Monosomal Karyotype Predicts Poor Survival After Allogeneic Stem Cell

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ORIGINAL ARTICLE Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia

M van Gelder1, LC de Wreede2, J Schetelig3, A van Biezen2, L Volin4, J Maertens5, M Robin6, E Petersen7, T de Witte8 and N Kro¨ ger9 on behalf of the EBMT Chronic Malignancies Working Party

Treatment algorithms for poor cytogenetic-risk myelodysplastic syndrome (MDS), defined by chromosome 7 abnormalities or complex karyotype (CK), include allogeneic stem cell transplantation (alloSCT). We studied outcome of alloSCT in chromosome 7 abnormal MDS patients as this data are scarce in literature. We specifically focused on the impact of the extra presence of CK and monosomal karyotype (MK). The European Group for Blood and Marrow Transplantation database contained data on 277 adult MDS patients with a chromosome 7 abnormality treated with alloSCT. Median age at alloSCT was 45 years. Median follow-up of patients alive was 5 years. Five-year progression-free survival (PFS) and overall survival (OS) were 22% and 28%, respectively. In multivariate analysis, statistically significant predictors for worse PFS were higher MDS stages treated, but not in complete remission (CR) (hazards ratio (HR) 1.7), and the presence of CK (HR 1.5) or MK (HR 1.8). Negative predictive factors for OS were higher MDS stages treated, but not in CR (HR 1.8), and the presence of CK (HR 1.6) or MK (HR 1.7). By means of the cross-validated log partial likelihood, MK showed to have a better predictive value than CK. The results are relevant when considering alloSCT for higher-stage MDS patients having MK including a chromosome 7 abnormality.

Leukemia (2013) 27, 879–888; doi:10.1038/leu.2012.297 Keywords: chromosome 7 abnormality; myelodysplastic syndrome; secondary acute myeloid leukemia; allogeneic stem cell transplantation; complex karyotype; monosomal karyotype

INTRODUCTION patients with poor karyotypic risk in these studies is very low, Myelodysplastic syndrome (MDS) results from ineffective hema- which prevents to draw firm conclusions. Only one prospective topoiesis causing one or more cytopenias. The International trial addressed the question whether outcome of poor-risk MDS Prognostic Scoring System consists of several factors that together patients treated with intensive chemotherapy followed by alloSCT predict the speed of transformation to secondary acute myeloid was superior to consolidation with autologous SCT in a donor leukemia (sAML) and death. The International Prognostic Scoring versus no donor comparison.6,23 No difference in OS was found in System factors include the percentage of blasts in bone marrow the first analysis of 117 evaluable patients,6 but at longer follow- and blood, the number of cytopenias and specific karyotypic up, alloSCT predicted better progression-free survival (PFS) and abnormalities.1 Poor-risk karyotypic abnormalities are defined OS.23 Again, in this study, the number of patients with a poor-risk either as complex abnormalities (that is, X3 chromosomal karyotype was low (n ¼ 29). abnormalities, complex karyotype (CK)) or as chromosome 7 Other factors that predicted a poor outcome of MDS/sAML abnormalities, both of which carry a poor prognosis in AML as patients after alloSCT were age, time from diagnosis to alloSCT, well.2,3 Recently, monosomal karyotype (MK) was shown to be a blast percentage or remission state at alloSCT15,16,21,22,24–27 and more accurate predictor of poor outcome in AML.4 prior remission-induction therapy,28 although contradictory results The results of AML-like remission induction and consolidation have been reported.13,14,29 therapies in MDS patients with advanced stages and poor-risk To better estimate outcome of patients with cytogenetically karyotypes are disappointing. Complete remission (CR) rates are high-risk MDS/sAML, we performed a retrospective analysis on low, and because of relapses, survival (OS) is almost 0% at longer patients with a chromosome 7 abnormality treated with alloSCT follow-up.5–11 Given this poor outcome, many patients are offered using the European Group for Blood and Marrow Transplantation an allogeneic stem cell transplantation (alloSCT) because it is (EBMT) database. In addition to the role of well-known risk considered the only curative treatment. Unfortunately, many factors,30 we studied the impact of extra chromosomal instability studies show that the presence of poor-risk karyotypes adversely defined as either CK or MK in addition to the presence of a affects outcome after alloSCT.6,12–22 However, the number of chromosomal 7 abnormality.

