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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e3283257a74
Myeloid disease: Edited by Martin S. Tallman

Optimal sequencing of treatments for patients with myelodysplastic syndromes

Itzykson, Raphaela; Fenaux, Pierrea,b

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aService d'hématologie clinique, Hôpital Avicenne, (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 13 University, Bobigny, France

bINSERM Unit 848, Institut Gustave Roussy, Villejuif, France

Correspondence to Pierre Fenaux, MD, PhD, Service d'hématologie clinique, Hôpital Avicenne/Paris 13 University, 125 rue de Stalingrad, 93009 Bobigny, France E-mail: pierre.fenaux@avc.aphp.fr

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Abstract

Purpose of review: Myelodysplastic syndromes (MDS) are characterized by chronic cytopenias and a high risk of transformation to acute myeloid leukemia. To date, only allogeneic stem cell transplantation has shown curative potential in MDS. The heterogeneous nature of MDS, and the paucity of randomized studies make individual therapeutic decisions, still largely based on the international prognostic scoring system, difficult.

Recent findings: In lower-risk MDS, recent advances include demonstration of a possible survival advantage with erythropoiesis stimulating agents, the role of lenalidomide in cases with del 5q (which lead to its approval in the treatment of lower-risk MDS with del 5q by the Food and Drug Administration), and recognition of the importance of iron overload on prognosis. In higher-risk patients, progress has come from the use of reduced intensity conditioning allogeneic SCT in elderly patients, and from results obtained with the hypomethylating agents azacytidine and decitabine, leading to their approval for the treatment of symptomatic MDS by the Food and Drug Administration. In particular, results of a phase III trial show a significant survival benefit for azacytidine over conventional treatments in higher-risk MDS. This is the first time a drug demonstrates a survival impact in higher-risk MDS.

Summary: We review these recent advances in this paper.

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Introduction

On the basis of the International Prognostic Scoring System (IPSS), MDS patients are often separated, for therapeutic purposes, in lower-risk myelodysplastic syndromes (MDS) [including low and intermediate (int)-1 IPSS] and higher-risk MDS (int-2 or high-risk IPSS). To date, allogeneic stem cell transplantation (SCT) remains the only potentially curable treatment in MDS. Lower-risk MDS have relatively prolonged survival, and limited risk of acute myeloid leukaemia (AML) progression. Correction of cytopenias, notably anemia, is the main purpose of treatment. Conversely, in higher-risk MDS, survival is short with frequent AML transformation, and treatments capable of modifying the disease course and prolonging survival are needed. After two decades of very slow progress in the treatment of MDS, several important improvements have been shown in the last 2 or 3 years, both in lower-risk and higher-risk MDS.

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Higher-risk myelodysplastic syndromes (IPSS intermediate-2 or high)

Several recent reports have indeed further explored the role of nonmyeloablative allogeneic SCT, mainly in higher-risk MDS, whereas the hypomethylating agents have shown interesting results. One of them, azacytidine (AZA), has in particular demonstrated that it could significantly improve survival of higher-risk MDS.

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Allogeneic stem cell transplantation

Despite their advanced age, a greater number of MDS patients can be offered allogeneic SCT, thanks to progresses in reduced intensity conditioning (RIC) and better matching of unrelated donors. With myeloablative regimens, it is generally considered that allogeneic SCT must be restricted to higher-risk MDS, and delayed until progression in lower-risk MDS [1], but two recent papers suggest that therapy-related MDS [2] and MDS with marrow fibrosis [3] may benefit from earlier SCT.

A recent prospective study with long-term follow-up of 93 patients, including 34 with high-risk MDS, confirms the feasibility of RIC allogeneic SCT in elderly MDS patients [4•]. The 4-year nonrelapse mortality (NRM) and disease-free survival (DFS) in the MDS subgroup were 21 and 49%, respectively. Long-term disease control was seemingly mediated by a graft-versus-leukemia effect, as chronic graft-versus-host disease was associated with improved overall survival (OS) and reduced relapse rate.

Laport et al. [5] reported the Stanford experience in 65 patients with MDS using low-dose total-body irradiation (2 Gy) with or without fludarabine. The 3-year DFS was 27% and the relapse risk was 40%. Nakamura et al. [6] successfully engrafted 43 MDS patients after fludarabine–melphalan with a 2-year DFS of 51%, whereas Martino et al. [7] treated 39 patients with fludarabine and oral busulfan and obtained a 4-year NRM and DFS of 20 and 59%, respectively, but all patients entered in this study were in complete response (CR).

Comorbidities in hematopoietic stem cell transplantation (HCT) with variable conditioning intensity can be more precisely assessed with the modified HCT-comorbidity index (HCT-CI) score [8]. With this score, Sorror et al. [9•] recently reported a large cohort including 186 MDS patients undergoing myeloablative or RIC SCT. High HCT-CI was the strongest determinant of NRM, OS, and DFS, but was also surprisingly correlated to a higher relapse risk. In young patients (less than 50 years of age) with high HCT-CI, the NRM of myeloablative SCT is unacceptably high, suggesting that these patients, despite their age, should possibly receive RIC SCT.

Two recent papers confirm that matched unrelated donor now has similar outcome as sibling donor allogeneic SCT after both RIC [6] and myeloablative conditioning [10•], with even a trend for lower relapse rate with matched unrelated donors. Peripheral blood stem cells can be safely substituted for bone marrow [10•,11]. Finally, apart from preliminary data in 13 patients after nonmyeloablative conditioning [12], there are no recent data regarding cord-blood transplants in MDS.

Whether patients should be pretreated with intensive chemotherapy before allogeneic SCT remains debated [13]. A large recent retrospective study found no impact of intensive chemotherapy before myeloablative SCT [10•]. This may be different with RIC that relies predominantly on the immunological effect of allogeneic transplantation. Indeed, some recent papers suggest that RIC may be equally effective as conventional SCT only in patients transplanted in CR [7], and some [10•], but not all [4•] authors found a trend for lower relapse rate in patients with prior intensive chemotherapy.

Relapse after SCT remains frequent, with no validated strategy in this situation. Donor lymphocyte infusions have limited efficacy (reviewed in [14]). In a recent series of 16 patients, the CR rate was 21%, and long-term survival was infrequent [15]. Finally, the important report of an adverse prognostic value of elevated pretransplant serum ferritin on overall and DFS found by Armand et al. [16••] was confirmed by others [17]. Iron overload appears to increase the risk of early and late complications after SCT, including infections, liver disease, acute, and chronic GVD (reviewed in [18]). Future studies are required to determine whether iron chelation can reduce NRM in MDS patients.

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Chemotherapy

New series of anthracycline-cytarabine intensive chemotherapy published in recent years have confirmed the relatively high CR rates, but the short CR duration [13], the low response rates in patients with high-risk cytogenetics [19], and important toxicities in elderly patients [20]. Alternatives to standard ‘3+7’ anthracycline–cytarabine (araC) regimens include clofarabine, a novel nucleoside analog, which has shown alone or combined with intermediate-dose araC response rates of 60% in AML patients younger than 60 years, with limited toxicities [21]. In MDS or AML patients older than 60 years, it can be safely used at lower dosages and combined to low-dose cytarabine (LD araC) [22•] with a CR rate of 63%, including 43% in patients with unfavorable cytogenetics. Cloretazine is a novel alkylating agent with activity in AML. In a phase II study, the overall response rate in higher-risk MDS was 40% (6 of 15 patients, including 4 CR and 2 complete remission with incomplete platelet recovery CRp) [23], justifying further studies in MDS.

The use of LD araC, largely advocated for MDS in the 1980s, has recently come back as an option in elderly AML not eligible for intensive chemotherapy [24]. Its efficacy, however, seems lower than those of clofarabine in AML [25] and AZA in higher-risk MDS [26••], and it has very limited efficacy in case of high-risk karyotype [24].

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Hypomethylating agents and histone deacetylase inhibitors

In the last years, several works have confirmed a role for hypomethylating agents in MDS. Those drugs allow reexpression of epigenetically silenced tumor-suppressor genes or differentiation genes [27], although it is not yet demonstrated that this is their main mechanism of action in vivo. In phase II MDS trials, both AZA and decitabine (DAC) give 40–60% overall responses [28–31], including 20–35% of CR and partial remission and 25–30% hematologic improvements. Phase III studies where AZA and DAC were compared with best supportive care (BSC) showed no significant survival improvement for the hypomethylating agent, an absence of benefit possibly due to the crossover design of the AZA versus BSC study [28], and the small number of courses (median three cycles) in the DAC versus BSC trial [32]. Results of a randomized phase III trial of 358 higher-risk MDS [26••], where AZA administered for a median of nine cycles was compared with conventional care regimens (CCR, including LD araC, intensive chemotherapy and supportive care), showed a significant 9.4 months median overall survival advantage with AZA, found irrespective of patient (age, gender) and disease (FAB and WHO classification, karyotype) characteristics. Moreover, a predefined sub-group analysis showed that AZA was significantly better than BSC and LD araC in terms of survival and AML transformation. Hematological improvements [including red blood cell (RBC) transfusion independence] were also more durable with AZA. Intensive chemotherapy, in this subgroup analysis, yielded a higher CR rate than AZA, but with a trend for shorter overall survival. Likewise, in a retrospective comparison between 115 DAC-treated patients and a historical cohort of 375 higher-risk MDS treated with intensive chemotherapy, CR rates were higher with intensive chemotherapy, but CR were generally short, and more toxic deaths were seen compared with DAC. Median survival was 22 months after DAC compared with 12 months with intensive chemotherapy [33].

Prognostic factors for response to hypomethylating agents are still not completely known, but patients with -7/del 7q that fare poorly with chemotherapy seem to particularly benefit from AZA [34] and DAC [35].

Using DAC, a randomized study found superior response rates (including 39% CR) with a regimen consisting of 20 mg/m2 daily 1-h intravenous injection during 5 days [36•] over other administration schedules, and this regimen appeared at least as good as the Food and Drug Administration (FDA)-approved regimen (classical 8-h intravenous schedule over 3 days).

Clinical activity of histone deacetylase inhibitors (HDACIs) is also promising [27]. A phase I study of vorinostat, (the only HDACIs so far approved in cutaneous T-cell lymphomas), was conducted in other hematologic malignancies, including a few MDS patients, yielding 7/31 improvements in AML patients, but no response in three MDS patients [37]. MGCD0103 is another HDACI currently in development. In a phase I study one out of five MDS patients has achieved marrow response [38]. HDACIs show in-vitro synergy with hypomethylating agents [27]. Phase II combination studies with AZA or DAC have been conducted: 5/10 previously untreated MDS and AML post-MDS achieved CR or marrow CR with DAC and valproic acid in a phase1/2 study [39]. A similar rate of CR+ marrow CR (52%) was obtained in 32 AML or MDS patients treated with a combination of AZA, valproic acid, and ATRA [40].

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Other drugs

Farnesylation is a posttranslational modification required for membrane anchoring of various proteins, including the Ras oncogenes, which are mutated in 10–40% of MDS [41]. Although activity of Farnesyl-transferase inhibitors as single agent has been disappointing in randomized trials when compared with BSC in AML [41], it may be more encouraging in higher-risk MDS. In a multicenter phase II study of tipifarnib in 82 higher-risk MDS [42•], the overall response rate was 32% including 15% CR (which lasted for a median of 12 months) and 17% hematologic improvement, including 27% platelet transfusion independence. These results, notably platelet count improvements, have also been observed in other trials with tipifarnib [43] or lonafarnib [44]. Finally, arsenic trioxyde has moderate activity in higher-risk MDS, inducing hematological improvements in 20–25% cases [45,46], but may find renewed interest in combination therapies, for example, with LD araC [47].

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Lower-risk MDS

Lower-risk MDS patients suffer mainly from the consequences of cytopenias, principally anemia, and several important papers have been published on the treatment of anemia in the past 2 years.

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Treatment of anemia: erythropoiesis stimulating agents and lenalidomide

Anemia is present at diagnosis in 90% of MDS patients, requiring chronic transfusions in 80%. Two large series have confirmed that erythropoiesis stimulating agents (ESAs) [including recombinant erythropoietin (EPO) and darbepoietin], alone or combined to Granulocyte Colony Stimulating Factor (G-CSF), can correct anemia of lower-risk MDS in about 60% of the patients, with an average response duration of 2 years [48••,49••]. Prognostic factors for ESA response are confirmed to be low or int-1 IPSS, low endogenous EPO level, and relatively low RBC transfusion requirements. Perhaps more importantly, those two papers strongly suggest for the first time that ESAs could improve OS in lower-risk MDS, by comparison with transfusion support only.

In the first study, Park et al. [49••] retrospectively analyzed 403 patients treated with ESAs, with or without G-CSF, and compared them with matched lower-risk MDS from the historical International MDS risk analysis workshop (IMRAW) cohort that served to establish the IPSS, and where patients received supportive care only [50]. No difference in rates of progression to AML was seen between the two cohorts, but the French cohort had significantly improved OS (5-year OS, 64 versus 39%). Jadersten et al. [48••] compared three cohorts treated with ESAs and G-CSF in Scandinavia to Italian patients (Pavia area) treated with RBC transfusions alone, and came to the same conclusion. Although neither study was randomized, it appears that, contrary to solid malignancies where ESAs have been suspected of accelerating disease progression [51], ESAs do not increase the risk of leukemic progression in MDS. Explanations for the survival improvement seen in patients receiving ESAs, restricted to nonleukemic deaths, could result from fewer complications of chronic anemia or less transfusional iron overload or both. Indeed, chronic anemia in the elderly has been shown to result in increased cardiovascular morbidity and more frequent complications during hospitalizations (reviewed in [52]). Transfusional iron overload also appears to be an independent adverse prognostic factor in MDS [53].

Thus ESAs, although not formally approved by FDA or European Medicines Agency in this indication, may be considered as the first-line treatment of anemia in lower-risk MDS that do not have both high endogenous EPO levels and high RBC transfusion requirements. One exception, however, is lower-risk MDS with del 5q, where the response rate to ESAs is significantly lower and ESA responses are shorter (median duration 1 year) than in other lower-risk MDS [54]. In those patients, lenalidomide (LEN) yields erythroid response in 76% of cases (66% of complete transfusion independence) and 73% cytogenetic responses in assessable patients [55]. An updated analysis of this trial, so far only presented at meetings, shows a median response duration of 2.2 years, with about one third of the responders having sustained responses [56].

Non-del 5q patients, who do not respond to ESAs or relapse after initial response, require other treatments. A recent French GFM study shows that even at very low dose (50–100 mg/day) thalidomide, although it yields response in about one third of those patients, is associated to side effects hardly compatible with prolonged use [57]. On the contrary, Raza et al. [58•] recently reported results of a phase II trial of LEN in 214 transfusion-dependent low-risk MDS patients without del 5q, with mostly normal karyotype. The erythroid response rate was 43%, including 26% transfusion independence, lasting an average 41 months. In those patients, LEN gave less hematologic toxicities than in del 5q patients (25–30% versus 45–55%). Predictive factors of response included low transfusion requirement, high platelet counts, LDH value in the normal range, and short disease duration. An expression profile predictive of response was determined by gene expression analysis [59]. Other second line treatments of anemia (i.e., after ESA failure) in lower-risk MDS include hypomethylating agents and antithymocyte globulin (ATG). Eleven out of 12 lower-risk MDS patients treated with AZA in Cancer and Leukemia Group B9221 trial reached erythroid transfusion independence [29]. Nine of 19 lower-risk MDS reached complete response with DAC [36•]. Immunosuppressive therapy with ATG, with or without ciclosporine, is another option, because immune bone marrow aggression occurs in MDS [60] and because early trials with ATG or ciclosporin (CsA) or both have shown erythroid and multilineage responses in MDS. Two large series of MDS treated with ATG have recently been published [61,62••]. In a pooled analysis of 129 patients prospectively treated in successive protocols, Sloand et al. [62••] found an overall response rate of 30%, confirmed that responses to ATG were multilineage in most (80%) responders, and suggested that adding CsA to ATG could increase response rates from 25 to 45%, for a median duration of 3 years. Age younger than 60 years and HLA-DR15 haplotype were confirmed as the most important prognostic factors of response to ATG. A matched analysis with the IMRAW cohort showed that ATG may improve OS, and delay AML progression over supportive care alone, but the survival benefit was restricted to younger patients (<60 years).

In a retrospective multicenter study of 96 MDS patients treated with ATG, 42% responded, and lower-risk IPSS and hypocellularity were predictive factors of response to ATG. Response to ATG was also found to improve OS [61].

Finally, allogeneic SCT gives excellent results in low-risk MDS [10•,63], but its place in this context has to be defined, possibly in patients with severe cytopenias resistant to several lines of treatment.

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Iron overload and chelation

In MDS, transfusional iron overload generates cardiac and liver damage [64•], and possibly affects overall survival [53]. The importance of iron overload in MDS prognosis is, however, debated, as transfusion dependency could merely reflect the intrinsic severity of MDS. Three recent studies have shown that evaluation of T2* time by cardiac MRI was a reliable method to assess myocardial iron overload [65–67]. They found that myocardial overload was rare and delayed compared with liver overload, and was not correlated to ferritin values. Oral molecules are being developed as alternatives to continuous-infusion deferoxamine: recent trials have confirmed that deferasirox is well tolerated and effective in MDS patients [68,69]. A number of recommendations for using chelation therapy in MDS have been proposed by national scientific societies [70], and by international groups of experts [71•]. They all refine the ‘Nagasaki proposals’ to chelate patients with lower-risk, transfusion-dependant MDS devoid of severe comorbidities or candidates for SCT with ferritin value above 1000-1500 μg/l [72].

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Treatment of thrombocytopenia

Although anemia is generally the predominant cytopenia in lower-risk MDS, thrombocytopenia is sometimes the most important debilitating clinical feature [73]. Preliminary results of a phase II trial show that a thrombopoetin receptor agonist, AMG 531, can significantly improve platelet counts [74,75]. Some patients can develop transient increases in marrow blasts; this drug should be restricted to lower-risk MDS.

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Conclusion

Together with progresses in allogeneic SCT procedures, recent data showing in lower-risk MDS a survival advantage with ESAs, a dramatic erythroid response in patients with del 5q to LEN, and in higher-risk MDS a survival advantage with AZA treatment all challenge current concepts on MDS treatments. These agents allow the clinician to refine first-line therapy of MDS based on the well studied disease parameters (WHO, karyotype, IPSS). The individual treatment decision must also take in consideration the less well studied host characteristics such as age, performance status, comorbidities, and patient preferences.

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References and recommended reading

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Papers of particular interest, published within the annual period of review, have been highlighted as:

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• of special interest

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•• of outstanding interest

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Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 149).

1 Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104:579–585.

2 Chang C, Storer BE, Scott BL, et al. Hematopoietic cell transplantation in patients with myelodysplastic syndrome or acute myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in patients with de novo disease and disease following prior therapy or antecedent hematologic disorders. Blood 2007; 110:1379–1387.

3 Scott BL, Storer BE, Greene JE, et al. Marrow fibrosis as a risk factor for posttransplantation outcome in patients with advanced myelodysplastic syndrome or acute myeloid leukemia with multilineage dysplasia. Biol Blood Marrow Transplant 2007; 13:345–354.

4• Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26:577–584. A prospective cohort of RIC SCT in high-risk MDS or AML with long-term follow-up, showing limited toxicity and interesting long-term results of this procedure in high-risk MDS.

5 Laport GG, Sandmaier BM, Storer BE, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant 2008; 14:246–255.

6 Nakamura R, Rodriguez R, Palmer J, et al. Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome. Bone Marrow Transplant 2007; 40:843–850.

7 Martino R, Valcarcel D, Brunet S, et al. Comparable nonrelapse mortality and survival after HLA-identical sibling blood stem cell transplantation with reduced or conventional-intensity preparative regimens for high-risk myelodysplasia or acute myeloid leukemia in first remission. Bone Marrow Transplant 2008; 41:33–38.

8 Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106:2912–2919.

9• Sorror ML, Sandmaier BM, Storer BE, et al. Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 2007; 25:4246–4254.

10• Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood 2008; 112:895–902.

11 Guardiola P, Runde V, Bacigalupo A, et al. Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood 2002; 99:4370–4378.

12 Brunstein CG, Barker JN, Weisdorf DJ, et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood 2007; 110:3064–3070.

13 Deschler B, de Witte T, Mertelsmann R, Lubbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006; 91:1513–1522.

14 Porter D, Levine JE. Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. Semin Hematol 2006; 43:53–61.

15 Campregher PV, Gooley T, Scott BL, et al. Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation. Bone Marrow Transplant 2007; 40:965–971.

16•• Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109:4586–4588.

17 Pullarkat V, Blanchard S, Tegtmeier B, et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2008. [Epub ahead of print]

18 Majhail NS, Lazarus HM, Burns LJ. Iron overload in hematopoietic cell transplantation. Bone Marrow Transplant 2008; 41:997–1003.

19 Knipp S, Hildebrand B, Kundgen A, et al. Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. Cancer 2007; 110:345–352.

20 Kantarjian H, Beran M, Cortes J, et al. Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer 2006; 106:1099–1109.

21 Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood 2006; 108:45–51.

22• Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 2008; 112:1638–1645.

23 Giles F, Rizzieri D, Karp J, et al. Cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, in patients age 60 years or older with previously untreated acute myeloid leukemia. J Clin Oncol 2007; 25:25–31.

24 Burnett AK, Milligan D, Prentice AG, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007; 109:1114–1124.

25 Burnett AK, Mohite U. Treatment of older patients with acute myeloid leukemia–new agents. Semin Hematol 2006; 43:96–106.

26•• Fenaux P, Mufti GJ, Santini V, et al. Azacitidine (AZA) Treatment Prolongs Overall Survival (OS) in Higher-Risk MDS Patients Compared with Conventional Care Regimens (CCR): Results of the AZA-001 Phase III Study. Blood (ASH Annual Meeting Abstracts), 2007 110: Abstract 817. Results of a phase III trial showing that AZA improves OS of high-risk MDS over conventional care regimens, including low and high-dose chemotherapy. This represents the first time any drug is shown to improve OS in MDS.

27 Griffiths EA, Gore SD. DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Semin Hematol 2008; 45:23–30.

28 Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002; 20:2429–2440.

29 Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006; 24:3895–3903.

30 Wijermans P, Lubbert M, Verhoef G, et al. Low-dose 5-aza-2′-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18:956–962.

31 Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia 1997; 11:1–5.

32 Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106:1794–1803.

33 Kantarjian HM, O'Brien S, Huang X, et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer 2007; 109:1133–1137.

34 Raj K, John A, Ho A, et al. CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. Leukemia 2007; 21:1937–1944.

35 Ruter B, Wijermans P, Claus R, et al. Preferential cytogenetic response to continuous intravenous low-dose decitabine (DAC) administration in myelodysplastic syndrome with monosomy 7. Blood 2007; 110:1080–1082, author reply 1083.

36• Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109:52–57.

37 Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood 2008; 111:1060–1066.

38 Garcia-Manero G, Assouline S, Cortes J, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. Blood 2008; 112:981–989.

39 Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood 2006; 108:3271–3279.

40 Soriano AO, Yang H, Faderl S, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007; 110:2302–2308.

41 Braun T, Fenaux P. Farnesyltransferase inhibitors and their potential role in therapy for myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol 2008; 141:576–586.

42• Fenaux P, Raza A, Mufti GJ, et al. A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome. Blood 2007; 109:4158–4163.

43 Kurzrock R, Kantarjian HM, Blascovich MA, et al. Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome. Clin Cancer Res 2008; 14:509–514.

44 Feldman EJ, Cortes J, DeAngelo DJ, et al. On the use of lonafarnib in myelodysplastic syndrome and chronic myelomonocytic leukemia. Leukemia 2008; 22:1707–1711.

45 Schiller GJ, Slack J, Hainsworth JD, et al. Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 2006; 24:2456–2464.

46 Vey N, Bosly A, Guerci A, et al. Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol 2006; 24:2465–2471.

47 Roboz GJ, Ritchie EK, Curcio T, et al. Arsenic trioxide and low-dose cytarabine in older patients with untreated acute myeloid leukemia, excluding acute promyelocytic leukemia. Cancer 2008; 113:2504–2511.

48•• Jadersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol 2008; 26:3607–3613.

49•• Park S, Grabar S, Kelaidi C, et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 2008; 111:574–582.

50 Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079–2088.

51 Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in nonsmall-cell lung cancer with disease-related anemia. J Clin Oncol 2007; 25:1027–1032.

52 Steensma DP, Tefferi A. Anemia in the elderly: how should we define it, when does it matter, and what can be done? Mayo Clin Proc 2007; 82:958–966.

53 Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol 2005; 23:7594–7603.

54 Kelaidi C, Park S, Brechignac S, et al. Treatment of myelodysplastic syndromes with 5q deletion before the lenalidomide era; the GFM experience with EPO and thalidomide. Leuk Res 2008; 32:1049–1053.

55 List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456–1465.

56 Melchert M, List AF. Management of RBC-Transfusion Dependence. Hematology Am Soc Hematol Educ Program 2007; 2007:398–404.

57 Tamburini J, Elie C, Park S, et al. Effectiveness and tolerance of low to very low dose thalidomide in low-risk myelodysplastic syndromes. Leuk Res 2008. [Epub ahead of print]

58• Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111:86–93.

59 Ebert BL, Galili N, Tamayo P, et al. An erythroid differentiation signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med 2008; 5:e35.

60 Sloand EM, Rezvani K. The role of the immune system in myelodysplasia: implications for therapy. Semin Hematol 2008; 45:39–48.

61 Lim ZY, Killick S, Germing U, et al. Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 2007; 21:1436–1441.

62•• Sloand EM, Wu CO, Greenberg P, et al. Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26:2505–2511.

63 Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 2002; 100:1997–2004.

64• Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol 2007; 78:487–494. This paper suggests that a large proportion of MDS patients with elevated ferritin die from cardiac failure.

65 Chacko J, Pennell DJ, Tanner MA, et al. Myocardial iron loading by magnetic resonance imaging T2* in good prognostic myelodysplastic syndrome patients on long-term blood transfusions. Br J Haematol 2007; 138:587–593.

66 Di Tucci AA, Matta G, Deplano S, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008; 93:1385–1388.

67 Konen E, Ghoti H, Goitein O, et al. No evidence for myocardial iron overload in multitransfused patients with myelodysplastic syndrome using cardiac magnetic resonance T2 technique. Am J Hematol 2007; 82:1013–1016.

68 Metzgeroth G, Dinter D, Schultheis B, Dorn-Beineke A, Lutz K, Leismann O, Hehlmann R, Hastka J. Deferasirox in MDS patients with transfusion-caused iron overload-a phase-II study. Ann Hematol 2008. [Epub ahead of print]

69 Porter J, Galanello R, Saglio G, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008; 80:168–176.

70 Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008; 88:24–29.

71• Bennett JM, MDS Foundation's Working Group on Transfusional Iron Overload. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol 2008; 83:858–861.

72 Gattermann N, Porter J, Lopes L, Seymour J. Consensus statement on iron overload in myelodysplastic syndromes. Hematol Oncol Clin North Am 2005; 19:18–25.

73 Kantarjian H, Giles F, List A, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer 2007; 109:1705–1714.

74 Kantarjian H, Fenaux P, Sekeres MA, et al. Phase 1/2 study of AMG 531 in thrombocytopenic patients (pts) with low-risk myelodysplastic syndrome (MDS): update including extended treatment [abstract #250]. Blood 2007; 110.

75 Tiu RV, Sekeres MA. The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opin Biol Ther 2008; 8:1021–1030.

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Keywords:

allogeneic stem cell transplantation; azacytidine; erythropoietin; lenalidomide; myelodysplastic syndromes

© 2009 Lippincott Williams & Wilkins, Inc.

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