Biol Blood Marrow Transplant 18: , 2012 Upfront Allogeneic HSCT following FLAMSA for High-Risk MDS and saml 467

Transcription

1 Upfront Allogeneic Blood Stem Cell Transplantation for Patients with High-Risk Myelodysplastic Syndrome or Secondary Acute Myeloid Leukemia Using a FLAMSA-Based High-Dose Sequential Conditioning Regimen Christian Saure, Thomas Schroeder, Fabian Zohren, Anke Groten, Ingmar Bruns, Akos Czibere, Lars Galonska, Mustafa Kondakci, Christian Weigelt, Roland Fenk, Ulrich Germing, Rainer Haas, Guido Kobbe Patients suffering from high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) secondary to MDS (saml) are characterized by poor response to conventional cytotoxic chemotherapy. The purpose of our prospective single-center study was to examine the safety and efficacy of an allogeneic hematopoietic stem cell transplantation (HSCT) following a sequential conditioning regimen as first-line therapy for previously untreated patients with high-risk MDS or saml. Between November 2003 and June 2010, 30 patients (20 high-risk MDS, 10 saml) received fludarabine (4 30 mg/m 2 ), amsacrine (4 100 mg/m 2 ), and Ara-C (4 2 g/m 2, FLAMSA). After 2 to 3 days of rest, patients received high-dose melphalan alone (200 mg/m 2 for patients with an age\50 years, 150 mg/m 2 for patients with an age between 50 and 60 years, and 100 mg/m 2 for patients with an age.60 years; n 5 24) or melphalan and thiotepa (10 mg/kg, Mel/Thio, n 5 6). Following these high-dose conditioning regimens, a median number of CD34 1 cells/kg body weight (range: ) were transplanted from 13 related or 17 unrelated donors. Antithymocyte globulin (Fresenius mg/kg) as well as tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. All patients except 1 with primary graft failure achieved complete remission after HSCT. After a median follow-up time of 28 months (range: 7-81), 21 patients (70%) were alive and free of disease. Overall, 4 patients relapsed. At 2 years, overall survival, event-free survival, and treatment-related mortality were 70%, 63%, and 30%, respectively. Because of undue toxicity, thiotepa is no longer part of the conditioning regimen. Our results add to the body of evidence that a FLAMSA-based sequential conditioning therapy is effective for previously untreated patients with high-risk MDS or saml. Biol Blood Marrow Transplant 18: (2012) Ó 2012 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation KEY WORDS: Interleukin-2 receptor antagonists, Anti-CD25 monoclonal antibody, Peripheral blood stem cell transplantation, Unrelated donor, Graft-versus-host disease INTRODUCTION From the Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Duesseldorf, Germany. Financial disclosure: See Acknowledgments on page 471. Correspondence and reprint requests: Christian Saure, MD, Moorenstrasse 5, Duesseldorf, Germany ( Christian.Saure@med.uni-duesseldorf.de). Received April 6, 2011; accepted September 16, 2011 Ó 2012 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment for patients with high-risk myeloid malignancies, including patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) secondary to MDS (saml) [1-6]. Cutler et al. [7] showed that patients belonging to the intermediate 2 risk group or high-risk group according to the International Prognostic Scoring System have the longest overall life expectancy if transplanted at diagnosis, whereas patients with low-risk disease benefit from a wait-and-see approach with 466

2 Biol Blood Marrow Transplant 18: , 2012 Upfront Allogeneic HSCT following FLAMSA for High-Risk MDS and saml 467 regard to allogeneic HSCT [7]. Despite the use of allogeneic HSCT, patients with high-risk MDS or saml still have a high risk of relapse as well as an increased rate of treatment-related mortality (TRM), resulting in inferior long-term survival [8-14]. The role of reducing the tumor burden by a conventional induction regimen is controversial. So far, most patients in Europe received an induction regimen and then proceeded to allografting as soon as they had achieved a partial or full remission. This approach is associated with an inherent selection bias as patients with high-risk MDS or saml usually respond poorly to conventional induction chemotherapy [15-17] and