1Division of Hematology, Department of Internal Medicine, University Hospital Maastricht, MUMC, Maastricht, The Netherlands; 2Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands; 3Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany; 4Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; 5Department of Hematology, University Hospital Gasthuisberg, Leuven, Belgium; 6Department of Hematology-BMT, Hopital St Louis, Paris, France; 7Department of Hematology, University Medical Centre Utrecht, Utrecht, The Netherlands; 8Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, The Netherlands and 9Clinic for Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Correspondence: Dr M van Gelder, Division of Hematology, Department of Internal Medicine, University Hospital Maastricht, MUMC, Postbus 5800, Maastricht 6202 AZ, The Netherlands. E-mail: [email protected] Received 6 June 2012; revised 2 October 2012; accepted 3 October 2012; accepted article preview online 16 October 2012; advance online publication, 20 November 2012 Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 880 PATIENTS AND METHODS information on all variables introduced in the Cox model (n ¼ 243 for Patient population Cox models 1 and 2, and n ¼ 247 for all other Cox models). Baseline variables that are known to have predictive power on outcome after We interrogated the EBMT registry for MDS/sAML patients with chromo- alloSCT in a large cohort of patients,30 that is, age, remission status at some 7 abnormalities and who had received an alloSCT for the first time either from related or unrelated donors. We selected only patients with alloSCT, donor type, sex match and cytomegalovirus match, were also known cytogenetics within 1 year before alloSCT, in an attempt to reduce introduced into our Cox models. We did not introduce time from diagnosis the likelihood of clonal evolution. Chromosome 7 abnormalities were to transplant in the Cox model, first because this variable was found not to detected by metaphase karyotyping, FISH or both techniques. De novo be of prognostic significance in a large EBMT cohort of MDS patients containing all cytogenetic-risk groups.30 Moreover, in MDS, this variable is AML was excluded from the analysis. Two-hundred and seventy-seven evidently correlated with a variety of other covariates like stage at patients that fulfilled these criteria were extracted from the EBMT database. diagnosis, the feasibility of adequate supportive care, age, performance and comorbidity and is therefore not informative by itself. Intensity of conditioning was not used in the Cox models because it bears no relationship to the impact of additional cytogenetic abnormalities on Definitions 34,35 31 outcome. It was also not a predictor in earlier EBMT MDS studies, and We defined disease status at alloSCT according to FAB and remission its correlation with other (partly unknown) covariates like age, status. Patients designated as RA/RARS never had a higher stage before performance, comorbidity, MDS stage and application of pretreatment alloSCT. Patients with higher MDS stages, that is, (refractory anemia makes an estimation of its net effect impossible. We omitted year of with excess blasts) RAEB(t)/sAML, at any time point before alloSCT, were transplantation30 as this variable did not reveal any significance for PFS classified into three groups according to treatment with remission- and OS in a preliminary Cox analysis with our data set, and because we induction chemotherapy and its effect: CR, not in CR, and not pre- wanted to focus on variables that can be used in clinical decision making treated. sAML is defined as AML arisen from lower-stage MDS or after for future patients. Variables indicating CK or MK, the presence of a single previous cytotoxic therapy for unrelated diseases (that is, malignant or chromosome 7 abnormality or the accompaniment of extra chromosomal autoimmune diseases) Patients were categorized as having either a abnormalities were entered as shown in the tables. We validated the monosomy 7 or another chromosome 7 abnormality. CK was defined as proportionality assumption of the model we used, to illustrate clinical X 1 the presence of 3 chromosomal abnormalities, and MK as the presence relevance using a test based on scaled Schoenfeld residuals, and found X of any autosomal monosomy accompanied by either 1 additional that it did not have to be rejected for any of the covariates. For the X 4 autosomal monosomies or 1 structural chromosomal abnormalities. purpose of plotting model-based PFS curves, a web-based OS visualization We defined the conditioning intensity as myeloablative or reduced tool has been developed by H J van der Wijk (Department of Medical intensity according to EBMT guidelines (www.ebmt.org/EBMT_Hand- Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the book.html). Donors were either an human leukocyte antigen-identical Netherlands, http://www.msbi.nl/SV/Chart.aspx?model=MvGMKCK&key= sibling or an alternative donor. The latter group consisted of matched ss51zo4bjt). The reader can create our curves and similar ones with this relatives other than siblings, mismatched relatives, matched unrelated and tool. Calculations were performed using the Statistical Package for the mismatched unrelated donors. The lack of high-resolution molecular Social Sciences (PASW Statistics, IBM, Armonk, NY, USA) software, version human leukocyte antigen-typing data in the majority of patients precluded 18.0 (SPSS Inc., Chicago, IL, USA) and R version 2.12.2, with packages narrowing down the degree of mismatching accurately. Patient and donor 30 ‘survival’ and ‘cmprsk’ (http://www.r-project.org/foundation). We com- sex mismatch was classified as described previously. Cytomegalovirus pared predictive performance (indicating how well the models predict the status was classified according to patient and donor cytomegalovirus IgG 32 failure times for individual patients) of a subset of the Cox models for PFS status as published recently. We defined PFS as OS without progressive by means of the cross-validated log partial likelihood (taking into account disease. Disease progression refers to relapse in patients with RA/RARS or the optimism due to model fitting on a single sample) as implemented in with higher stages in CR at alloSCT, and to progressive disease in higher- 36 the ‘penalized’ package in R. P-values o0.05 were considered to be stage patients that had no CR after remission induction or that had not statistically significant. received pretreatment.33 Nonprogression mortality (NPM) is defined as death from any cause except progressive disease. RESULTS Statistical analysis Patient characteristics The duration of OS/PFS or time to disease progression and NPM was Two-hundred and seventy-seven MDS/sAML patients with a calculated from the day of alloSCT onwards. Disease progression and NPM recognized chromosome 7 abnormality within one year before were considered as competing events and were analyzed by means of alloSCT were identified from the EBMT database. The distribution cumulative incidence statistics. We used the two-tailed log-rank test to of the various chromosomal subcategories, including CK and MK, identify factors with statistically significant impact on OS and PFS, whereas the Gray test was used in the same way for disease progression and NPM. is shown in Table 1. One hundred and sixteen patients had We applied multivariate Cox regression modeling to evaluate the chromosome 7 abnormalities other than monosomy 7. In 40 of predictive effect of baseline variables on NPM, progression, PFS and OS, these patients, the type of chromosome 7 abnormality was not and we focused specifically on the additional presence of CK or MK. All specified. In those that were specified, 26 patients had a 7q analyses were performed on a subset of patients with complete deletion; 11 had t(1;7)(q10;p10); 12 had other translocations, and 5

Table 1. Distribution of several kinds of extra chromosomal abnormalities in MDS patients with either a monosomy 7 ( À 7) or any other chromosome 7 abnormality (no À 7) treated with alloSCT

Total Single Single other chr. À 7 þ other chr. chr. 7 abn. þ other chr. 7 chr. 7 chr. 7 abn. (n ¼ 261) À 7 7 abn. but no abn. but no CK/ chr. abn., but no CK/ abn. þ CK but abn. þ MK and CK and (n ¼ 80) À 7(n ¼ 70) MK (n ¼ 5) MK (n ¼ 24) no MK but no CK MK (n ¼ 43) (n ¼ 14) (n ¼ 25)

À 7 145 80 (55%) — 5 (3%) — 0 (0%) 25 (17%) 35 (24%) no À 7 116 — 70 (60%) — 24 (21%) 14 (12%) 0 (0%) 8 (7%) Abbreviations: abn., abnormality; chr., chromosome; CK, complex karyotype; MDS, myelodysplastic syndrome; MK, monosomal karyotype. Data shown are of 261 patients as from 16 insufﬁcient data were available in the database for proper classiﬁcation in this way. The percentages indicate the distribution of the various chromosome 7 abnormalities, including the presence of CK and/or MK within the ‘ À 7’ and the ‘no À 7’ subgroup.

Leukemia (2013) 879 – 888 & 2013 Macmillan Publishers Limited Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 881 had other chromosome 7 abnormalities. Twenty-two of the 18.1–67.5). Table 2 shows the distribution of the different variables patients not having a monosomy 7 could be classiﬁed as having used for the univariate and multivariate analyses, categorized CK and/or MK. The median age at alloSCT was 45.2 years (range according to the indicated different karyotypic abnormalities.

Table 2. Disease- and transplantation-related characteristics of the MDS/sAML patients subjected to alloSCT with speciﬁcally documented various chromosome 7 abnormalities including the presence of CK and/or MK

Total Single Single other À 7 þ other chr. 7 abn. þ chr. 7 chr. 7 chr. 7 abn. (n ¼ 266a) À 7 chr. 7 abn. but Chr abn. but other chr. abn., abn. þ CK abn. þ MK and CK and (n ¼ 80) no À 7 no CK/MK but no CK/MK but no MK but no CK MK (n ¼ 47) (n ¼ 70) (n ¼ 5) (n ¼ 24) (n ¼ 15) (n ¼ 25)

Age at alloSCT in years (n ¼ 266) 18–40 99 38 (38%) 23 (23%) 3 (3%) 7 (7%) 5 (5%) 11 (11%) 12 (12%) 40–50 66 15 (23%) 22 (33%) 1 (1%) 5 (8%) 4 (6%) 5 (8%) 14 (21%) 450 101 27 (27%) 25 (25%) 1 (1%) 12 (12%) 6 (6%) 9 (9%) 21 (21%)

Time from diagnosis to alloSCT (n ¼ 266) p12 months 207 61 (30%) 48 (23%) 3 (1%) 22 (11%) 10 (5%) 22 (11%) 41 (20%) 412 months 59 19 (32%) 22 (37%) 2 (3%) 2 (3%) 5 (9%) 3 (5%) 6 (10%)

Remission status at alloSCT (n ¼ 262a) RA/RARS (no 50 27 (54%) 11 (22%) 1 (2%) 3 (6%) 1 (2%) 2 (4%) 5 (10%) pretreatment) RAEB(t)/sAML 71 16 (23%) 13 (18%) 1 (1%) 7 (10%) 4 (6%) 10 (14%) 20 (28%) in CR RAEB(t)/sAML, 62 12 (19%) 17 (27%) 0 (0%) 7 (11%) 5 (8%) 8 (13%) 13 (21%) treated but not in CR RAEB(t)/sAML, 78 25 (32%) 25 (32%) 3 (4%) 7 (9%) 5 (6%) 5 (6%) 9 (12%) untreated

Conditioning (n ¼ 266) Myeloablative 209 66 (32%) 58 28%) 3 (1%) 18 (9%) 11 (5%) 19 (9%) 34 (16%) Reduced 57 14 (25%) 12 (21%) 2 (4%) 6 (11%) 4 (7%) 6 (11%) 13 (23%) intensity

Stem cell source (n ¼ 264a) Bone marrow 140 47 (34%) 37 (26%) 3 (2%) 13 (9%) 6 (4%) 15 (11%) 19 (14%) Other (all 124 33 (26%) 32 (26%) 2 (2%) 10 (8%) 9 (7%) 10 (8%) 28 (23%) peripheral blood but one cord blood)

Donor type (n ¼ 266) HLA-identical 171 43 (25%) 44 (26%) 3 (2%) 19 (11%) 6 (4%) 19 (11%) 37 (22%) sibling Alternative 95 37 (39%) 26 (27%) 2 (2%) 5 (5%) 9 (10%) 6 (6%) 10 (11%) donor

Recipient–donor sex match (n ¼ 264a) Female donor 59 17 (29%) 14 (24%) 0 (0%) 5 (9%) 7 (12%) 4 (7%) 12 (20%) for male patient All other 205 63 (31%) 55 (27%) 4 (2%) 19 (9%) 8 (4%) 21 (10%) 35 (17%) combinations

CMV IgG status (n ¼ 254a) –/– 59 12 (20%) 16 (27%) 0 (0%) 3 (5%) 7 (12%) 5 (9%) 16 (27%) –/ þ 40 11 (28%) 10 (25%) 2 (5%) 4 (10%) 2 (5%) 3 (6%) 8 (16%) þ / þ or – 155 51 (33%) 42 (27%) 3 (2%) 16 (10%) 6 (4%) 15 (10%) 22 (14%)

Period of alloSCT (n ¼ 266) o1998 81 29 (36%) 19 (24%) 1 (1%) 7 (9%) 4 (5%) 12 (15%) 9 (11%) 1998–2001 96 23 (24%) 20 (21%) 2 (2%) 12 (13%) 5 (5%) 7 (7%) 27 (28%) 42001 89 28 (32%) 31 (35%) 2 (2%) 5 (6%) 6 (7%) 6 (7%) 11 (12%) Abbreviations: abn., abnormality; AlloSCT, allogeneic stem cell transplantation; chr., chromosome; CK, complex karyotype; CMV, cytomegalovirus; HLA, human leukocyte antigen; MK, monosomal karyotype; À 7, monosomy 7. aData shown are of 266 MDS patients with chromosome 7 abnormalities with complete data for classiﬁcation based on various speciﬁc and/or extra chromosomal abnormalities. Of an additional four patients, disease status at alloSCT was unknown, and of two patients, stem cell source was unknown; recipient sex match and CMV IgG was unknown in 2 and 12 patients, respectively. The percentages indicate the distribution of the various chromosome 7 abnormalities, including the presence of CK and/or MK within every subgroup.

& 2013 Macmillan Publishers Limited Leukemia (2013) 879 – 888 Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 882

1.0 1.0 OS PFS

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2

0.0 0.0

Nr at risk: 277 98 70 60 43 3825 15 12 8 Nr at risk: 277 84 61 48 33 30 21 14 11 7 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Figure 1. Kaplan–Meier curves of OS and PFS of MDS/sAML patients with any chromosome 7 abnormality after alloSCT. Limits of pointwise 95% conﬁdence intervals are shown by dashed lines.

Univariate analysis associated with increased NPM (HR 1.73, P ¼ 0.03 and HR 1.83, Median follow-up of patients who were still alive was 5 years P ¼ 0.02 in third and fourth model, respectively) as was patient (range 0–18 years). Estimated 5-year PFS and OS were 22±6% cytomegalovirus IgG positivity (HR 1.79, P ¼ 0.05 in both models). (95% confidence interval) and 28±6%, respectively (Figure 1). The Disease progression: CK (HR 1.90, P ¼ 0.0005) and MK (HR 2.21, probability of disease progression at 3, 12 and 60 months was Po0.001) were associated with increased risk of progressive 9±3%, 29±5% and 38±6%, respectively. NPM at 3, 12 and 60 disease. months was 21±5%, 36±6% and 40±6%, respectively. Results of PFS: ‘Higher stages, treated but not in CR’ (HR 1.65, P ¼ 0.03) and univariate analysis for 5-year NPM, disease progression, PFS and CK (HR 1.51, P ¼ 0.02) were associated with decreased PFS in the OS are shown in Table 3. third Cox model, whereas only MK (HR 1.82, Po0.001) was NPM: Lower age and myeloablative conditioning were asso- associated with decreased PFS in the fourth Cox model. ciated with a higher NPM (P ¼ 0.004 and 0.03, respectively). OS: Lower age was associated with decreased OS but the HR Disease progression: Lower age (P ¼ 0.007), disease status at was only 0.99 (P ¼ 0.03 and 0.05 in the third and fourth Cox model, alloSCT (P ¼ 0.06), CK (P ¼ 0.02) and MK (Po0.001) were associated respectively). ‘Higher stages, treated but not in CR’ were with increased risk of progressive disease. SCT from human associated with decreased OS in both the third and fourth Cox leukocyte antigen-identical siblings (P ¼ 0.04) and the use of model (HR 1.81, P ¼ 0.02 and HR 1.75, P ¼ 0.02, respectively) as peripheral blood stem cells (P ¼ 0.06) were also associated with were CK (HR 1.63, P ¼ 0.004) and MK (HR 1.72, P ¼ 0.002). Female increased disease progression. donor for male patient was also associated with decreased OS (HR PFS: Disease status at alloSCT (P ¼ 0.04), CK (P ¼ 0.01) and MK 1.44, P ¼ 0.05). (Po0.001) was associated with decreased PFS. OS: Disease status at alloSCT (P ¼ 0.02), CK (P ¼ 0.006) and MK MK is better predictive for PFS and OS than CK. To test more (Po0.001) were associated with decreased OS. directly whether CK or MK was most predictive for outcome, we introduced both factors in a fifth Cox model. The HRs for PFS and Multivariate analyses OS were then only statistically significantly increased for MK and The focus of this analysis was to identify the cytogenetic not for CK (data not shown). When an interaction between CK and abnormality with best predictive value for outcome. For this MK was added, this term did not have a significant HR (data not purpose we prepared several Cox models that differ in the shown). We then compared all Cox models for PFS (Cox models 3 cytogenetic subcategorization only. and 4 and the fifth model with the interaction of CK and MK) by means of the cross-validated log partial likelihood. Of these, the Comparison of monosomy 7, the absence of monosomy 7, the model with only MK (model 4) performed best and that with only presence of additional chromosomal abnormities and either CK or CK (model 3) performed worst (the difference in cross-validated MK. We first studied the relative predictive impact of the log partial likelihood was 3.8). The clinical relevance for PFS from presence of a monosomy 7 or of other chromosome 7 the increased hazard ratios for MK and the different disease stages abnormalities, and of the presence of extra chromosomal at alloSCT is illustrated in the Cox model-based PFS curves abnormalities, including either CK (Table 4, first Cox model) or (Figure 2, corresponding to Cox model 4). MK (Table 4, second Cox model), for PFS and OS. In both Cox models, there were no statistically significant differences between the different cytogenetic subcategories except for the presence of DISCUSSION MK (hazards ratio (HR) 1.68, P ¼ 0.01 for PFS and HR 1.58, P ¼ 0.04 To the best of our knowledge, this is the first report on a large for OS). series of MDS/sAML patients with high-risk disease as defined by the presence of a chromosome 7 abnormality who had been Comparison of CK and no CK, or of MK and no MK. As Cox models treated with allogeneic SCT. In multivariate analysis, three factors with variables containing many subcategories are less stable, and had a statistically significant negative impact on PFS and/or OS in because the hazard ratios for PFS and OS for the different values all models: lower age, ‘higher stages, treated but not in CR’ and of the cytogenetic variables without either CK or MK were not the presence of extra chromosomal abnormalities that classify statistically significantly different (Table 4), we built two additional either for CK or MK. models with which we addressed the relative impact of the Although the HR for age hardly differed from 1.0, its impact is presence of CK or MK, respectively, for NPM, progression, PFS and illustrated when one calculates the HR for a 20-year difference in OS (Table 5, third and fourth Cox model, respectively). age at time of alloSCT. This HR will then be 0.9920 ¼ 0.82. This NPM: Lower age was associated with a higher NPM (HR 0.97, difference resulted at least in part from a difference in NPM. This is Po0.001 in both models). Female donor for male patient was also in contrast to some previous reports on outcome of alloSCT

Leukemia (2013) 879 – 888 & 2013 Macmillan Publishers Limited Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 883 Table 3. Univariate analysis for 5-year NPM, disease progression, PFS and OS of MDS/sAML patients with any chromosome 7 abnormality treated with alloSCT for patient-, disease- and transplantation-related variables (n ¼ 277)

Variables n ¼ % NPM (%) Disease Progression (%) PFS (%) OS (%)

All patients 277 100 40 38 22 28

Age at alloSCT in years 18–40 101 36 51 26 23 26 40–50 71 26 42 43 16 23 450 105 38 28 47 25 32 P-value 0.004 0.007 0.45 0.29

Time from diagnosis to alloSCT p12 months 215 78 40 40 20 25 412 months 62 22 40 31 29 37 P-value 0.83 0.27 0.35 0.60

Disease status at alloSCT RA/RARS (no pretreatment) 52 19 42 26 33 42 RAEB(t)/sAML in CR 74 27 33 45 23 28 RAEB(t)/sAML, treated but not in CR 63 23 43 46 11 13 RAEB(t)/sAML, untreated 82 30 42 35 23 31 Missing 6 1 P-value 0.40 0.06 0.04 0.02

Various chr. 7 abnormalities and CK À 7 only 80 29 46 27 27 37 Single 7 abn. not À 7702536412332 À 7 þ extra abnormality, no CK 30 11 44 47 9 17 7 abn. not À 7 þ extra abn., no CK 24 9 29 31 40 45 chr. 7 abn. þ CK 62 22 37 52 11 10 Missing 11 4 P-value 0.54 0.02 0.03 0.04

Complex karyotype (CK) Absent 213 77 41 34 25 34 Present 62 22 37 52 11 10 Missing 2 1 P-value 0.60 0.003 0.01 0.006

Various chr. 7 abnormalities and MK À 7 only 80 29 46 27 27 37 single 7 abn. not À 7702536412332 7 abn. not À 7 þ extra abn., no MK 38 14 26 47 37 40 chr. 7 abn. þ MK 72 26 38 52 8 10 missinga 17 6 P-value 0.28 0.004 0.003 0.01

Monosomal karyotype (MK) Absent 194 70 40 34 27 35 Present 71 26 39 55 6 8 Missing 12 4 P-value 0.74 o0.001 o0.001 0.001

Conditioning Myeloablative 217 78 43 36 21 26 Reduced intensity 60 22 26 48 26 33 P-value 0.03 0.15 0.23 0.10

Stem cell source Bone marrow 147 53 44 33 23 29 Other (all peripheral blood but one cord) 128 47 36 44 19 25 Missing 1 — P-value 0.28 0.06 0.46 0.52

Donor type HLA-identical sibling 177 64 38 43 19 26 Alternative donor 100 36 44 29 27 32 P-value 0.15 0.04 0.65 0.75

Recipient–donor sex match Female donor for male patient 60 22 49 31 19 23 All other combinations 215 77 38 40 22 29

& 2013 Macmillan Publishers Limited Leukemia (2013) 879 – 888 Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 884 Table 3. (Continued )

Variables n ¼ % NPM (%) Disease Progression (%) PFS (%) OS (%)

Missing 2 1 P-value 0.32 0.44 0.56 0.29

CMV IgG of recipient and donor –/– 61 22 26 48 27 35 –/ þ 42 15 42 40 18 31 þ / þ or – 161 58 43 37 20 25 Missing 13 5 P-value 0.08 0.33 0.50 0.21

Abbreviations: abn., abnormality; alloSCT, allogeneic stem cell transplantation; À 7, monosomy 7; chr., chromosome; CK, complex karyotype; CMV, cytomegalovirus; MK, monosomal karyotype; NPM, nonprogression mortality; OS, overall survival; PFS, progression-free survival; sAML, secondary acute myeloid leukemia. The two-tailed log-rank test was used for identiﬁcation of single factors with statistically signiﬁcant impact on OS and PFS, whereas the Gray test was used for the same purpose for the outcome disease progression and NPM. aThese 17 patients with missing data include, besides the 12 mentioned in the variable ‘MK absent or present’, 5 additional patients with ‘ À 7 þ extra abnormality, no MK’ that were withdrawn from the analysis due to the low number of patients.

Table 4. Multivariate analysis for PFS and OS focussing on the various chromosome 7 subcategories and CK or MK for MDS/sAML patients with any chromosome 7 abnormality treated with alloSCT

Cox model 1: karyotypic subcategories including CK Cox model 2: karyotypic subcategories including MK

PFS OS PFS OS

HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value

Various chr. 7 Various chr. 7 abn. and CK abn. and MKa À 7 only 1 — 1 — À 7 only 1 — 1 — Single 7 abn. 0.99 (0.66–1.48) 0.95 0.98 (0.64–1.50) 0.94 Single chr. 7 abn. 1.0 (0.66–1.50) 0.98 1.0 (0.65–1.53) 0.99 not À 7 not À 7 À 7 þ extra 1.29 (0.75–2.24) 0.36 1.05 (0.59–1.88) 0.87 chr. 7 abn. not 0.73 (0.45–1.20) 0.22 0.73 (0.44–1.22) 0.23 abn., no CK À 7 þ extra chr. abn, no MK chr. 7 abn. 0.69 (0.38–1.27) 0.24 0.65 (0.35–1.23) 0.19 chr. 7 abn. þ MK 1.68 (1.11–2.55) 0.01 1.58 (1.02–2.43) 0.04 not À 7 þ extra chr. abn., no CK chr. 7 abn. þ CK 1.45 (0.96–2.19) 0.08 1.49 (0.97–2.28) 0.07

Abbreviations: abn., abnormality; alloSCT, allogeneic stem cell transplantation; À 7, monosomy 7; chr., chromosome; CK, complex karyotype; CI, confidence interval; HR, hazards ratio; MK, monosomal karyotype; MDS, myelodysplastic syndrome; OS, overall survival; PFS, progression-free survival; sAML, secondary acute myeloid leukemia. Two Cox models, all based on 243 patients with complete covariate information, were fitted as indicated in the upper rows, for PFS as well as for OS. Shown are the results for the various cytogenetic subgroups and CK (model 1) or MK (model 2). aThe subgroup ‘ À 7 þ extra abnormality but no MK’ was omitted because of the very low number of patients in this category (n ¼ 5). The variable in bold indicate statistical significance at the 5% level. Results for the other covariates (age, remission status at alloSCT, donor type, sex match and CMV match) are not shown for clarity reasons and because the results for these covariates are actually similar to the results in the third and fourth Cox models (Table 5).

in MDS/sAML patients where higher age was accompanied Their PFS and OS seem to come close to that of patients with by a higher NPM.15,16,25,26 In other reports, however, age was intermediate risk cytogenetics as was also reported in previous not significantly predictive for any outcome parameter12,14,17,19,22,29,37 studies.6,12–19,21–23,28,37 We suppose that the negative impact of or had not been evaluated by multivariate analysis.13 The impact the classical poor-risk cytogenetic abnormalities in previously of younger age on NPM and OS may well be related to the fact published studies on the effect of alloSCT in MDS patient that the study cohort only comprises patients with poor cohorts,6,12–19,21,22,37 in fact, may just represent the poor risk of cytogenetic risk. In the presence of alleged confounders that are having CK or MK but not the mere presence of a chromosome 7 not retrievable from the EBMT database like comorbidity, poor abnormality. The observed heterogeneity within the classical high performance and less-perfectly matched donors, treating cytogenetic risk group defined by the presence of a chromosome physicians may be more inclined to accept the risks of alloSCT 7 abnormality may also explain why in a study on the effect of in younger patients. alloSCT in patients with RA/RARS high cytogenetic risk was not of In the multivariate analyses, the negative predictive power of prognostic impact.34 Indeed, this group comprized only 41 RA/ MK was shown to be slightly higher than that of CK for PFS. The RARS patients, of whom probably a low percentage had CK or MK. HRs of CK and MK for PFS and OS were fairly similar, because of Our results are in line with a recent publication, showing that the the considerable overlap between patients having CK or MK. It is original International Prognostic Scoring System chromosome risk apparent that in the absence of CK or MK, HRs of the other classification needs to be reconsidered because of differential OS cytogenetic subcategories for PFS and OS were (almost) p1.0. between, in this case, patients with particular chromosome 7

Leukemia (2013) 879 – 888 & 2013 Macmillan Publishers Limited & 03McilnPbihr Limited Publishers Macmillan 2013

Table 5. Multivariate analysis for NPM, PFS and OS including the absence or presence of CK (Cox model 3) or MK (Cox model 4) for MDS/sAML patients with any chromosome 7 abnormality treated with alloSCT

NPM Progression PFS OS

HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value

Cox model 3: CK vs no CK Age at allo (in years) 0.97 (0.95–0.99) o0.001 1.01 (1.00–1.03) 0.15 0.99 (0.98–1.00) 0.13 0.99 (0.97–1.00) 0.03

Disease status at alloSCT RA/RARS (no pretreatment) 1.0 — 1.0 — 1.0 1.0 RAEB(t)/sAML in CR 0.75 (0.38–1.46) 0.39 1.56 (0.79–3.08) 0.20 1.14 (0.72–1.81) 0.58 1.17 (0.72–1.91) 0.52 RAEB(t)/sAML, treated, but not in CR 1.55 (0.83–2.88) 0.17 1.80 (0.89–3.62) 0.10 1.65 (1.04–2.62) 0.03 1.81 (1.12–2.92) 0.02 RAEB(t)/sAML, untreated 1.27 (0.70–2.31) 0.43 1.39 (0.70–2.78) 0.35 1.32 (0.84–2.07) 0.23 1.36 (0.85–2.19) 0.20 CK vs no CK 1.19 (0.72–1.97) 0.49 1.90 (1.22–2.96) 0.005 1.51 (1.09–2.10) 0.02 1.63 (1.16–2.28) 0.004 Alternative donor (vs HLA-identical sibling) 1.20 (0.79–1.82) 0.40 0.71 (0.45–1.12) 0.14 0.93 (0.68–1.25) 0.61 0.94 (0.69–1.29) 0.72 Female donor for male male patient (vs all other combinations) 1.73 (1.06–2.85) 0.03 0.80 (0.46–1.39) 0.43 1.14 (0.79–1.65) 0.47 1.29 (0.89–1.86) 0.18

CMV IgG (recipient/donor) –/– 1.0 — 1.0 — 1.0 1.0 –/ þ 1.72 (0.83–3.57) 0.15 1.03 (0.54–1.95) 0.94 1.32 (0.82–2.12) 0.26 1.36 (0.82–2.26) 0.24

þ / þ or – 1.79 (1.01–3.16) 0.05 0.88 (0.55–1.40) 0.58 1.19 (0.83–1.70) 0.34 1.39 (0.95–2.02) 0.09 MDS Gelder abnormal van 7 M chromosome in outcome Transplant

Cox model 4: MK vs no MK Age at allo (in years) 0.97 (0.95–0.99) o0.001 1.02 (1.00–1.03) 0.11 0.99 (0.98–1.00) 0.18 0.99 (0.97–1.00) 0.05

Disease status at alloSCT al et RA/RARS (no pretreatment) 1.0 — 1.0 — 1.0 1.0 RAEB(t)/sAML in CR 0.67 (0.34–1.34) 0.26 1.37 (0.68–2.75) 0.37 1.02 (0.64–1.64) 0.93 1.10 (0.67–1.81) 0.70 RAEB(t)/sAML, treated but not in CR 1.45 (0.78–2.72) 0.24 1.76 (0.88–3.54) 0.11 1.57 (0.99–2.50) 0.06 1.75 (1.08–2.83) 0.02 RAEB(t)/sAML, untreated 1.29 (0.72–2.31) 0.40 1.45 (0.73–2.90) 0.29 1.36 (0.87–2.13) 0.17 1.43 (0.90–2.29) 0.13 MK vs no MK 1.51 (0.91–2.51) 0.12 2.21 (1.41–3.44) o0.001 1.82 (1.30–2.54) o0.001 1.72 (1.22–2.43) 0.002 Alternative donor (vs HLA-identical sibling) 1.28 (0.83–1.97) 0.27 0.82 (0.52–1.30) 0.41 1.03 (0.75–1.40) 0.87 1.04 (0.75–1.45) 0.80 Female donor for male male patient (vs all other combinations) 1.83 (1.12–3.00) 0.02 0.92 (0.53–1.59) 0.76 1.26 (0.88–1.81) 0.21 1.44 (1.00–2.08) 0.05

CMV IgG (recipient/donor) –/– 1.0 — 1.0 — 1.0 1.0 –/ þ 1.70 (0.82–3.53) 0.16 0.99 (0.52–1.87) 0.97 1.28 (0.80–2.06) 0.31 1.33 (0.80–2.20) 0.27 þ / þ or – 1.79 (1.01–3.15) 0.05 0.80 (0.51–1.27) 0.34 1.15 (0.81–1.64) 0.43 1.35 (0.93–1.95) 0.12 ekma(03 7 888 – 879 (2013) Leukemia Abbreviations: alloSCT, allogeneic stem cell transplantation; CI, confidence interval; CK, complex karyotype; CMV, cytomegalovirus; HR, hazards ratio; MK, monosomal karyotype; NPM, nonprogression mortality; OS, overall survival; PFS, progression-free survival; sAML, secondary acute myeloid leukemia. The two Cox models were based on 247 patients with complete covariate information, and were fitted as indicated in the respective upper rows, for NPM, progression, PFS and OS. Variables in bold indicate statistical significance at the 5% level. 885 Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 886

1.0 no MK 1.0 no MK MK MK

0.8 0.8

0.6 0.6

0.4 0.4 Probability of PFS Probability of PFS 0.2 0.2

0.0 0.0 024681012 024681012 Years after alloSCT Years after alloSCT

1.0 no MK 1.0 no MK MK MK

0.8 0.8

0.6 0.6

0.4 0.4 Probability of PFS

Probability of PFS 0.2 0.2

0.0 0.0 024681012 024681012 Years after alloSCT Years after alloSCT Figure 2. Cox model-based PFS curves illustrating the impact of MK on MDS/sAML patients with any chromosome 7 abnormality with emphasis on the different disease stages at alloSCT. The Cox model was based on 247 patients with complete covariates information (see Table 5, Cox model 4). MK was introduced as the variable of interest as it appeared to have a somewhat stronger predictive impact on PFS than CK as discussed in the Results section. For all curves, age at alloSCT, donor type, cytomegalovirus (CMV) IgG serostatus and sex match were kept constant at median age (45.5 years), human leukocyte antigen (HLA)-identical sibling, donor and recipient both CMV IgG-negative, and no female donor for male patient, respectively. Predicted PFS for patients without MK is shown by the black lines, and for patients with MK by the gray lines. The reader can recreate these and similar curves through the web-based OS visualization tool described under Statistical analysis in the Patients and methods section. (a) Predicted PFS for patients that never had a higher MDS stage than RA/RARS at any time before alloSCT. Median PFS in the absence or presence of MK 21 and 6 months and 5-year PFS 40% and 19%, respectively. (b) Predicted PFS for patients with RAEB(t)/sAML in CR. Median PFS 20 and 6 months and 5-year PFS 40% and 18%, respectively in the absence or presence of MK. (c) Predicted PFS for patients with RAEB(t)/sAML, treated but not in CR. Median PFS in the absence or presence of MK 8 and 4 months and 5-year PFS was 24% and 7%, respectively. (d) Predicted PFS for patients with RAEB(t)/sAML, untreated. Median PFS 9 and 4 months and 5-year PFS 29% and 11%, respectively in the absence or presence of MK.

abnormalities and those with complex abnormalities that were or who failed pretreatment.16,22,24,27,28 Other studies show that treated with non-intensive supportive interventions.38 In further outcome after successful remission induction is similar to outcome studies in a nonselected group of MDS patients, we will test the of untreated higher-stage MDS patients while unsuccessfully hypothesis that PFS and OS after alloSCT without CK or MK is pretreated patients do worse,13,41,43 or reveal that both higher- similar irrespective of the presence of a chromosome 7 stage MDS and induction treatment are independently associated abnormality. In addition, the impact of CK and MK on the with poor outcome (the latter because of a higher NPM).13 In absence of a chromosome 7 abnormality will be studied.39 contrast, some studies showed no statistically significant MDS patients with any chromosome 7 abnormality that differences in outcome whether MDS patients had been received alloSCT without prior progression to a higher MDS stage pretreated or not.14,44 In this context, it has to be taken into than RA/RARS, or with higher stages in remission at transplanta- account that patients with poor-risk cytogenetics more often tion, had the best outcome, especially, in the absence of CK or MK. failed remission induction and, additionally, suffered more The fact that outcome after alloSCT for lower-stage MDS is frequently from early relapse after AML-like chemotherapy.8,22 accompanied by better OS than that for higher stages is in The role, if any, of remission induction before alloSCT in higher- accordance with other studies.13–15,17,26,34,40–42 New is that this stage MDS remains to be elucidated. It also remains to be seen if also holds true for the patients who up to now are considered to the outcome of higher-stage poor-risk MDS patients is better with have a high risk due to a chromosome 7 abnormality. Also, new is alloSCT than with conventional chemotherapy only. The only the impact of additional CK or MK in these patients. Outcome (PFS prospective study that addressed this issue suggests improved OS and OS) of patients with higher stages than RA/RARS was worse, after alloSCT in classically defined poor cytogenetic-risk higher- as reflected by higher HRs, although the difference was only stage MDS patients, after successful remission induction.23 statistically significant for patients with ‘higher stages, treated but However, the number of patients with and without CK/MK in not in CR’. The value of MDS disease status at alloSCT differed this study is not known. substantially among each other in other studies. Some authors The relevance of our results for clinical decision making seems report that OS was superior for those transplanted in CR, whereas obvious. As illustrated in Figure 2, PFS is seriously low in RAEB(t)/ outcome was uniformly poor for those who either never received sAML patients with chromosome 7 abnormalities having MK and

Leukemia (2013) 879 – 888 & 2013 Macmillan Publishers Limited Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 887 either being treated, but not in CR, or being untreated. Performing 10 Estey EH, Kantarjian HM, O’Brien S, Kornblau S, Andreeff M, Beran M et al. High alloSCT in patients with these characteristics is questionable. remission rate, short remission duration in patients with refractory anemia with Treatment with alloSCT should be reconsidered even more in the excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leuke- presence of other risk factors like increased comorbidity, as OS mia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF). after alloSCT is very poor in these patients. On the other hand, Cytokines Mol Ther 1995; 1: 21–28. because no studies have been performed comparing alloSCT vs no 11 Gardin C, Chaibi P, de Revel T, Rousselot P, Turlure P, Miclea JM et al. Intensive alloSCT directly in this high-risk patient group, a potential slight chemotherapy with idarubicin, cytosine arabinoside, and granulocyte colony- benefit cannot be captured in a HR. It may be possible that a very stimulating factor (G-CSF) in patients with secondary and therapy-related acute myelogenous leukemia. Club de Reflexion en Hematologie. Leukemia 1997; 11: limited number of MDS patients with chromosome 7 abnormality 16–21. and additional MK may still benefit from alloSCT, as in the case of 12 Nevill TJ, Fung HC, Shepherd JD, Horsman DE, Nantel SH, Klingemann HG et al. 45 AML, where the HR for performing alloSCT is rather low Cytogenetic abnormalities in primary myelodysplastic syndrome are highly pre- compared with no alloSCT. Because of the lack of prospective dictive of outcome after allogeneic bone marrow transplantation. Blood 1998; 92: randomized clinical trials in this field, this view remains 1910–1917. hypothetical. 13 Nakai K, Kanda Y, Fukuhara S, Sakamaki H, Okamoto S, Kodera Y et al. Value of There is clearly room for exploring more promising approaches chemotherapy before allogeneic hematopoietic stem cell transplantation from an for MDS patients with chromosome 7 abnormalities and additional HLA-identical sibling donor for myelodysplastic syndrome. Leukemia 2005; 19: MK. One example is the use of hypomethylating agents after 396–401. 46 14 Chang C, Storer BE, Scott BL, Bryant EM, Shulman HM, Flowers ME et al. Hema- relapse. Another direction is the application of donor- topoietic cell transplantation in patients with myelodysplastic syndrome or acute lymphocyte infusions (DLIs) in relapsed patients. Although only myeloid leukemia arising from myelodysplastic syndrome: similar outcomes in 47,48 few seem to benefit from DLI as the exclusive treatment, the patients with de novo disease and disease following prior therapy or antecedent 49,50 use of preceding cytoreduction warrants further exploration. hematologic disorders. Blood 2007; 110: 1379–1387. Another alternative might be to apply DLI in a preemptive setting 15 Alessandrino EP, Della Porta MG, Bacigalupo A, Van Lint MT, Falda M, Onida F et al. before signs of relapse. 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. CONFLICT OF INTEREST 16 Kroger N, Brand R, van Biezen A, Zander A, Dierlamm J, Niederwieser D et al. Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leuke- The authors declare no conflict of interest. mia treated with allogeneic stem cell transplantation. Haematologica 2009; 94: 542–549. 17 Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelo- ACKNOWLEDGEMENTS dysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998; We thank to all centers completing ‘MedB forms’ for the EBMT registry. We also thank 12(Suppl 1): S25–S29. Dr Cećile de Pont and Dr Peter de Leeuw for thoroughly checking grammar and 18 Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti C et al. A decision stylistic errors. 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. 19 Armand P, Deeg HJ, Kim HT, Lee H, Armistead P, de Lima M et al. Multicenter REFERENCES validation study of a transplantation-specific cytogenetics grouping scheme for 1 Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International patients with myelodysplastic syndromes. Bone Marrow Transplant 2010; 45: scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 877–885. 1997; 89: 2079–2088. 20 Onida F, Brand R, van Biezen A, Frassoni F, Beelen D, Finke J et al. Effect of 2 Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The cytogenetics classification according to IPSS on the outcome of allogeneic importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 HSCT from HLA-identical siblings in patients with MDS or secondary AML: a patients entered into the MRC AML 10 trial. The Medical Research Council Adult retrospective analysis from the EBMT-CLWP. Bone Marrow Transplant 2007; and Children’s Leukaemia Working Parties. Blood 1998; 92: 2322–2333. 39(Suppl 1): 454. 3 Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. 21 de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C et al. Intensive Karyotypic analysis predicts outcome of preremission and postremission therapy chemotherapy followed by allogeneic or autologous stem cell transplantation for in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Coop- patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia erative Oncology Group Study. Blood 2000; 96: 4075–4083. following MDS. Blood 2001; 98: 2326–2331. 4 Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl 22 Castro-Malaspina H, Jabubowski AA, Papadopoulos EB, Boulad F, Young JW, KB, Mellink CH et al. Monosomal karyotype in acute myeloid leukemia: a better Kernan NA et al. Transplantation in remission improves the disease-free survival of indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26: patients with advanced myelodysplastic syndromes treated with myeloablative T 4791–4797. cell-depleted stem cell transplants from HLA-identical siblings. Biol Blood Marrow 5 Estey EH, Pierce S, Keating MJ. Identification of a group of AML/MDS patients with Transplant 2008; 14: 458–468. a relatively favorable prognosis who have chromosome 5 and/or 7 abnormalities. 23 de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G et al. Value of Haematologica 2000; 85: 246–249. allogeneic versus autologous stem cell transplantation and chemotherapy in 6 Oosterveld M, Suciu S, Verhoef G, Labar B, Belhabri A, Aul C et al. The presence of patients with myelodysplastic syndromes and secondary acute myeloid leukemia. an HLA-identical sibling donor has no impact on outcome of patients with high- Final results of a prospective randomized European Intergroup Trial. Haemato- risk MDS or secondary AML (sAML) treated with intensive chemotherapy followed logica 2010; 95: 1754–1761. by transplantation: results of a prospective study of the EORTC, EBMT, SAKK and 24 Demuynck H, Verhoef GE, Zachee P, Emonds MP, van der Schueren E, GIMEMA Leukemia Groups (EORTC study 06921). Leukemia 2003; 17: 859–868. van den Berghe H et al. Treatment of patients with myelodysplastic 7 Hofmann WK, Heil G, Zander C, Wiebe S, Ottmann OG, Bergmann L et al. Intensive syndromes with allogeneic bone marrow transplantation from genotypically chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in HLA-identical sibling and alternative donors. Bone Marrow Transplant 1996; 17: patients with advanced myelodysplastic syndrome and high-risk acute myeloid 745–751. leukemia. Ann Hematol 2004; 83: 498–503. 25 Al-Ali HK, Brand R, van Biezen A, Finke J, Boogaerts M, Fauser AA et al. A retro- 8 Knipp S, Hildebrand B, Kundgen A, Giagounidis A, Kobbe G, Haas R et al. Intensive spective comparison of autologous and unrelated donor hematopoietic cell chemotherapy is not recommended for patients aged 460 years who have transplantation in myelodysplastic syndrome and secondary acute myeloid leu- myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes. kemia: a report on behalf of the Chronic Leukemia Working Party of the European Cancer 2007; 110: 345–352. Group for Blood and Marrow Transplantation (EBMT). Leukemia 2007; 21: 9 Bernasconi C, Alessandrino EP, Bernasconi P, Bonfichi M, Lazzarino M, Canevari A 1945–1951. et al. Randomized clinical study comparing aggressive chemotherapy with or 26 Runde V, de Witte T, Arnold R, Gratwohl A, Hermans J, van Biezen A et al. Bone without G-CSF support for high-risk myelodysplastic syndromes or secondary marrow transplantation from HLA-identical siblings as first-line treatment in acute myeloid leukaemia evolving from MDS. Br J Haematol 1998; 102: 678–683. patients with myelodysplastic syndromes: early transplantation is associated with

& 2013 Macmillan Publishers Limited Leukemia (2013) 879 – 888 Transplant outcome in chromosome 7 abnormal MDS M van Gelder et al 888 improved outcome. Chronic Leukemia Working Party of the European Group for patients with mds/secondary acute leukemia treated with allogeneic hemato- Blood and Marrow Transplantation. Bone Marrow Transplant 1998; 21: 255–261. poietic stem cell transplantation (HSCT): a retrospective survey on behalf of the 27 Warlick ED, Cioc A, Defor T, Dolan M, Weisdorf D. Allogeneic stem cell trans- Chronic Leukemia Working Party of the European Group for Blood and Marrow plantation for adults with myelodysplastic syndromes: importance of pre- Transplantation (EBMT). Blood 2010; 116: 578. transplant disease burden. Biol Blood Marrow Transplant 2009; 15: 30–38. 40 Anderson JE, Appelbaum FR, Schoch G, Gooley T, Anasetti C, Bensinger WI et al. 28 Yakoub-Agha I, de La Salmoniere P, Ribaud P, Sutton L, Wattel E, Kuentz M et al. Allogeneic marrow transplantation for refractory anemia: a comparison of two Allogeneic bone marrow transplantation for therapy-related myelodysplastic preparative regimens and analysis of prognostic factors. Blood 1996; 87: 51–58. syndrome and acute myeloid leukemia: a long-term study of 70 patients-report of 41 Sutton L, Chastang C, Ribaud P, Jouet JP, Kuentz M, Attal M et al. Factors influ- the French society of bone marrow transplantation. J Clin Oncol 2000; 18: encing outcome in de novo myelodysplastic syndromes treated by allogeneic 963–971. bone marrow transplantation: a long-term study of 71 patients Societe Francaise 29 Anderson JE, Gooley TA, Schoch G, Anasetti C, Bensinger WI, Clift RA et al. Stem de Greffe de Moelle. Blood 1996; 88: 358–365. cell transplantation for secondary acute myeloid leukemia: evaluation of trans- 42 Lee JH, Lee JH, Lim SN, Kim DY, Kim SH, Lee YS et al. Allogeneic hematopoietic cell plantation as initial therapy or following induction chemotherapy. Blood 1997; 89: transplantation for myelodysplastic syndrome: prognostic significance of pre- 2578–2585. transplant IPSS score and comorbidity. Bone Marrow Transplant 2010; 45: 30 Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T et al. Risk score 450–457. for outcome after allogeneic hematopoietic stem cell transplantation: a retro- 43 Martino R, Iacobelli S, Brand R, Jansen T, van Biezen A, Finke J et al. Retrospective spective analysis. Cancer 2009; 115: 4715–4726. comparison of reduced-intensity conditioning and conventional high-dose con- 31 Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. ditioning for allogeneic hematopoietic stem cell transplantation using HLA- Proposals for the classification of the myelodysplastic syndromes. Br J Haematol identical sibling donors in myelodysplastic syndromes. Blood 2006; 108: 836–846. 1982; 51: 189–199. 44 Laport GG, Sandmaier BM, Storer BE, Scott BL, Stuart MJ, Lange T et al. Reduced- 32 Ljungman P. CMV infections after hematopoietic stem cell transplantation. Bone intensity conditioning followed by allogeneic hematopoietic cell transplantation Marrow Transplant 2008; 42(Suppl 1): S70–S72. for adult patients with myelodysplastic syndrome and myeloproliferative dis- 33 Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD et al. Report orders. Biol Blood Marrow Transplant 2008; 14: 246–255. of an international working group to standardize response criteria for myelo- 45 Cornelissen JJ, Breems D, van Putten WL, Gratwohl AA, Passweg JR, Pabst T et al. dysplastic syndromes. Blood 2000; 96: 3671–3674. Comparative analysis of the value of allogeneic hematopoietic stem-cell trans- 34 de Witte T, Brand R, van Biezen A, Mufti G, Ruutu T, Finke J et al. Allogeneic stem plantation in acute myeloid leukemia with monosomal karyotype versus other cell transplantation for patients with refractory anaemia with matched related cytogenetic risk categories. J Clin Oncol 2012; 30: 2140–2146. and unrelated donors: delay of the transplant is associated with inferior survival. 46 Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A et al. Br J Haematol 2009; 146: 627–636. Azacitidine for treatment of imminent relapse in MDS or AML patients after 35 Lim Z, Brand R, Martino R, van Biezen A, Finke J, Bacigalupo A et al. Allogeneic allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26: 381–389. hematopoietic stem-cell transplantation for patients 50 years or older with 47 Depil S, Deconinck E, Milpied N, Sutton L, Witz F, Jouet JP et al. Donor lymphocyte myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol infusion to treat relapse after allogeneic bone marrow transplantation for mye- 2010; 28: 405–411. lodysplastic syndrome. Bone Marrow Transplant 2004; 33: 531–534. 36 Goeman JJ. L1 penalized estimation in the Cox proportional hazards model. Biom 48 Campregher PV, Gooley T, Scott BL, Moravec C, Sandmaier B, Martin PJ et al. J 2010; 52: 70–84. Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome 37 de Lima M, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C et al. after hematopoietic cell transplantation. Bone Marrow Transplant 2007; 40: Nonablative versus reduced-intensity conditioning regimens in the treatment of 965–971. acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant 49 Ravandi F, Kantarjian H, Cohen A, Davis M, O’Brien S, Anderlini P et al. Decitabine for long-term disease control after allogeneic hematopoietic stem cell trans- with allogeneic peripheral blood stem cell transplantation in the therapy of plantation. Blood 2004; 104: 865–872. leukemia relapse following a prior transplant: results of a phase I study. Bone 38 Schanz J, Tuchler H, Sole F, Mallo M, Luno E, Cervera J et al. New comprehensive Marrow Transplant 2001; 27: 1221–1225. cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and 50 Warlick ED, DeFor T, Blazar BR, Burns L, Verneris MR, Ustun C et al. Successful oligoblastic acute myeloid leukemia after mds derived from an international remission rates and survival after lymphodepleting chemotherapy and donor database merge. J Clin Oncol 2012; 30: 820–829. lymphocyte infusion for relapsed hematologic malignancies postallogeneic 39 Brands-Nijenhuis A, van Gelder M, de Witte T, Schetelig J, van Biezen A, Kroger N. hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18: Complex karyotype predicts outcome better than monosomal karyotype in 480–486.

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