Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome

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1 Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome Simrit Parmar, Marcos de Lima Allogeneic hematopoietic stem cell transplantation remains the only curative option for myelodysplastic syndrome, but patients with this disease are often older and frail, and treatment-related mortality and morbidity is a major obstacle to be overcome. Treatment of MDS is likely to benefit from the major lines of investigation in the field of allogeneic transplantation, especially interventions postulated to decrease the morbidity of the procedure, such as less toxic preparative regimens. In this review we summarize current recommendations and controversies surrounding HSCTas well as integration of the novel therapeutic agents in the peritransplant period. Biol Blood Marrow Transplant 16: S37-S44 (2010) Ó 2010 American Society for Blood and Marrow Transplantation KEY WORDS: MDS, Allogeneic stem cell transplant, Reduced intensity conditioning Myelodysplastic syndrome (MDS) comprises a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders characterized by peripheral cytopenias, hypercellular bone marrow (BM), and increased morbidity and mortality because of evolution to acute myelogenous leukemia (AML) or BM failure [1]. MDS is a disease of the elderly, with the median age at diagnosis in the eighth decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for this disease, despite new therapeutic interventions. But, the discrepancy between the age of the regular MDS patients and those who ultimately receive a transplant indicates that a significant selection bias exists, and HSCT results should be interpreted with that in mind [1,2]. The reduced transplantation toxicity over the last decade has led to an increase in the upper age limit of HSCT recipients, thereby potentially benefiting more patients with MDS. Several questions remain unanswered, including transplantation timing and proper integration with newer therapies. In addition, the success of allogeneic HSCT is often limited by graft-versus-hostdisease (GVHD) and relapse. Here, we review some of the controversies surrounding HSCT for MDS. From the Department of Stem Cell Transplantation and Cell Therapy, M.D. Anderson Cancer Center, Houston, Texas. Financial disclosure: See Acknowledgments on page S42. Correspondence and reprint requests: Marcos de Lima, MD, Department of Stem Cell Transplantation and Cell Therapy, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 423, Houston, TX ( mdelima@mdanderson.org). Received August 13, 2009; accepted October 20, 2009 Ó 2010 American Society for Blood and Marrow Transplantation /10/161S-0008$36.00/0 doi: /j.bbmt DEFINING THE TRANSPLANT CANDIDATE Age is a major deciding factor, and most patients under the age of 60 years are likely to be considered for transplantation before older patients. Disease stage is the other major determinant. The International Prognostic Scoring System (IPSS) categories intermediate-2 or high-risk (scoring based on cytopenias, cytogenetics, and blast percentage) are generally considered candidates for earlier HSCT [3,4]. However, the IPSS and World Health Organization (WHO) classifications may underestimate the impact of transfusion dependence (both platelets and red blood cells) in any given category [5,6]. The WHO s Prognostic Scoring System (WPSS) represents one effort to improve risk stratification [7]. Cutler et al. [3] reported a retrospective registrybased analysis indicating that upfront transplantation was associated with a greater number of added life years for intermediate- 2 and high-risk IPSS patients. Delaying HSCT was the best strategy for patients in other risk categories. These conclusions were reached in a young cohort receiving HLA-identical sibling HSCT and must be interpreted in that context, however. In general, young patients with less advanced disease have better transplantation outcomes than patients with more aggressive disease [8]. Treatmentrelated mortality (TRM) is a major cause of failure after HSCT and must be taken into consideration when making a decision regarding transplantation in a patient with low-risk disease. The issue of low-risk disease is far from resolved, however. Recent data from the Gruppo Italiano Trapianto di Midollo Osseo suggest that lower-risk patients (according to the WHO classification system) did S37