a considerable number of them develop infectious complications precluding them from allografting. In the United States, a substantial number of patients received high-dose conditioning therapies followed by allogeneic HSCT without prior induction chemotherapy. Retrospective evaluations of this upfront strategy conducted at the Fred Hutchinson Cancer Research Center and the Kansai Medical University did not show a benefit of pretransplantation induction chemotherapy for patients with MDS or saml with regard to posttransplantation relapse-free survival (RFS) and overall survival (OS) [18,19], whereas randomized studies addressing this question had not been performed. The FLAMSA-sequential conditioning regimen developed by Kolb and coworkers [20-22] has shown promising results in high-risk patients with relapsed and refractory myeloid malignancies. Following administration of fludarabine, amsacrine, and Ara-C (FLAMSA), patients received a conditioning regimen consisting of low-dose total body irradiation (TBI) and cyclophosphamide (CY) or busulfan early during FLAMSA-induced cytopenia followed by allogeneic HSCT [20-22]. In light of these encouraging findings, we conducted a prospective single-center study in previously untreated patients with high-risk MDS and saml using an upfront FLAMSA-based sequential conditioning regimen and allogeneic HSCT. The results that we observed in this particular group of 30 patients confirms the efficacy of this upfront treatment modality. PATIENTS AND METHODS Patients Thirty previously untreated patients (10 female, 20 male) were included in a single-center study at the Heinrich-Heine-University Hospital (Duesseldorf, Germany), which scheduled upfront sequential conditioning using FLAMSA-Mel/Thio for patients with high-risk MDS or saml. All patients who presented with high-risk MDS between November 2003 and June 2010, who were eligible for allogeneic transplantation and for whom a donor could be identified during a considerable time period were included. Ten of 30 patients transformed to AML during the search for a HLA-compatible donor. For inclusion, the patient s age had to be.18 years. For donor selection, HLA-typing was performed using molecular methods (PCR-SSP, PCR- SSOP, and DNA sequencing) for all loci (HLA-A, -B, -C, -DR, and -DQ). For 13 patients, a related donor was available, whereas 17 patients received their allografts from unrelated donors. HLA-identical donors were available in 26 patients, whereas 3 patients had unrelated donors with 1 mismatch (1 HLA-B allelic mismatch and 2 HLA-C antigenic mismatches), and 1 patient had an unrelated donor with 2 mismatches (HLA-B allelic and HLA-C antigenic mismatch). The median time from diagnosis to transplantation was 134 days (range: ). Concomitant diseases were scaled using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI; Table 1) [23-25]. All patients received peripheral blood stem cells collected following mobilization with granulocyte colony-stimulating factor. At the time of analysis in January 2011, the median follow-up time for surviving patients was 28 months (range: 7-81). The detailed characteristics of the patients are given in Table 1. Preparative Regimen Patients received fludarabine 30 mg/m 2 (total dose 120 mg/m 2 ), amsacrine 100 mg/m 2 (total dose 400 mg/m 2 ), and high-dose cytarabine 2 g/m 2 (total dose 8 g/m 2 ) therapy from days 9 to 6. High-dose conditioning therapy consisted of melphalan (day 2, n 5 24) or melphalan and thiotepa (day 2, 3, n 5 6). The dose of melphalan was adapted to the patient s age as follows: \50 years: 200 mg/m 2, years: 150 mg/m 2, and.60 years: 100 mg/m 2 ). Thiotepa at a dose of 10 mg/kg body weight (BW) was given to 6 patients with an age of \55 years. Except for 8 with HLA-identical sibling donors, the patients received rabbit antithymocyte globulin (Fresenius, Munich, Germany) at a dose of 3 10 mg/kg BW in 7 patients and 3 20 mg/kg BW in 15 patients on days 5, 4, and 3. Graft-versus-Host Disease (GVHD) Prophylaxis and Supportive Care Immunosuppressive therapy following allografting consisted of tacrolimus (day 1 aiming at concentrations between 10 and 15 ng/ml) and mycophenolate mofetil (started 1 hour after HSCT at a dose of 15 mg/kg BW). In the absence of GVHD, mycophenolate mofetil was halved on day 128 and

3 468 C. Saure et al. Biol Blood Marrow Transplant 18: , 2012 Table 1. Patients Characteristics Values Number of patients 30 Sex, no. (%) Female 10 (33) Male 20 (67) Median age at transplantation (range) 49 (36-66) Diagnosis, no. (%) Primary MDS 12 (40) Therapy-related MDS 8 (27) AML secondary to MDS 10 (33) WHO classification for MDS at transplantation, no. (%) MDS (RCMD) 2 (7) MDS (RAEB I) 8 (27) MDS (RAEB II) 7 (23) CMML 3 (10) IPPS for primary MDS at transplantation, no. (%) INT-2 6 (20) High 3 (10) WPSS for primary MDS at transplantation, no. (%) High 6 (20) Very High 3 (10) Cytogenetic subgroups, no. (%) Good 12 (40) Intermediate 7 (23) Poor 11 (37) Therapy before transplantation, no. (%) None 30 (100) Comorbidity Index (HCT-CI), no (%) 0 12 (40) 1 5 (17) 2 2 (7) 3 5 (17) >3 6 (20) Median time from diagnosis to transplantation d (range) 134 ( ) Stem cell source, no. (%) Peripheral blood stem cells 30 (100) Donor type, no. (%) Fully matched unrelated donor 13 (43) Partially matched unrelated donor 4 (13) Fully matched sibling donor 13 (43) Median no. CD34 + cells within the 7.7 ( ) graft, 10 6 /kg BW (range) RCMD indicates refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; CMML, chronic myelomonocytic leukemia; IPPS, International Prognostic Scoring Sytem; INT, intermediate; WPSS, WHO classification-based prognostic scoring system. discontinued on day 142, whereas tapering of tacrolimus was started between day 180 and day The aim was to be off immunosuppressive therapy between days 120 and 140. Granulocyte colony-stimulating factor starting as early as 1 day posttransplantation was given to hasten neutrophil recovery in 17 patients (57%). The usual standard supportive care was used as described before [26]. Monitoring and Definitions After patients were discharged from the hospital, they were seen in the outpatient clinic twice a week up to day Afterward, the intervals were increased depending on clinical course. Grading of acute and chronic GVHD (agvhd, cgvhd) was performed according to the usual criteria [27-29]. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria (CTC), version 2.0. At days 128, 1100, and 1360 disease response and chimerism were assessed in bone marrow (BM) and peripheral blood. Complete remission (CR) was defined as \5% blasts in the BM, no evidence of dysplasia, as well as restoration of neutrophils.1500/ml in the peripheral blood. Leukocyte engraftment was defined as the first of 3 consecutive days of white blood cell count.1000/ml, and the day of platelet engraftment was defined as the first of 7 consecutive days with platelet counts of.50,000/ml. Statistics Event free survival (EFS), RFS, OS, and TRM, as well as GVHD-onset were calculated from the day of transplantation to the respective event. Death independent of its cause ever was rated as an event for the estimation of OS. Death from any cause and relapse were counted as an event in case of EFS. All time-to-event curves were estimated by using the Kaplan-Meier method [30]. For comparison of group characteristics, a chi-square test and Student t test were used for univariate analysis. Univariate analysis was performed for age, sex, presence of cytogenetic abnormalities, donor type, percentage of blasts in the BM, presence of comorbidities, cytomegalovirus status, antithymocyte globulin dosage, number of transplanted CD34 1 cells, and time from diagnosis to transplantation. The statistical analyses were performed using SPSS statistical software. RESULTS Hematologic Reconstitution and Chimerism Although all patients developed an individually varying degree of neutropenia as a consequence of the FLAMSA therapy, hematologic reconstitution following allografting was observed in all of them but 1. For neutrophil recovery, a median time of 13 days (range: 9-31) was required. Taken together, the period of FLAMSA-related and of posttransplantation neutropenia the median duration of CTC grade IV neutropenia was 18 days (range: 11-39). As far as platelet reconstitution is concerned, the median time to reach a stable platelet count of.50/nl was 17 days (range: 8-56). Looking for donor chimerism in BM at days 128 and 1100, we found a median proportion of 100% at both time points (range: 89.6%-100% at day 130 and 78.9%-100% at day 1100). GVHD, Toxicity, and Infections Acute GVHD developed in 22 patients (73%) at a median time of 34 days (range: ) after

4 Biol Blood Marrow Transplant 18: , 2012 Upfront Allogeneic HSCT following FLAMSA for High-Risk MDS and saml 469 transplantation. According to the National Institutes of Health criteria, 11 patients (37%) had classic agvhd and 11 (37%) late agvhd. Of these, 6 patients had a persistent subtype (20%), 4 patients late onset (13%), and 1 patient a recurrent subtype (3%). Skin, liver, and gut were affected in 11, 11, and 11 patients, respectively. As far as the severity is concerned, there were 16 patients (53%) with grade I-II agvhd and 6 (20%) with grade III-IV agvhd (3 with HLAidentical donors and 3 with unrelated donors, including 1 of them with HLA-C antigenic mismatch). Five of these 6 patients died of complications related to the severe agvhd. Thirteen patients who developed agvhd are currently alive and free of disease. Chronic GVHD not including late agvhd was observed in 19 patients of 25 patients who had survived more than 100 days following allografting. Of these, 14 (56%) had limited cgvhd, whereas 5 of them (20%) suffered from extensive cgvhd. Two patients developed extensive GVHD following the administration of donor lymphocytes (DLI) for the treatment of relapse or incomplete chimerism on days 1307 and 1498, respectively. According to the National Institutes of Health, cgvhd was graded as mild in 10 patients (40%), moderate in 4 patients (16%), and severe in 5 patients (20%). The median interval from transplantation to onset of de novo cgvhd was 133 days (range: ). Seventeen of 19 patients with cgvhd are currently alive and free of disease. Two patients suffering from extensive cgvhd died on days 1368 and It should be noted that 4 of the 19 patients (21%) who had developed cgvhd are currently without immunosuppressive therapy and any signs of cgvhd. For the treatment of GVHD, systemic corticosteroids were administered in 22 patients, whereas 5 patients received monoclonal antibodies (Basiliximab, n 5 1; Infliximab, n 5 1; Etanercept, n 5 1; Basiliximab 1 Infliximab, n 5 1; Basiliximab 1 Etanercept, n 5 1) because of steroid-refractory disease. Using univariate analysis, we could not define any patient characteristic or parameter before transplantation indicating a particular risk of developing agvhd or cgvhd. Looking at the treatment-related complications in general, 17 patients developed grade III-IV toxicities according to the National Cancer Institute-CTC 2.0. Infectious complications were most prominent with 16 patients who had fevers of unknown origin and 6 patients with pneumonia (Aspergillus spp, n 5 2; Candida spp, n 5 1; and bacterial pneumonia n 5 3) according to radiological criteria. Grade III-IV mucositis was seen in 15 patients. Organ toxicity related to liver was noted in 9 patients, central nervous system in 2, and 4 patients had cardiac problems such as atrial fibrillation. Light and moderate renal toxicity limited to grades I and II was transient, except for 1 patient who developed acute renal failure and died of pneumonia 4 weeks later. There was also 1 patient with a venous-occlusive disease. A total of 7 patients required treatment on our interdisciplinary intensive care unit for a median time of 28 days (range: days). Disease Response, Relapse, and Survival At day 128 after allogeneic HSCT, 29 of 30 patients (97%) achieved CR. At the time of writing this report, 21 patients (70%) are alive and free of disease (Figure 1). The group of 21 patients in CR includes 33% who received melphalan/thiotepa and 79% who received melphalan alone. The median follow-up time for this group is 28 months (range: 7-81). Concentrating on the patients with saml, 8 of 10 patients (80%) are still alive and free of disease after a median follow-up of 24 months. Four patients who had received melphalan alone relapsed on days 190, 1377, 1764, and 1853, reflecting an RFS of 93% at 2 years (Figure 2). Remarkably, following second-line therapy, all of these patients are still alive and free of disease, with the longest follow-up of 50 months. All received azacytidine and DLI after transplantation. Two patients achieved a CR, 1 patient converted to 100% donor chimerism but remained thrombocytopenic, and none of these patients relapsed so far. The fourth patient also responding to azacitidine and DLI with a partial response (PR) underwent a second transplantation with FLAMSA-treosulfan conditioning therapy. There were 9 patients who died between days 144 and 1626 (median, day 181) Figure 1. Overall survival (OS) and event-free survival (EFS). *Following second-line therapy with 5-azacytidine and DLI, all 4 relapsed patients are still alive and free of disease.

5 470 C. Saure et al. Biol Blood Marrow Transplant 18: , 2012 The risk of treatment-related death was related to the development of agvhd grade III-IV (5 of 6 patients died), whereas an age of \50 years was associated with a better probability for survival (P 5.04). In univariate analysis, there was no other pretransplantation variable associated with OS. DISCUSSION Figure 2. Cumulative incidence of relapse. because of treatment-related complications, including 4 patients of 6 (67%) who had received melphalan/ thiotepa and 5 of 24 (21%) who had received melphalan alone (Figure 3). This observation prompted us early to remove thiotepa from the protocol. Looking at the patients with a fatal outcome in more detail, the causes of death were related to infectious complications in 2 patients, to GVHD in combination with infectious disease in 5 patients, whereas 2 patients developed thrombotic microangiopathy. At 2 years, EFS was 63%. Figure 3. Treatment-related mortality. The results of this single-center study show that a FLAMSA-based high-dose therapy is an efficacious first-line treatment for patients with high-risk MDS or saml. A similar regimen has been shown to be very successful in patients with relapsed and refractory myeloid malignancies [21,22]. Different from the original protocol proposed by Kolb et al. [20-22], we omitted CY and low-dose TBI and used high-dose melphalan alone or in combination with thiotepa. The idea behind this change was to avoid the more intensive immunosuppression related to CY and TBI, also assuming that melphalan per se or in combination with thiotepa could exert a stronger antileukemic efficacy. The latter combination was abandoned because of undue toxicity, whereas the age-adapted high-dose therapy with melphalan alone was generally well tolerated. Looking at the efficacy of the sequential therapy, we can note that with a median follow-up time of 28 months, 21 of the 30 patients (70%) are alive and free of disease. Concentrating on the patients who received melphalan alone, the proportion of those remaining alive is 79%. So far, only 4 patients (13%) have relapsed in our study. It is worth noting that all of them responded to treatment with azacitidine and DLI, 3 with CR and 1 with PR. The latter received a second transplant with FLAMSA-treosulfan conditioning. All patients have remained in CR since then. Our observations support the results of Czibere et al. [31] and L ubbert et al. [32], showing the efficacy of azacitidine in combination with DLI for patients with MDS who relapse after allogeneic HSCT. Neither karyotype, comorbidity, nor the number of blasts in BM were of prognostic relevance with regard to RFS or OS. Still, patients younger than 50 years had a longer OS in comparison to the patients with an age.50 years (P 5.04). The cumulative rate of TRM in our study was 30% for all patients and 21% for patients who had received melphalan monotherapy. This is in line with the results of other clinical trials using standard myeloablative conditioning [12-14,33,34]. Sequential conditioning using the combination of FLAMSA with melphalan requires 9 days of treatment. Following the allogeneic peripheral blood stem cell transplantation, we observed full donor chimerism on day 128 in 29 of 30 patients (97%). With a median time of 18 days of severe neutropenia, this critical period was shorter than observed following

6 Biol Blood Marrow Transplant 18: , 2012 Upfront Allogeneic HSCT following FLAMSA for High-Risk MDS and saml 471 conventional induction chemotherapy in patients with MDS/AML [5,35,36]. Independent of the relatively rapid hematologic recovery, the most relevant toxicity was related to agvhd (73%), which developed at a median time of 34 days (range: ). Patients with grade III-IV agvhd required intensive immunosuppressive therapy, leading to infectious complications associated with a mortality rate of 83%. In order to decrease the probability of relapse in high-risk MDS patients, GVHD prophylaxis was tapered between day 80 and 100 and discontinued around day 140. This is shorter than the usual 6 months of immunosuppressive treatment and may be 1 reason for the low relapse rate, but also for a high incidence of late agvhd. Our upfront approach using a FLAMSA-based high-dose therapy with HSCT is based on data published by Cutler et al. [7] showing that patients belonging to the intermediate 2 or high-risk group according to the International Prognostic Scoring System have the greatest life expectancy if transplanted at diagnosis without delay. This avoids the increasing risk for acquiring comorbidities. For instance, there is the risk of accumulation of iron when the transplantation is postponed in favor of supportive care only or conventional cytotoxic chemotherapy [1,37]. We have to point out that the patients in this study had a relative stable disease, allowing us to search for a donor without the need of early treatment. This is crucial, especially for patients with fast transformation to AML, where the tempo of disease often makes it necessary to applicate chemotherapy as soon as possible. Considering an upfront approach with allografting, the role of an anteceding induction chemotherapy with regard to the probability of RFS and OS is still not answered. In a French trial including 70 patients with tmds or taml, an improved survival was observed for those patients who had achieved CR before they proceeded to high dose and allografting compared with patients with active disease [36]. Therefore, as it has been shown by several other investigators, the leukemic burden at the time of high-dose therapy is a major prognostic factor for patients with MDS who undergo myeloablative or dose-reduced conditioning regimens before allografting [38,39]. On the other hand, there are 2 retrospective studies of patients with MDS or saml conducted at the Fred Hutchinson Cancer Research Center and Kansai Medical University that did not find a beneficial effect of induction therapy before allogeneic HSCT [18,19]. Pondering the pros and cons with regard to induction therapy, we believe that induction-sensitive patients in CR represent a particularly favorable group with improved outcome following allografting. In contrast, patients who have resistant disease following conventional chemotherapy may not benefit from induction attempts, as they are not likely to enter remission, whereas they are at great risk of additional toxicity. This view is supported by results of the recently published CRIANT study. There were 194 of 341 patients (57%) with high-risk MDS who achieved a (CR or PR) remission as a result of induction therapy [6]. Still, the proportion of patients undergoing an allogeneic blood stem cell transplantation was only 15%, clearly showing that many patients are lost on the way to transplant because of poor response to chemotherapy or treatment complications during induction chemotherapy. In summary, the results of our study indicate that an upfront sequential conditioning therapy using FLAMSA followed immediately by high-dose melphalan offers an efficient treatment modality for patients with high-risk MDS and saml. ACKNOWLEDGMENT Financial disclosure: GK received research support and lecture fees from Astellas. REFERENCES 1. Oliansky DM, Antin JH, Bennet 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: Lodewyck T, Cornelissen JJ. Allogeneic stem cell transplantation in acute myeloid leukemia: a risk-adapted approach. Blood Rev. 2008;22: Gratwohl A, Baldomero H, Passweg J, et al. Hematopoietic stem cell transplantation for hematological malignancies in Europe. Leukemia. 2003;17: Witherspoon RP, Deeg HJ, Storer B, Anasetti C, Storb R, Appelbaum FR. Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol. 2001;19: Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995;332: De Witte T, Hagemeijer A, Suciu S, et al. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial. Haematologica. 2010;95: 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: Kindwall-Keller T, Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant. 2009;43: Anderson JE, Gooley TA, Schoch G, et al. Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 1997;89: Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990;76:

7 472 C. Saure et al. Biol Blood Marrow Transplant 18: , Deeg HJ, Appelbaum FR. Hematopoietic stem cell transplantation for myelodysplastic syndrome. Curr Opin Oncol. 2000;12: De Witte T, Hermans J, Vossen J, et al. Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes and secondary acute myeloid leukemias: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2000;110: Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and cyclophosphamide for hematopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood. 2002;100: Sierra J, Perez WS, Rozman C, et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100: De Witte T, Oosterveld M, Span B, Muus P, Schattenberg A. Stem cell transplantation for leukemias following myelodysplastic syndromes or secondary to cytotoxic therapy. Rev Clin Exp Hematol. 2002;6: Pedersen-Bjergaard J, Philip P, Larsen SO, Jensen G, Byrsting K. Chromosome aberrations and prognostic factors in therapy-related myelodysplasia and acute nonlymphocytic leukemia. Blood. 1990;76: Ballen KK, Antin JH. Treatment of therapy-related acute myelogenous leukemia and myelodysplastic syndromes. Hematol Oncol Clin North Am. 1993;7: Scott BL, Storer B, Loken MR, Storb R, Appelbaum FR, Deeg HJ. Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome. Biol Blood Marrow Transplant. 2005;11: Nakai N, 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: 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: Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108: Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol. 2005;23: Sperr WR, Wimazal F, Kundi M, et al. Comorbidity as prognostic variable in MDS: comparative evaluation of the HCT-CI and CCI in a score datatest of 419 patients of the Austrian MDS Study Group. Ann Oncol. 2010;116: Boehm A, Sperr WR, Leitner G, et al. Comorbidity predicts survival in myelodysplatic syndromes or secondary acute myeloid leukemia after allogeneic stem cell transplantation. Eur J Clin Invest. 2008;38: 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;20: Zohren F, Czibere A, Bruns I, et al. Fludarabine, amsacrine, high-dose cytarabine and 12 Gy total body irradiation followed by allogeneic hematopoietic stem cell transplantation is effective in patients with relapsed or high-risk acute lymphoblastic leukemia. Bone Marrow Transplant. 2009;44: Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18: Przepiorka D, Weisdorf D, Martin P, et al Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995; 15: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005; 11: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: Czibere A, Bruns I, Kr oger N, et al. 5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-sct: a retrospective analysis. Bone Marrow Transplant. 2010;45: L ubbert M, Bertz H, W asch R, et al. Efficacy of a 3-day, low dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting. Bone Marrow Transplant. 2010;45: 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: Runde V, de Witte T, Arnold C, 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: Ossenkoppele GJ, van der Holt B, Verhoef GE, et al. A randomized study of granulocyte colony-stimulating factor applied during and after chemotherapy in patients with poor risk myelodysplastic syndromes: a report from the HOVON Cooperative Group. Dutch-Belgian Hemato-Oncology Cooperative Group. Leukemia. 1999;13: Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myloid leukemia: a long-term study of 70 patients-report of the French society of bone marrow transplantation. J Clin Oncol. 2000;18: Itzykson R, Fenaux P. Optimal sequencing of treatments for patients with myelodysplastic syndromes. Curr Opin Hematol. 2009;16: 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: 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 reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2007;13: