodium phenylbutyrate, FK2228,

SAHA, MS275

Farnesyl-transferase inhibitors R115777 (tipifarnib, Zarnestra™)

SCH66336 (lonafarnib, Sarasar™)

BMS-214662

Anticytokine therapysoluble recombinant TNF receptor fusion proteinanti-TNF monoclonal antibody

Etanercept (Enbrel™)

Infl iximab (Remicade™)

Arsenicals As2O

3 (Trisenox™)As

4S

4

Proteasome inhibitors Bortezomib (Velcade™)

Tyrosine kinase inhibitors Imatinib (Gleevec™)

Nucleoside analogs Clofarabine

Flt-3 inhibitors MCN512, PKC412, BAY43-9006

Glutathione analog inhibitors of GST

TLK199

Table 1. Novel agents for the treatment of myelodysplastic syndromes.

IMiDs – immunomodulatory drugs; SAHA – suberoylanilide hydroxamic acid; ΜΜPs – matrix metalloproteinases; Flt-3 – fms-like tyrosine kinase 3; GST – glutathione S-transferase.

Review Article Med Sci Monit, 2006; 12(9): RA194-206

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In the largest phase I trial on MDS to date, 43 patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low proba-bility of benefi t from such therapy. The response to treat-ment was assessed after 16 weeks. Twenty-four patients had a response (56%): 20 had sustained independence from transfusion, one had an increase in the hemoglobin level

of more than 2 g per deciliter, and three had more than a 50% reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83% compared with 57% among those with a normal karyotype and 12% among those with other karyotypic abnormalities; p=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50% reduction in abnormal cells in metaphase, including 10 (50%) with complete cytogenetic remission. After a median follow-up

Authors No of patients Dose (mg/day) Overall response (n-%) Drop-out (n-%)

Raza et al., 2001 [20]Strupp et al., 2002 [106]Musto et al., 2002 [107]Moreno-Aspitia et al., 2002 [21]Bortolheiro et al., 2003 [108]Bouscary et al., 2003 [109]

83 48 40 69 13 48

100–400 100–500 100–300 200–1000 100–300 200–800

16 (19.2) 23 (47.9) 8 (20.0) 7 (10.1) 5 (38.4) 10 (20.8)

32 (38.5) 13 (27.0) 15 (37.5) 41 (56.1) 5 (38.4) 31 (64.5)

Total 301 69 (22.9) 137 (44.9)

Table 2. Studies evaluating thalidomide treatment as a single agent in myelodysplastic syndromes.

· Hb>1.5 g/dl if pretreatment Hb<11 g/dL,

· an absolute number of at least 4 RBC treansusions/8 weekscompared to the pretreatment transfusion number in the previous

8 weeks; only RBC transfusions given for a HB £9 g/dLpretreatment will count in the RBC transfusion response evaluation

· absolute increase of 30´109/L for patients starting with >20´109/Land <100´109/L

· increase from <20´109/L to >20´109/L and by least 100%

· 100% increase and an absolute increase >0.5´109/L ifpretreatment levels were <1.0´109/L

Pretreatment counts averages of at least 2 measurements (notinfluenced by transfusions) 1 week apart.

Erythroid

Platelets

Neutrophils

Completeremission (CR)

Partialremission (PR)

Stabledisease (SD)

Failure

Bone marrowblasts <5%

trilinage maturationon dysplasia

¯blasts >50%, and blast counts >5%

Failure to achieve at least PR,but without evidence of progression for at least 2 months

Death during treatment or disease progressioncharacterized by worsening of cytopenias, increase in % of

bone marrow blasts, or progression to a more advancedMDS FAB subtype than pretreatment

as for CR

BloodHB >11 g/dLuntransfused

ANC ³1.0´109/LPLT >100´109/L

no blastsno dysplasia

Haematologicimprovement

Change indisease history(response mustlast ³4 weeks)

Response criteriain MDS

Figure 2. Novel IWG modifi ed response criteria for MDS by Cheson et al. [19].


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of 81 weeks, the median duration of transfusion independ-ence had not been reached and the median hemoglobin level was 13.2 g/dl. Neutropenia and thrombocytopenia, the most common adverse events, with respective frequen-cies of 65% and 74%, necessitated the interruption of treat-ment or a dose reduction in 25 patients (58%). Other ad-verse events were mild and infrequent [27].

The effect of lenalidomide in a larger group of patients with 5q- aberration was recently reported. Among a total of 148 patients, 66% achieved an erythroid response, the majori-ty obtaining a major or complete response as defi ned using International Working Group criteria. The response rate was higher in patients with the isolated 5q31 aberration than in those with additional chromosomal aberrations. After a median follow-up of 9.3 months, the median duration of re-sponse had not been reached. Lenalidomide caused grade III–IV neutropenia and thrombocytopenia in more than a third of the patients and, interestingly, the maximum toler-ated dose is clearly lower in MDS than in myeloma. Long-term results regarding response duration, AML evolution, and survival are still to be reported and will infl uence the role for lenalidomide in the 5q– syndrome [28].

Lenalidomide has been approved by the FDA for the treat-ment of 5q- syndrome. The results of randomized studies eval-uating the effects of two doses of lenalidomide versus placebo in 5q- patients, followed by studies on non-5q- MDS patients and high-risk patients with 5q- aberration, will reveal the role of lenalidomide in the management of patients with MDS.

VEGF-receptor tyrosine kinase inhibitors

During the last fi ve years, a number of inhibitors of VEGF receptor tyrosine kinase have been designed and tested in MDS. This drug category includes mainly AG-013736, SU5416, SU11248, and PTK787. However, their results seem to be disappointing in MDS patients [29–32].

Other antiangiogenic agents

Bevacizumab (Avastin™) is a recombinant anti-VEGF hu-manized monoclonal antibody which inhibits both VEGF and TNFa function and bone marrow production [33]. It has been tested in 15 MDS patients, producing an overall re-sponse of approximately 20% [34]. Another group of agents with antiangiogenic effect includes the inhibitors of matrix metalloproteinases (MMPs). The MMPs represent a family of zinc-dependent endopeptidases that function as effectors of the angiogenic response [35]. MMPs degrade structural com-ponents of the extracellular matrix, disrupt integrin/stro-mal adhesion signals, and promote local VEGF, TNFa, and soluble fas ligand liberation via proteolytic cleavage of pro-teoglycan- or membrane-bound forms [36]. AG3340 is a po-tent, orally bioavailable, selective inhibitor of MMPs 2, 9, and 13 with limited experience in MDS [37].

In conclusion, angiogenesis inhibitors, and specifi cally le-nalidomide, seem to be effective in selective MDS patients. Methods that can distinguish these patients are required to reveal the exact role of these drugs in MDS.

Epigenetic therapy

DNA methyltransferase inhibitors

Abnormalities of cytosine methylation constitute some of the best characterized and most common epigenetic chang-es in cancer. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene tran-scription (Figure 3) [38]. Inappropriate inhibition of the transcription of tumor suppressor genes, genes that inhib-it angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulat-ed growth and proliferation of a cell and carcinogenesis [39]. In malignant myeloid cells, the most widely reported methylated gene is the cyclin-dependent kinase inhibitor p15INK4B [40]. Methylation of the p15 promoter has been demonstrated in 68% of primary AML and 35% of MDS; the frequency of methylation increases with MDS disease progression [41]. A variety of other genes are methylated in myeloid neoplasms. These include p73, RARb, E-cadherin, fragile histidine triad (FHIT), and others [42,43]. The molec-ular mechanisms by which aberrant DNA methylation takes place during leukemiogenesis are still not clear. However, the large number of target genes that are silenced by ab-errant methylation suggests that inhibition of this process may have potential as anti-leukemia and anti-MDS therapy, possibly restoring the normal gene transcription.

The majority of experience to date has been accumulated with the DNA methyltransferase inhibitors 5-azacitidine (Vidaza™), which has been approved by the FDA for ther-apy in MDS (20/5/2004) [44], and 5-aza-2’-deoxycytidine (decitabine, Dacogen™). In a phase III study, the Cancer

Figure 3. Tumor gene methylation. The CG island is a short stretch of DNA in which the frequency of the CG sequence is higher than other regions. It is also called the CpG island, where “p” simply indicates that “C” and “G” are connected by a phosphodiester bond. CpG islands are often located around the promoters of housekeeping genes or other genes crucial for cell survival. At these locations the CG sequence is not methylated. By contrast, the CG sequences in inactive genes are usually methylated to suppress their expression. The pattern of DNA methylation in a cell dramatically aff ects the function of the DNA by switching genes on or off . Abnormal methylation events occur during leukemiogenesis. The DNA methyltransferase inhibitors can reverse the over-methylation of a tumor suppressor gene, thereby switching the gene back on.


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and Leukemia Group B (CALGB) compared observation (92 MDS patients) and 5-azacitidine (99 MDS patients) giv-en at a subcutaneous dose of 75 mg/m2 daily for seven days every four weeks. The dose was increased by 33% in patients who demonstrated no benefi t by day 57. Responding pa-tients received three additional cycles after CR; those with less than CR continued until CR or relapse. Responses oc-curred in 63% of 5-azacitidine-treated patients (CR: 6%, PR: 10%, hematological improvement: 47%) compared with 7% in the observation arm, which was limited to hemato-logical improvement. Trilineage responses were reported in 23% of patients. Median response duration was 15 months. Median time to leukemia transformation (21 months vs. 13 months; p=0.01) and quality of life were superior in patients who were treated with 5-azacytidine, while there was a bor-derline superiority of 5-azacitidine in terms of median sur-vival (20 months vs. 14 months; p=0.10) [45]. In another study, 48 MDS patients who were anemic and/or thrombo-cytopenic were treated with 5-azacitidine at the same dos-age schedule. Overall response rate was ~40% and median response duration was seven months [46]. In both studies, hematological toxicity was mild and consisted of thrombo-cytopenia and leukopenia, while extramedullary toxicity was very uncommon and consisted of pneumonia, arthral-gia, diarrhea, and injection-site irritation. Treatment-relat-ed mortality was lower than 1%.

The effect of azacitidine on survival and AML evolution is currently being evaluated in an international randomized phase III trial of patients with Int-2 and high-risk MDS. Patients in the control arm are treated with “doctor’s choice”: supportive care, low-dose cytosine arabinoside (ara-C), or in-duction chemotherapy. The Nordic MDS Group is investigat-ing the effect of azacitidine given as long-term maintenance treatment in CR after induction chemotherapy in patients with high-risk MDS and AML following MDS [47].

5-Azacitidine is a prodrug for decitabine, as it undergoes conversion to decitabine before DNA incorporation and ir-reversible binding to DNA methyltransferases. Decitabine is a more potent hypomethylating agent than 5-azacitidine and has been found to activate tumor suppressor genes in leukemic cells in vitro and in mononuclated cells of the bone marrow of MDS patients [48,49]. Furthermore, a genome-wide demethylating activity of decitabine in tumor material from patients with MDS has been reported [50]. In a phase III trial, 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenous-ly over three hours every eight hours for three days (total dose: 135 mg/m2 per cycle) and repeated every six weeks or best supportive care. Patients who were treated with decit-abine achieved a signifi cantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (p<0.001). An additional 12 patients who were treated with decitabine (13%) achieved hemato-logical improvement. Responses were durable (median: 10.3 months) and were associated with transfusion independ-ence. Patients treated with decitabine had a trend toward a longer median time to AML progression or death compared with patients who received supportive care alone: 12.1 vs. 7.8 months (p=0.16) for all patients; those with IPSS Int-2/high-risk disease, 12 vs. 6.8 months (p=0.03); those with de novo disease, 12.6 vs. 9.4 months (p=0.04); and treatment-naive patients, 12.3 vs. 7.3 months (p=0.08) [51].

The results of three European phase II trial using decitabine showed that the response rate in the 177 patients evaluated (median age: 70 years) was 49%. The median response du-ration was 36 weeks and the median survival was 15 months. Analysis of the data according to sex, age, French-American-British classifi cation, percentage of blasts in the bone mar-row, IPSS risk group, lactate dehydrogenase, and cytogenet-ics did not reveal any factor predictive of response. Overall, 69% of patients benefi ted, including those with stable dis-ease during therapy. Response duration was signifi cantly shorter with increasing risk (according to the IPSS classi-fi cation). Hemoglobin level and neutrophil count showed an inverse correlation to the IPSS classifi cation. Univariate analysis showed a signifi cantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic ab-normalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormali-ties. When analyzed according to the IPSS risk classifi cation, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; how-ever, compared with the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukemia. Decitabine showed a rather low tox-icity profi le in this elderly patient group [52].

Decitabine seems to be extremely effective in thrombocyto-penic patients. In a retrospective analysis of 126 MDS patients with intermediate- or high-risk IPSS scores who had received decitabine, the platelet response rate was 69%. Furthermore, in 58% of these patients a platelet response had been already seen after one cycle of therapy [53]. Decitabine seems also to induce restoration of nonclonal hematopoiesis both in early and late stages of treatment, at least in patients achieving a hematologic and cytogenetic response [54]. Issa et al. stud-ied a lower-dosed prolonged-exposure schedule of decitab-ine, trying to establish a minimally biologic effective dose of decitabine, thus avoiding cytotoxicity and myelosuppression. A dose of 15 mg/m2 intravenously over one hour daily for 10 days induced most responses, with no additional benefi t from further increases in dose or treatment duration. Among pa-tients with MDS, four of seven patients (57%) achieved ob-jective responses, including a CR and hematological improve-ment in one patient each. Some responses were slow to occur, with eventual recovery of normal hematopoiesis at 5–6 weeks, suggesting a noncytotoxic mode of action [55].

The median number of courses to response has been noted as 3–4 with both azacitidine and decitabine. However, the dif-ferences in duration of therapy for decitabine studies (usu-ally a maximum of six months) compared with the CALGB 5-azacitidine studies may contribute to the differences in re-sponse rate and duration. Accordingly, a comparison of stud-ies involving these drugs may be compromised if patients are taken off the study at varying times. The ability to give mul-tiple courses of decitabine may be increased by the develop-ment of low-dose schedules and is being investigated.

Histone deacetylase inhibitors

Gene transcription is a complex process of chromatine re-modeling in which histones play a crucial role. Acetylation


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of the lysine residues at the N terminus of histone pro-teins removes positive charges, thereby reducing the affi n-ity between histones and DNA. This makes RNA polymer-ase and transcription factors easier to access the promoter region. Therefore, in most cases, histone acetylation en-hances transcription, while histone deacetylation repress-es transcription. Histone acetylation is catalyzed by histone acetyltransferases (HATs) and histone deacetylation is cat-alyzed by histone deacetylases (HDACs) [56]. The effi cacy of different histone deacetylase inhibitors, such as valproic acid (VPA), sodium phenylbutyrate, FK228 (depsipeptide), SAHA (suberoylanilide hydroxamic acid), and MS-275, is investigated in clinical trials in MDS.

VPA, as an oral agent, was initially reported to have a re-sponse rate of 44% in a limited number of high-risk MDS and leukemia patients [57]. In a recent phase II study, 20 older patients with recurrent or refractory AML or MDS were treated in a phase II protocol with sequential VPA and retinoic acid (ATRA) therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve a serum con-centration of 45–100 μg/ml. ATRA was added at 45 mg/m2 per day when VPA reached the target serum concentration. Hematological improvement was observed in almost 55% of evaluable patients. The median duration of response was 189 days (range: 63–550 days), while grade III neurocorti-cal toxicity and severe bone pain were observed in four pa-tients. Treatment with ATRA did not modify the response observed with VPA alone [58].

The future in epigenetic therapy will focus on trials that will try to confi rm the optimal dose and schedule of DNA meth-yltransferase inhibitors given as monotherapy or in combi-nation with histone deacetylase inhibitors, retinoids, and other MDS effective agents. In a very recent such trial, 10 evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azaci-tidine at 75 mg/m2 followed by fi ve days of sodium phenyl-butyrate given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a benefi cial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplanta-

tion and is alive without evidence of disease 39 months lat-er. The combination regimen was well tolerated, with com-mon toxicities of injection-site skin reaction (90% of the patients) from 5-azacytidine and somnolence/fatigue from the sodium phenylbutyrate infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated [59]. Results from that pilot study demonstrated that a combination ap-proach targeting different mechanisms of transcription-al modulation is clinically feasible with acceptable toxici-ty and measurable biological and clinical outcomes. Such studies will reveal the future role of epigenetic treatments in MDS management.

Farnesyl-transferase inhibitors

During the last decade there has been great interest in de-veloping novel agents that target the ras family of onco-proteins, which is a critical network of signal transduction pathways that affects cellular proliferation, survival, and dif-ferentiation. Following isoprenylation in the cytosol, the ras protein migrates to the cell membrane, where it is capable of activating downstream signaling events. The transfer of a farnesyl group is mediated by the enzyme farnesyl-trans-ferase (FT), whereas transfer of a geranyl group is mediated by geranylgeranyl transferase. The ras protein exists in spe-cifi c isoforms (N-ras, K-ras, H-ras) that differ in their affi nity to specifi c isoprenyl groups. For example, K-ras is able to be farnesylated or geranylgeranylated, whereas H-ras is prefer-entially farnesylated. While membrane bound, ras protein fl uctuates between an active deoxyguanosine triphosphate (GTP)-bound form and an inactive guanosine diphosphate (GDP)-bound form, an equilibrium that is regulated by sur-face proteins such as SOS (a guanine nucleotide exchange factor) and GTPase-activating protein (GAP) (Figure 4). When mutated, ras protein fails to interact appropriately with its negative regulators and is found continuously in its active, GTP-bound, form [60]. The high frequency of ras mutations in MDS patients (~10–15%), which is even high-er in CMML patients [61], has, despite their debated role in predicting prognosis in MDS [62], spurred the develop-

Cell membrane

Nucleus

survival

Cytosol Cytosol

GAP SOS GRB-2Ras-F-GBPRas-F-GTP

tyrosine kinasereceptor

Ras-F

Ras

FTme

RalGDS

Golgi trafficking

Transcripiton regulation

Raf Rac PI3K AKT

S6 kinase

translationJNK Rho B

NFkB

Mek

Rik

Cell cyclepregression

Prolife-ration

Figure 4. Ras oncoproteins and farnesylation: Post-transcription and after isoprenylation in the cytosol, the ras protein migrates to the cell membrane, where it is capable of activating downstream signaling events. The transfer of a farnesyl group is mediated by the enzyme farnesyl-transferase (FT). In cell membrane, ras protein fl uctuates between an active deoxyguanosine triphosphate (GTP)-bound form and an inactive guanosine diphosphate (GDP)-bound form, an equilibrium that is regulated by surface proteins such as SOS and GAP. When mutated, ras fails to interact appropriately with its negative regulators, thereby leading to its constitutive activation in the GTP-bound form [63].


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ment of pharmacological inhibitors such as FT inhibitors (FTIs) for the treatment of MDS. This new agent group has produced very promising results in reducing the leukemia clone in both in vitro studies and animal models [63].

The two orally available FTIs, tipifarnib (R115777, Zarnestra™) and lonafarnib (SCH66336, Sarasar™), are the leading com-pounds in clinical trials of MDS and AML to date. In a phase II study, tipifarnib was given to 28 patients with all types of MDS at a dose of 600 mg twice daily for four weeks in a six-week-cycle. Three patients responded (overall response rate: 11%): two achieved CR and one achieved PR. All responders were patients with high-risk MDS. However, toxicities (mye-losuppression, constitutional symptoms, neurotoxicity, and skin reactions) necessitated dose reductions or discontinua-tion of therapy in 11 of 27 evaluable patients (40%), suggest-ing a dose of 300 mg orally twice daily as more appropriate for future use. In this study there was no correlation between the presence of ras mutations and response, indicating that the FTIs have a broader range of action [64].

In a phase I/II study of 67 patients with advanced MDS (32 patients with RAEB/RAEB-t and 35 patients with CMML), lonafarnib was given continuously at doses of 200–300 mg orally twice daily until disease progression or development of grade III-IV toxicity. Twelve out of 42 evaluable patients (29%) responded to treatment: two achieved CR and 10 showed hematological improvement. Grade III and IV tox-icities that required discontinuation of therapy occurred in 17 patients (26%; 6/17 due to diarrhea) [65]. Finally, an intravenous FTI, BMS-214662, has been studied in a phase I trial in patients with MDS and AML and produced an ac-ceptable toxicity profi le with promising effi cacy, which may be further improved with prolonged exposure [66].

Optimization of dose and schedule of the FTIs, identifi ca-tion of molecular targets and correlations with response, as well as combinations of FTIs with other agents will be of in-terest for future trials.

Anti-TNF-a therapies

TNFa is a pleiotropic cytokine with potent hematopoiet-ic inhibitory activity [67]. Serum levels of TNFa are in-creased and correlate with apoptosis rate in early MDS patients [68,69]; this phenomenon is not observed in ad-vanced MDS or AML. TNFa has become a target for novel therapy approaches. Studies evaluating the effects of anti-TNFa antibodies on the ineffective hematopoiesis and cy-topenias of MDS have reported only moderate hematolog-ical improvement in a minor subset of patients [70]. This may indicate that TNF-a expression is a secondary rather than a primary disease feature in MDS.

Pentoxifylline, which is an inhibitor of TNFa production either alone or in combined regimens (ciprofl oxacin, cip-rofl oxacin with amifostine and dexamethasone) has shown very little benefi t in MDS [71,72].

Success with the soluble, recombinant TNF-receptor fusion protein etanercept (Enbrel™) has also been very modest in MDS as monotherapy, although it has better results in com-bination with antithymocyte globulin in unselected MDS patients (overall response rate of 46%) [73,74].

Finally, infl iximab (Remicade™) is a chimeric IgG1k mon-oclonal antibody that neutralizes TNFa. It was given to 37 low-risk MDS patients in two cohorts: 5 and 10 mg/kg intra-venously every four weeks for four cycles. Median age was 68 years, 33 had primary MDS, 14 had RA, 14 RA with ringed sideroblasts, 9 RA with excess blasts. Nine patients stopped therapy prior to completing four cycles, three from cohort 1 and six from cohort 2. Six patients showed disease pro-gression, 14 had stable disease, and 8 showed hematologi-cal responses, 3/15 (20%) in cohort 1 and 5/13 (38%) in cohort 2. Two patients had multi-lineage responses, two had >100% increase in absolute neutrophils, one had >1 g/dl increase in hemoglobin, one had a reduction in blasts from 7% to 1%, and two had minor cytogenetic responses (>50% reduction in +8q- and 20q-metaphases, respectively) [75]. This study showed that infl iximab may have a variety of ac-tivities in low-risk MDS patients, is well tolerated with a high patient compliance, and may be considered for combina-tion therapy in the future.

Arsenic trioxide

Arsenic trioxide (As2O3, Trisenox™) has pleiotropic ef-fects on three distinct cellular pathways involved in the development of MDS: apoptosis, tumor cell differentia-tion, and angiogenesis [76]. Arsenic trioxide affects reg-ulatory components of the apoptotic response, inducing cell death by the abrogation of cytokines necessary for the viability of dysplastic cells and increasing the permeability of the mitochondrial membrane, thus rendering the cells sensitive to apoptosis in MDS [77,78]. It can also promote cell differentiation through G1 cell-cycle arrest via p21 and p27 activation and possesses anti-angiogenesis properties through the suppression of VEGF in activated neovascu-lature present in the bone marrow [76]. This diverse and signifi cant in vitro activity of As2O3 has driven the study of its use as a possible therapeutic agent for MDS in the clin-ical setting.

In a phase II study, As2O3 was given in 53 MDS patients as an intravenous infusion at a dose of 0.25 mg/kg over 1–2 hours per day on days 1 to 5 and on days 8 to 12 every 28 days. The patients belonged to all types of MDS according to the FAB classifi cation. The overall response rate was 26%. Erythroid response was observed in 9 patients (19.5%): ma-jor response in 5 of them and minor response in 4 patients. Patients with low-risk MDS (RA/RARS) showed a better response rate to As2O3 compared with advanced MDS pa-tients (RAEB/CMML) (38% vs. 16%). The median response duration was four months, while the interval to response ranged from two to six months. The most common drug-re-lated grade III or IV adverse events were observed in~10% of patients and included neutropenia, thrombocytopenia, hyperglycemia, congestive heart failure, dyspnea, hypoxia, and pleural effusion. No patient had a prolongation of QT or severe nausea or vomiting [79]. In another phase I/II study, As2O3 was administered in 86 MDS patients (56 with RAEB). The administration regimen included a loading dose of 0.3 mg/kg/day for fi ve days during the fi rst week, fol-lowed by 0.25 mg/kg/day twice weekly (maintenance dose) for more than 15 weeks. Hematological response was report-ed in 18 out of 76 evaluable patients (24%). Responses were fi rst seen two to six months after treatment initiation and had a median duration of approximately 4 months. As2O3


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was generally well tolerated in this study, with most treat-ment-related adverse events mild to moderate in intensi-ty and manageable. Only 2 patients experienced grade IV thrombocytopenia or neutropenia. QT prolongation was reported in only one patient [80].

In addition to studies of its use as a single agent therapy, As2O3 has demonstrated effi cacy in MDS when combined with other agents. A recently published pilot study in 28 MDS patients evaluated As2O3 in combination with low-dose thalid-omide. Seven patients (25%) achieved responses, including one CR. This response rate is not higher that that observed with As2O3 or thalidomide monotherapy. The combination therapy regimen was generally well tolerated and did not exacerbate toxicities [81]. Alternative dosing schedules of As2O3, combinations of As2O3 with other agents (e.g. 5-aza-citidine), and novel preparations (such as oral tetra arsenic tetrasulfi de, As4S4) are currently being explored.

Other novel agents tested in MDS patients

Bortezomib (Velcade™)

Bortezomib is a proteasome inhibitor which can effective-ly inhibit nuclear factor kB, which is implicated in cytokine production, such as that of TNFa. In a phase II study, bort-ezomib produced a PR rate of 35% in 32 patients with pri-mary MDS [82].

Imatinib (Gleevec™)

No responses after imatinib have been demonstrated in un-selected patients with AML or MDS. In a small subset of pa-tients with CMML, a reciprocal translocation transposes the platelet-derived growth factor receptor-beta (PDGFRb) gene on chromosome 5q33 to various fusion partners on other chromosomes, leading to constitutive activation of the ty-rosine kinase function of PDGFRb. In six such patients re-ported to date, imatinib induced durable hematological and cytogenetic responses [83].

Clofarabine (2-chloro-2’-fl uoro-deoxy-9-beta-D-arabinofuran-osyladenine), which is a second-generation nucleoside ana-log, has shown effi cacy in a small cohort of MDS patients and continues to be evaluated in high-risk MDS and AML [84]. A signifi cant number of new compounds directed towards various cellular mechanisms are being evaluated in clinical protocols: TLK199, a glutathione analogue inhibitor of GST P1-1 for high-risk MDS, Src family kinase inhibitors, and new TPO-R agonists for severe thrombocytopenia [47].

The role of high-intensity chemotherapy and stem cell transplantation in MDS

Stem cell transplantation (SCT) is a treatment with cura-tive potential in MDS. However, SCT has an attendant in-creased risk of treatment-related mortality (TRM), which is near 40% in patients who have undergone an allogeneic SCT. Therefore it is usually reserved to patients with high-risk MDS, because their prognosis is as unfavorable as in AML. Age and performance status have to be considered in the treatment decision. High-intensity therapy is most ap-propriate for patients aged <60 years who have a good per-formance status (Figure 5).

High-intensity chemotherapy

Several studies have shown that intensive chemotherapy produces remission rates from 40% to 60% and TRM rates below 10% [85–87]. Age <50 years, normal karyotype, and FAB diagnosis of RAEB-t have a positive infl uence on out-comes with intensive chemotherapy. Although remission rates are comparable to the results in AML, CR duration is short, and less than 10% of patients can be expected to be alive and disease-free beyond two years [88]. In a multivari-ate analysis, Beran et al. analyzed the outcomes of 394 new-ly diagnosed patients with high-risk MDS who were treat-ed with various chemotherapy combinations. The overall CR rate was 58%. Response was associated with karyotype, performance status, age, duration of antecedent hemato-logical disorder, and treatment in laminar air-fl ow rooms. There was no difference in the CR rate based on the regi-men used. Topotecan-based regimens had the lowest induc-tion of mortality, especially in patients aged more than 65 years. The topotecan plus cytarabine regimen was also par-ticularly safe and effective in patients with RAEB. Overall survival was similar to that of patients who were treated with idarubicin and cytarabine [89].

Stem cell transplantation

Allogeneic SCT (ASCT) is the only therapeutic modality at present that may be delivered with curative intent in MDS. Allogeneic SCT replaces recipient dysplastic hemopoiesis with healthy donor hemopoiesis and immune system with an attendant graft-versus-leukemia effect. Its applicability, however, is limited by the age of MDS patients, high rates of TRM, and the availability of a suitable HLA-matched donor. Results from several large centers indicated three-year over-all survival rates of 20–45%, which are almost equal to the re-sults obtained by intensive chemotherapy alone. Failure was due primarily to TRM in patients with low-risk MDS and to disease recurrence in patients with high-risk MDS [90,91]. Allogeneic SCT seems to be suitable even for selected pa-tients over 60 years of age, producing three-year OS and re-lapse rates of 34% and 24%, respectively [92].

In an update of the International Bone Marrow Transplant Registry, 452 patients who underwent HLA-identical sibling transplantations had an overall survival rate at three years equal to 42%. The median patient age was 38 years, and most patients (60%) had high-risk MDS. Favorable prog-nostic factors included age <50 years and platelet counts >100×109/l. The incidence of relapse was higher in pa-tients who had high percentages of bone marrow blasts at the time of transplantation, high IPSS scores, and received T cell-depleted SCT. The possibility of being alive at fi ve years was 60% in the low-risk group, 36% in the intermedi-ate-1 risk group, and 28% in the intermediate-2 risk group. This was compared with fi ve-year survival rates of 55%, 35%, and 7%, respectively, for unselected patients who did not undergo SCT. The authors concluded that allogeneic SCT mostly benefi ted patients with high-risk MDS. However, the appropriate timing and optimal bone marrow ablation reg-imen remain disputed [93].

Allogeneic SCTs from matched unrelated donors produce poorer results than matched related sibling transplanta-tions. In a recent update from the US National Marrow


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Donor Program in MDS, the two-year survival rate was 29%, the TRM was 54%, and the recurrence probability was 14% [94]. Better survival rates (three-year relapse-free survival rate: 59%) have been reported by the Seattle group using conditioning regimens with targeted busulfan and cyclo-phosphamide [95].

In an attempt to reduce TRM and deliver allogeneic SCT in a greater subgroup of MDS patients, many researchers used reduced-intensity allografts (RIC or “mini”-allograft) for MDS. Although differences in patient populations, pre-parative regimens, and graft-versus-host disease prophylax-is as well as donor source (related vs. unrelated) have to be considered, overall survival of up to 40% at three years and disease-free survival rates of almost 35% at three years have been reported in selected centers [96–99]. RIC-SCT has been demonstrated to be safe and feasible as an alterna-tive to standard conditioning regimens. The main cause for treatment failure in patients who undergo an RIC-transplant is disease recurrence, which is greater compared with pa-tients who underwent allogeneic SCT, especially in patients who had advanced-stage disease [96]. Overall, the prelimi-nary experience suggests that RIC-SCT may become a valu-able alternative for older patients or for patients who are at high risk for complications after undergoing standard allo-geneic SCT. However, the optimal choice of transplant con-ditioning intensity in MDS has not yet been clearly defi ned. A comparison between nonmyeloablative regimens (2 Gy total body irradiation alone or with fl udarabine 90 mg/m2) and myeloablative regimen (busulfan 16 mg/kg and cyclo-phosphamide 120 mg/kg) showed no difference in MDS pa-tients with respect to overall survival, progression-free surviv-al, and non-relapse mortality [100]. Graft-vs.-leukemia effects may be more important than conditioning intensity in pre-venting progression in patients in chemotherapy-induced

remissions at the time of transplantation. Randomized pro-spective studies are needed to further address the optimal choice of transplant conditioning intensity in MDS.

Autologous SCT has been extremely investigated in MDS. In a EBMT trial the three-year DFS of the 173 patients trans-planted with ASCT was 30%. The TRM was 29%, while treat-ment failure resulted mainly from a high relapse risk and was 55%. Non-relapse mortality was 25%. The DFS of patients transplanted beyond CR-1 was 18%. Age had a borderline signifi cant effect on treatment outcome. The relapse inci-dence was similar for all age groups [101]. In a recent study with long-term follow-up of 53 patients with MDS autograft-ed in fi rst complete remission, 5 (9.4%) died from the pro-cedure, whereas hematological reconstitution occurred in all the remaining patients. Forty patients (75%) relapsed, with 87.5% of the relapses occurring within two years of the autologous transplant. With a median follow-up of 6.2 years, the median actuarial disease-free survival and overall survival were 8 and 17 months after autograft, respective-ly. Karyotype was the only prognostic factor for disease-free and overall survival. The eight survivors (15%), including two patients with unfavorable or intermediate karyotype, remained in fi rst complete remission 50+ to 119+ months after transplantation and are probably cured [102]. The source of stem cells (peripheral blood or bone marrow) seems not to infl uence survival [103]. Therefore, given the more rapid hematopoietic recovery, peripheral blood is the preferred source of stem cells.

In general ASCT is limited to patients who have achieved a CR, can be harvested, and are candidates for the procedure. ASCT after successful induction chemotherapy may increase the proportion of long-term survivors, thus improving CR du-ration in some patients with MDS, particularly in younger pa-

IPSS risk groups

Low or intermediate-1

5-azacitidine,low intensity,

SCT, AML induction, supportive care

SCT, 5-azacitidine, AML induction,

low intensitysupportive care

5-azacitidine, low intensitysupportive care

5-azacitidine,AML inductionlow intensity, supportive care

Age>60PS>2

Age>60PS>2

Age£60PS£2

Age£60PS£2

Age>60PS£2

Low intermediate-2 or right5q-anomaly

consider lenalidomide

Figure 5. Treatment algorithm, which illustrates the decision to use low-intensity versus high-intensity treatment based on the IPSS score, patient age, and performance status (PS). Low-intensity treatment includes predominantly the use of growth factors (erythropoietin and/or G-CSF), immunosuppressive drugs (antithymocyte globulin, antilymphocyte globulin, cyclosporine A; mainly in hypocellular MDS), and low-dose chemotherapy (cytarabine, melphalan). 5-azacitidine may be used in all MDS subtypes as it is the only agent which has been approved for such use. Patients with 5q-anomaly may be given lenalidomide if it is available. SCT – stem cell transplantation.


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tients in remission. Results for older patients are unsatisfacto-ry. Therefore there is very little enthusiasm for the future of ASCT in the management of MDS patients [104,105].

Treatment suggestions

We suggest that patients with low- and intermediate-1-risk MDS according to IPSS may be treated with high-quali-ty transfusion and chelation therapy, while growth factors (erythropoietin with or without G-CSF) may produce a re-sponse rate of up to 50%. Immunosuppressive treatment is suitable for some patients with RA (those with a HLA-DR15 phenotype, young age (<60 years), and a short duration of transfusion dependency) or in patients with hypoplastic bone marrow. We have to consider curative approaches, such as allogeneic stem cell transplantation for intermediate-1-risk young patients with MDS. Patients with 5q- aberration have to be treated with lenalidomide if it is available. For other patients, and patients with no or lost response to the above treatment, we suggest the use of hypomethylating agents if they are available or their participation in clinical trials.

Patients with intermediate-2 or high-risk MDS according to IPSS may be treated with allogeneic stem cell transplan-tation (either standard or reduced-intensity) if they are el-igible for such procedure. Otherwise, hypomethylating agents, if available, high-intensity chemotherapy (individ-ual risk analysis based on performance status and probabil-ity of response) or low-dose chemotherapy has to be taken into consideration (Figure 5).

CONCLUSIONS

The development of novel agents with anti-MDS activity has helped us to better understand the biology of this hetero-geneous group of diseases. DNA methyltransferase inhib-itors and novel immunomodulatory derivatives of thalido-mide seem to be very effective and are possibly going to be used in the routine management of patients with MDS in the near future. With further molecular dissection of MDS and the development of new and targeted drugs, it is hoped that signifi cant progress will soon contribute to improved survival and quality of life for patients with MDS.

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Novel agents for the management of myelodysplastic syndromes