2 S38 S. Parmar and M. de Lima Biol Blood Marrow Transplant 16:S37-S44, 2010 well with allogeneic HSCT, whereas those with excess blasts had a 5-year overall survival (OS) of only 25%- 28% [9]. The 5-year OS was 80% in refractory anemia (RA), 57% in RA with multilineage dysplasia, 51% in RA with excess blasts (RAEB)-1, 28% in RAEB-2, and 25% in acute leukemia arising from MDS. In another series that included 374 patients with low-risk MDS (median age, 39 years), the 4-year OS was 52% [10]. Furthermore, no survival difference was seen between HLA-identical sibling and HLA-matched unrelated donor (MUD) transplants, and improved survival and lower TRM were associated with transplantations performed early after diagnosis [10]. An American Society for Blood and Marrow Transplantation 2009 consensus paper [11] recommended early HSCT for patients with an IPSS score of intermediate-2 or high-risk at diagnosis and a suitable donor who meet the transplantation center s eligibility criteria, as well as for selected patients with lower-risk disease at diagnosis who have poor prognostic features (eg, older age, refractory cytopenia, transfusion dependence). The use of newer prognostic tools, such as flow cytometry and molecular markers, is expected to improve our ability to select patients based on disease characteristics. Newer risk models that identify covariates affecting outcomes across medical and HSCT therapies and individual risk factors (such as comorbidities) also should be considered when weighing the decision of whether to proceed to allogeneic HSCT. AGE AND COMORBIDITIES Age per se is not considered a contraindication to HSCT (at least up to age years); however, aging is associated with disease refractoriness and poorer characteristics, and also with the development of comorbid conditions. It is intuitive to assume that diabetes and coronary artery disease, for example, will increase the possibility of TRM. MDS, on the other hand, is likely the greatest threat to survival of a patient with this diagnosis, a fact that must be considered when weighing comorbidities in the decision to proceed to transplantation. The HSCT-specific comorbidity index (HCT-CI) score may be used to stratify risk groups, although it has not yet been used systematically in a prospective fashion [12]. Both HCT-CI and Karnofsky performance status have been reported to be independent predictors of outcome in allogeneic HSCT with both conventional (high-dose) conditioning and reduced-intensity conditioning (RIC) [13,14]. A pretransplantation serum ferritin level mg/ L has been shown to have an adverse impact on OS as well as other outcomes of MDS in general, specifically after HSCT, regardless of blood transfusion burden [15]. Other adverse consequences of iron overload in the HSCT setting may include increased risk of septicemia, invasive fungal infections, and sinusoidal obstruction syndrome [16,17]. At present, it is unclear whether iron chelation will reduce these risks for MDS patients; prospective clinical trials are needed to clarify this issue [18]. ROLE OF TREATMENT BEFORE TRANSPLANTATION AND THE IMPACT OF CYTOREDUCTION In the absence of randomized prospective trials, the value of induction chemotherapy before allogeneic HSCT remains unresolved (Table 1). Nakai et al. [19] compared the outcomes of 283 adults with MDS (76%) or secondary AML (saml) who received (n 5 188) or did not receive (n 5 95) induction chemotherapy before HLA-identical sibling donor HSCT and found no difference in survival, with 5-year OS probabilities of 54% and 57%, respectively. Similarly, Scott et al. [20] failed to show a clear survival advantage for a cohort of patients in Seattle studied retrospectively that received induction chemotherapy before HSCT, although the risk of relapse was somewhat reduced in these patients. The intrinsic bias with retrospective analyses of this nature is that patients selected for chemotherapy likely were different from those who Table 1. Role of Induction Chemotherapy before Transplantation in MDS Reference Pretransplantation induction therapy CR RFS OS Relapse Follow-Up Nakai et al., 2005 [19] Yes, 188; no, 9 43%/0 4-year RFS: 5-year OS: 54%/ 27.6%/26.2% 36.5 months 28.9%/17.3% 57% (P 5.81) Oosterveld et al., 2002 [24] Yes, 184; no, %/63% 4-year OS: 34.4%/25.5% Median,3.6 years/ 3.0 years Scott et al., 2005 [20] Yes, 33; no, 92 54%/22% 3-year RFS: 13%/ 42%/28% 26% (P 5.26) de Witte et al., 1990 [61] Yes, 34; no, 44 47%/0 35%/25% 23%/22% Warlick e al., 2009 [21] Yes, 42%; no, 58% 6%/0 54%/10% 53%/35% 18%/35% 2.4 years Castro-Malaspina et al., 2008 [22] 30%/38% 77 months Yes, 36; no, 13 61%/0 3-year RFS: responders, 45%; untreated, 15%; failures, 0 3-year OS: responders, 54%; untreated, 31%; failures, 0 MDS indicates myelodysplastic syndrome; CR, complete remission; RFS, relapse-free survival; OS, overall survival.

3 Biol Blood Marrow Transplant 16:S37-S44, 2010 HSCT for Myelodysplastic Syndrome S39 did not receive induction therapy (most often because of having higher-risk disease, with more blasts, etc), making comparisons very difficult. Conversely, being in remission at the time of HSCT may favorably affect relapse and TRM rates (keeping in mind that complete remission [CR] with any treatment is achieved in only a small minority of patients with MDS). Warlick et al. [21] studied 84 patients undergoing allogeneic HSCT while in remission and found a 1-year cumulative incidence cumulative index (CI) of relapse of 18%, compared with 35% in those undergoing transplantation with active disease. In a retrospective analysis of 49 MDS/AML patients treated with T cell7 depleted grafts, the 2-year CI of TRM was 23% for patients with responsive disease, 38% for untreated patients, and 40% for patients with refractory disease [22]. Oran et al. [23] also noted the benefit of minimal tumor burden at the time of transplantation in patients with high-risk MDS/AML receiving RIC HSCT. CR at HSCT was associated with a day-100 TRM of 0 and a 2-year TRM of 20%. Estimates of 2-year OS were 66% for patients in remission, 40% for those with active disease without circulating blasts, and 23% for those with circulating blasts [23]. Considering the lack of prospective studies, the decision to use pre-hsct induction therapy should be made on an individual basis. Classic AMLtype chemotherapy is being used with decreasing frequency as other drugs become available, although whether this approach will change the long-term outcome is unclear [11,24]. THE ROLE OF PERITRANSPLANTATION TREATMENT WITH NOVEL AGENTS Treatment with azacitidine has been shown to prolong survival in patients with MDS [25]. Whether treatment with hypomethylating agents before transplantation will influence post-hsct survival, toxicities, or other outcome parameters is unclear, however. Field et al. [26] reported the effect of pretransplantation 5-azacytidine in 30 patients who received a median of 4 cycles of the drug compared with 24 patients who received no treatment before HSCT. The 1-year estimates of OS, relapse-free survival (RFS), and CI of relapse were 47%, 41%, and 20%, respectively, for the 5-azacitidine treated patients and 60%, 51%, and 32% for the untreated patients. These findings suggest a trend toward decreased early relapse, but not improved survival, in patients receiving pre-hsct 5-azacitidine [26]. In an M.D. Anderson Cancer Center (MDACC) retrospective analysis of 17 MDS patients (median age, 55 years) who underwent allogeneic HSCT (12 with sibling donors and 5 with MUD) after previous therapy with decitabine, no unexpected toxicities were observed, and 11 patients were alive in CR at a median follow-up of 12 months [27]. Thus, hypomethylating agents may be of value in stabilizing the disease without adding toxicity to HSCT, thereby allowing time for patients to reach transplantation, possibly with downstaged disease, similar to what is expected with conventional chemotherapy. In the MDACC experience, however, the outcomes of patients who fail to respond to hypomethylating agents are dismal [28]. Whether or not HSCT can salvage patients who fail to respond to therapy with decitabine or azacitidine is largely unknown; thus, timely detection of such patients and early discussion of allogeneic HSCT are important. Another unresolved question regarding these agents pertains to the responders: Should a patient be considered for HSCT at the time of best response or when the disease no longer responds or progresses? These and related questions can be answered only by well-conducted, prospective clinical studies. We have hypothesized that azacitidine may have immunomodulatory effects (such as increased expression of tumor antigens) that could potentially increase the graft-versus-leukemia (GVL) effect after HSCT. Low doses actually may be as effective as standard doses [29] and be better tolerated after HSCT. A phase I trial identified a 5-azacytidine dose of 32 mg/m 2 /day for 5 days in 28-day cycles as safe and well tolerated when started during week 6 or 7 post-hsct [30]. Preliminary results indicated prolonged RFS for relapsed and refractory MDS/AML patients compared with historical controls. We have kept patients on maintenance therapy for up to 2 years with low-dose azacitidine with no unexpected toxicities. Given this promising preliminary experience, a Phase III study comparing maintenance with azacitidine versus standard of care (ie, no maintenance) for MDS and AML patients at high risk for relapse has been initiated at MDACC [31]. AUTOLOGOUS AND ALLOGENEIC TRANSPLANTATIONS Most studies comparing autologous and allogeneic HSCT reflect the practices of the previous decade, and as such illustrate the trade-off between higher TRM and lower relapse rates with allogeneic HSCT. A multicenter study compared allogeneic and autologous HSCT as postconsolidation therapy for patients with advanced MDS, secondary AML, or chronic myelomonocytic leukemia (CMML), dependent on the availability of an HLA-matched related donor [32]. Four-year RFS and OS were 31% and 36% for patients with a donor and 27% and 33% for those without a donor, although several patients did not receive the autologous transplant as

4 S40 S. Parmar and M. de Lima Biol Blood Marrow Transplant 16:S37-S44, 2010 Table 2. Comparison of Related and Unrelated Donor Transplantations for MDS Reference Donor Type NRM RFS OS agvhd Follow-Up Deeg et al., 2002 [37] Ho et al., 2004 [38] Jurado et al., 2002 [39] Hallemeier et al., 2006 [40] Nakamura et al., 2007 [41] Kroger et al., 2003 [42] 45 related; 64 unrelated Day 100/3 years: related, 12%/28%; unrelated, 13%/30% Day 100: 0%/5%; 11%/21% 3-year RFS: related, 56%; MUD, 9%; mismatched unrelated, 29% 1-year RFS: 61%/59% Related, 64%; MUD, 68%; mismatched unrelated, 100% 1-year grade III/IV agvhd: 17%/23% 24 related; 38 unrelated 1-year OS: 73%/71% 524 days/ 420 days 20 related; 35%/55% 3-year RFS: 35%/20% Grade II-IV agvhd: 54 months 40 unrelated 85%/83% 21 related; 3-year TRM: 31%/51% 3-year relapse 3-year OS: Grade II-IV 3.7 years 30 unrelated risk:/31%/46% 48%/30% agvhd: 11%/37% 19 related; 2-year TRM: Relapse risk: 38.5%/7% 2-year OS: 38 months 24 unrelated 31.6%/37.5% 47.4%/58.3% 19 related; 45%/12% (P 5.03) 3-year RFS: 51%/25% 3-year OS: 20 months 18 unrelated 45%/31% MDS indicates myelodysplastic syndrome; NRM, nonrelapse mortality; RFS, relapse-free survival; OS, overall survival; agvhd, acute graft-versus-host disease. originally intended. Three studies by the European Bone Marrow Transplant (EBMT) group have investigated the use of autologous HSCT for MDS and treatment-related AML. In a large series of 184 MDS patients who underwent induction chemotherapy, 100 patients achieved CR and were to receive further therapy with allogeneic or autologous HSCT, based on donor availability [32]. Twenty-eight patients received an allograft, and 36 patients without a donor received an autograft while in first CR. The 4-year RFS rate was 31% in the first group and 27% in the second group, and the respective 4-year survival rates from CR were 36% and 33% [32]. A study of 65 patients who underwent autologous HSCT reported a CI of relapse of 58% and a TRM of 2% [33]. De Witte et al. [34] reported a registry analysis of allogeneic unrelated or related donor and autologous HSCT showing a 3-year RFS of 25%, 36%, and 30%, respectively, and a relapse rate of 41%, 36%, and 58%, respectively. A more recent retrospective study of 593 patients compared unrelated donor HSCT with autologous HSCT and reported the following 3-year OS rates: unrelated donor in first CR, 50%; autologous HSCT in first CR, 41%; and unrelated donor untreated, 40% (P 5.01), with a higher relapse rate for autologous transplantations (62%) [35]. Although autologous HSCT may be feasible in a small proportion of patients with MDS, it is associated with a higher relapse rate and prolonged cytopenias and thus should be pursued only within clinical trials [36]. High-resolution HLA typing and general improvements in supportive care have led to a perceived equivalence in outcomes after unrelated and related donor HSCT [37-42] (Table 2). Deeg et al. [37] reported the Seattle experience in 109 MDS patients. The 3-year RFS was 56% for related transplant recipients and 59% for unrelated transplant recipients. No difference in TRM was seen at 100 days (12% vs 13%) or at 3 years (28% vs 30%). Ho et al. [38] studied 62 MDS patients undergoing RIC HSCT with fludarabine (Flu), busulfan (Bu), and alemtuzumab conditioning and found a 1-year OS of 73% for sibling donor HSCT and 71% for unrelated transplant recipients, with a respective RFS of 61% and 59%. ALTERNATIVE STEM CELL SOURCES Relatively few patients have received cord blood (CB) or haploidentical HSCT for MDS [43]. A prospective study from Japan using conventional doseconditioning CB transplants for 13 adult patients with advanced MDS found a 2-year RFS of 76% [44]. Three patients relapsed, 1 patient failed to engraft, and 10 patients were alive in CR at days after transplantation. Parikh et al. [45] reported 23 pediatric MDS patients (median age, 11 years) treated with total body irradiation (TBI)-based conditioning regimens before transplantation with 4 or 5 of 6 HLA antigen-matched CB units; with a median follow up of 5.3 years, the probability of RFS at 1 year and 3 years was 69.6% and 60.9%, respectively. The grafts contained a median of total nucleated cells (TNCs)/kg, and the CI of neutrophil and platelet engraftment was 91.3% and 69.6%, respectively. Ooi [46] reported data on 22 adult MDS patients (median age, 40 years) who received singleunit CB transplants containing a median TNC dose of /kg. The median time to myeloid engraftment was 23 days. Of the 22 patients, 17 were alive and disease-free at 1-7 years of follow-up, with a 4-year probability of RFS of 76%. Majhail et al reported CB HSCT for MDS in patients age 55 years and older [47]. All underwent RIC HSCT, using either an HLA-matched related donor (n 5 47) or CB (n 5 43; 88% received 2 CB units). With a median follow-up of 27 months, the 3-year probabilities of RFS and OS were similar (30% vs 34% and 43% vs 34%, respectively) [47]. The CIs of grade II-IV acute GVHD (agvhd; 42% vs 49%) and day 180

5 Biol Blood Marrow Transplant 16:S37-S44, 2010 HSCT for Myelodysplastic Syndrome S41 Table 3. Role of GVHD Prophylaxis in Allogeneic HSCT for MDS Reference n GVHD Prophylaxis Conditioning TRM, Day 100/1 Year, % agvhd II-IV/III-IV, % cgvhd, % OS, % Van Besien et al., 2009 [62] Tacrolimus Tacrolimus/MTX Flu/Mel 140/Campath Flu/Mel / / / / Lim et al., 2006 [63] 75 Cyclosporine Bu/Flu/Campath 8/30 36/ Platzbecker et al., 2009 [64] 24 Everolimus/tacrolimus Bu/Flu (n 5 21); 12.5/29 38/18 82% 47 Bu/Cy (n 5 3) Small et al., 2007 [65] 43 Tacrolimus/MTX Bu/Mel Chan et al., 2003 [66] 18 Cyclosporine/ MTX Photopheresis/pentostatin/TBI GVHD indicates graft-versus-host disease; MDS, myelodysplastic syndrome; MTX, methotrexate; Bu, busulfan; Flu; fludarabine; Mel, melphalan; Cy, cyclophosphamide; TBI, total body irradiation; TRM, treatment-related mortality, agvhd, acute graft-versus-host disease; cgvhd, chronic graft-versus-host disease; OS, overall survival. TRM (23% vs 28%) were comparable as well, with a lower incidence of chronic GVHD (cgvhd) favoring the recipients of CB HSCT (17% vs 40%). The data on haploidentical HSCT for MDS are limited. De Witte et al. [34] reported an analysis of 1378 transplantations performed on behalf of the EBMT, with 91 patients undergoing allogeneic HSCT from genotypically nonidentical related donors. The 3-year survival and TRM rates were 28% and 66%, respectively, higher than with any other type of transplantation. In a more recent series of 28 patients undergoing T cell depleted haploidentical HSCT and conditioning with Flu, melphalan (Mel), thiotepa, and antithymocyte globulin (ATG), patients with\15% marrow blasts had better survival than those with more advanced disease (42% vs 0; P 5.03), with a day-100 TRM of 9% and a 1-year TRM of 32% [48]. To summarize, several studies have demonstrated the long-term curative potential with both related and unrelated donor allogeneic HSCT in MDS. Nonetheless, extending allogeneic HSCT to more patients with MDS will necessarily involve the use of donors who are not fully matched related or are unrelated, given the constraints of donor availability and procurement. Enrollment in clinical trials will be decisive for the critical evaluation of alternative donor transplants in this setting. BONE MARROW VERSUS PERIPHERAL BLOOD CELL GRAFTS The use of HSCs from peripheral blood (PB) is associated with faster engraftment and increased cgvhd rates compared with BM. Retrospective analyses have suggested that PB is a better stem cell source than BM for MDS patients undergoing related donor transplantation [49,50]. The survival benefit in those studies resulted from faster engraftment, lower TRM, and lower relapse rates (with cgvhd). Guardiola et al. [51] retrospectively studied 234 MDS patients and compared outcomes after PB and BM HSCT. Significantly improved 2-year TRM, RFS (50% vs 39%), and treatment failure were observed with PB [51]. As in other diseases and clinical situations, there are insufficient prospective data to clearly guide the choice of stem cell source, which often is made based on individual or institutional priorities and perceptions. PREPARATIVE REGIMEN INTENSITY: CONVENTIONAL-INTENSITY (MYELOABLATIVE) VERSUS REDUCED- INTENSITY CONDITIONING The list of unresolved clinical questions would not be complete without a discussion of preparative regimens. The choice of conditioning regimen type and intensity is strongly associated with investigator preference, experience, and even geographic location! In the absence of large prospective, randomized studies, recommendations often are subject to personal or institutional biases. In our perception, TBI-based conventional conditioning regimens are being used with decreasing frequency in patients with MDS. Bu (either with oral dosing with pharmacokinetic guidance or provided intravenously) in combination with cyclophosphamide (Cy) or Flu is a widely used alternative to TBI [52-54]. The decision to decrease the regimen intensity is not always straightforward. A lower dose intensity may lead to higher relapse rates for MDS, in a trade-off with lower TRM rates. To complicate matters, RIC regimens encompass a wide range of combinations, ranging from the least myeloablative (fludarabine and cyclophosphamide or fludarabine and 200 cgy TBI) to regimens that approach the strength of conventional regimens of cyclophosphamide plus high-dose TBI or busulfan plus cyclophosphamide. Most reported series combined AML and MDS patients, and often included transplantations performed with the use of Campath (alemtuzumab), antithymocyte globulin, or other GVHD prophylaxis (Table 3), adding more variability to the mix. In addition, median age and number of comorbidities usually were higher in the RIC cohorts, because most patients are selected for dose reduction on that basis. In a retrospective analysis of results in 836 patients (215 receiving RIC and 621 receiving conventional conditioning), those receiving RIC had a significantly

6 S42 S. Parmar and M. de Lima Biol Blood Marrow Transplant 16:S37-S44, 2010 higher 3-year relapse rate but a significantly lower TRM [55]. Parker et al. [56] reported that RIC and allogeneic sibling or unrelated donor transplantation was associated with significantly shorter duration of marrow aplasia, less mucositis and infections, less need for parenteral nutrition, lower incidence of agvhd and cgvhd, and lower TRM (9% vs 31%) compared with HSCT for MDS after conventional-intensity conditioning. The 2-year actuarial OS and RFS was 48% and 39%, respectively, in the RIC group, and 44% and 44% in the conventional group, with a respective TRM of 31% and 50%. In unrelated donor transplant recipients, OS was superior in the RIC arm (49% vs 34%) [56]. Others have reported similar outcomes after conventional-conditioning and RIC transplantations in retrospective studies [57,58]. Our bias is to recommend the highest dose intensity that a patient is expected to be able to tolerate, which often is difficult to judge. When age is the sole determining factor, we offer high-dose Flu and single daily dose of i.v. Bu to patients up to age years [53]. Bu, this recommendation is subject to the biases and limitations discussed earlier, and at this time there are insufficient data to make a recommendation for optimal conditioning regimen intensity. Patients in their early 60s who are fit (other than their MDS) are now eligible for conventional-intensity conditioning regimens in our institution and elsewhere, but the controversy surrounding dose intensity will not be resolved without randomized prospective studies [59]. Older patients and those with comorbidities who are candidates for allogeneic HSCT should be considered for RIC regimens, and as in all of the aforementioned scenarios, should be enrolled in clinical trials. FUTURE DIRECTIONS We believe that pharmacologic or immunologic interventions after HSCT should be investigated. Improved integration of pretransplantation treatments and the preparative regimen is likely to play an important role in the overall management of patients with MDS [60]. The incorporation of newer drugs into the conditioning regimen, as investigated by several groups, may lead to improved antileukemic efficacy. As discussed, defining the roles of CB and haploidentical HSCT likely will make an important contribution. ACKNOWLEDGMENTS Financial disclosure: The author have nothing to disclose. REFERENCES 1. Nimer SD. Myelodysplastic syndromes. Blood. 2008;111: Deeg HJ. Optimization of transplant regimens for patients with myelodysplastic syndrome (MDS). Hematol Am Soc Hematol Educ Progr. 2005; 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: Runde V, de Witte T, Arnold R, et al. Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1998;21: Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89: Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100: Malcovati L, Germing U, Kuendgen A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25: Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100: 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: de Witte T, Brand R, van Biezen A, et al. Allogeneic stem cell transplantation for patients with refractory anaemia with matched related and unrelated donors: delay of the transplant is associated with inferior survival. Br J Haematol. 2009;146: Oliansky DM, Antin JH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009;15: 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: Lee JH, Lim SN, Kim DY, et al. Allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: prognostic significance of pre-transplant IPSS score and comorbidity. Bone Marrow Transplant In Press. 14. Sorror M, Storer B, Sandmaier BM, et al. Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer. 2008;112: Pullarkat V, Blanchard S, Tegtmeier B, et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2008;42: Kontoyiannis DP, Chamilos G, Lewis RE, et al. Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer. 2007;110: Maradei SC, Maiolino A, de Azevedo AM, et al. Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation. Blood. 2009;114: de Lima M. SOS: too many irons in the fire!. Blood. 2009;114: Nakai K, Kanda Y, Fukuhara S, et al. Value of chemotherapy before allogeneic hematopoietic stem cell transplantation from an HLA-identical sibling donor for myelodysplastic syndrome. Leukemia. 2005;19:

7 Biol Blood Marrow Transplant 16:S37-S44, 2010 HSCT for Myelodysplastic Syndrome S Scott BL, Storer B, Loken MR, et al. Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome. Biol Blood Marrow Transplant. 2005;11: Warlick ED, Cioc A, Defor T, et al. Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden. Biol Blood Marrow Transplant. 2009;15: Castro-Malaspina H, Jabubowski AA, Papadopoulos EB, et al. Transplantation in remission improves the disease-free survival of patients with advanced myelodysplastic syndromes treated with myeloablative T cell depleted stem cell transplants from HLA-identical siblings. Biol Blood Marrow Transplant. 2008;14: Oran B, Giralt S, Saliba R, et al. Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reducedintensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2007;13: Oosterveld M, Muus P, Suciu S, et al. Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors. Leukemia. 2002;16: Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10: Field T, Perkins J, Huang Y, et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant In Press. 27. de Padua Silva L, de Lima M, Kantarjian H, et al. Feasibility of allo-sct after hypomethylating therapy with decitabine for myelodysplastic syndrome. Bone Marrow Transplant. 2009;43: Jabbour E, Shan J, O Brien S, et al. Outcome of patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) post-decitabine failure. Blood. 2008;112. Abstract. 29. 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: de Lima M, Giralt S, Komanduri K, et al. Maintenance therapy with low-dose azacitidine (AZA) after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed or refractory AML or MDS: a dose- and schedule-finding study. Blood. 2008;112. Abstract. 31. Jabbour E, Giralt S, Kantarjian H, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009;115: de Witte T, Suciu S, Verhoef G, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood. 2001;98: Kroger N, Brand R, van Biezen A, et al. Autologous stem cell transplantation for therapy-related acute myeloid leukemia and myelodysplastic syndrome. Bone Marrow Transplant. 2006; 37: de Witte T, Hermans J, Vossen J, et al. Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2000;110: Al-Ali HK, Brand R, van Biezen A, et al. A retrospective comparison of autologous and unrelated donor hematopoietic cell transplantation in myelodysplastic syndrome and secondary acute myeloid leukemia: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia. 2007;21: Oosterveld M, Suciu S, Verhoef G, et al. The presence of an HLA-identical sibling donor has no impact on outcome of patients with high-risk MDS or secondary AML (saml) treated with intensive chemotherapy followed by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and GIMEMA Leukemia Groups (EORTC study 06921). Leukemia. 2003;17: Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood. 2002;100: Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood. 2004;104: Jurado M, Deeg HJ, Storer B, et al. Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality. Biol Blood Marrow Transplant. 2002;8: Hallemeier CL, Girgis MD, Blum WG, et al. Long-term remissions in patients with myelodysplastic syndrome and secondary acute myelogenous leukemia undergoing allogeneic transplantation following a reduced intensity conditioning regimen of 550 cgy total body irradiation and cyclophosphamide. Biol Blood Marrow Transplant. 2006;12: 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: Kroger N, Bornhauser M, Ehninger G, et al. Allogeneic stem cell transplantation after a fludarabine/busulfan-based reducedintensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol. 2003;82: Laughlin MJ, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351: Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood. 2003;101: Parikh SH, Mendizabal A, Martin PL, et al. Unrelated donor umbilical cord blood transplantation in pediatric myelodysplastic syndrome: a single-center experience. Biol Blood Marrow Transplant. 2009;15: Ooi J. The efficacyof unrelated cord blood transplantation for adult myelodysplastic syndrome. Leuk Lymphoma. 2006;47: Majhail NS, Brunstein CG, Tomblyn M, et al. Reduced-intensity allogeneic transplantation in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor. Biol Blood Marrow Transplant. 2008;14: Ciurea SO, Saliba R, Rondon G, et al. Reduced-intensity conditioning using fludarabine, melphalan, and thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant In Press. 49. del Canizo MC, Martinez C, Conde E, et al. Peripheral blood is safer than bone marrow as a source of hematopoietic progenitors in patients with myelodysplastic syndromes who receive an allogeneic transplantation: results from the Spanish registry. Bone Marrow Transplant. 2003;32: Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood. 2002;100: 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

8 S44 S. Parmar and M. de Lima Biol Blood Marrow Transplant 16:S37-S44, 2010 stem cell transplantation using HLAidentical sibling donors in myelodysplastic syndromes. Blood. 2002;99: Russell JA, Duan Q, Chaudhry MA, et al. Transplantation from matched siblings using once-daily intravenous busulfan/fludarabine with thymoglobulin: a myeloablative regimen with low nonrelapse mortality in all but older patients with high-risk disease. Biol Blood Marrow Transplant. 2008;14: de Lima M, Couriel D, Thall PF, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004; 104: Scott B, Deeg HJ, Storer B, et al. Targeted busulfan and cyclophosphamide as compared to busulfan and TBI as preparative regimens for transplantation in patients with advanced MDS or transformation to AML. Leuk Lymphoma. 2004;45: Martino R, Iacobelli S, Brand R, et al. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108: Parker JE, Shafi T, Pagliuca A, et al. Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. Br J Haematol. 2002;119: Scott BL, Sandmaier BM, Storer B, et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006; 20: Kojima R, Kami M, Kanda Y, et al. Comparison between reduced-intensity and conventional myeloablative allogeneic stem cell transplantation in patients with hematologic malignancies aged between 50 and 59 years. Bone Marrow Transplant. 2005;36: Alatrash GAB, Pelosini M, Rondon G, et al. Myeloablative, reduced-toxicity IV busulfan/fludarabine (BuFlu) and allogeneic hematopoietic stem cell transplant (HSCT) for patients in the 6th and 7th decades of life with AML or MDS. Blood. 2008;112. Abstract. 60. Schmid C, Schleuning M, Hentrich M, et al. High antileukemic efficacy of an intermediate-intensity conditioning regimen for allogeneic stem cell transplantation in patients with high-risk acute myeloid leukemia in first complete remission. Bone Marrow Transplant. 2008;41: de Witte T, Zwaan F, Hermans J, et al. Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Br J Haematol. 1990;74: van Besien K, Kunavakkam R, Rondon G, et al. Fludarabinemelphalan conditioning for AML and MDS: alemtuzumab reduces acute and chronic GVHD without affecting longterm outcomes. Biol Blood Marrow Transplant. 2009;15: Lim ZY, Ho AY, Ingram W, et al. Outcomes of alemtuzumabbased reduced-intensity conditioning stem cell transplantation using unrelated donors for myelodysplastic syndromes. Br J Haematol. 2006;135: Platzbecker U, von Bonin M, Goekkurt E, et al. Graft-versushost disease prophylaxis with everolimus and tacrolimus is associated with a high incidence of sinusoidal obstruction syndrome and microangiopathy: results of the EVTAC trial. Biol Blood Marrow Transplant. 2009;15: Small TN, Young JW, Castro-Malaspina H, et al. Intravenous busulfan and melphalan, tacrolimus, and short-course methotrexate followed by unmodified HLA-matched related or unrelated hematopoietic stem cell transplantation for the treatment of advanced hematologic malignancies. Biol Blood Marrow Transplant. 2007;13: Chan GW, Foss FM, Klein AK, et al. Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9: