Syndromes or Secondary Acute Myeloid Leukemia

Allogeneic Hematopoietic Stem-Cell Transplantation for Patients 50 Years or Older With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia ZiYi Lim, Ronald Brand, Rodrigo Martino, Anja van Biezen, Ju¨rgen Finke, Andrea Bacigalupo, Dietrich Beelen, Agnes Devergie, Emilio Alessandrino, Roel Willemze, Tapani Ruutu, Marc Boogaerts, Michele Falda, Jean-Pierre Jouet, Dietger Niederwieser, Nicolaus Kroger, Ghulam J. Mufti, and Theo M.De Witte From the Department of Haematological Medicine, King’s College London and King’s College Hospital National Health Services Foundation Trust, London, United Kingdom; Department of Medical Statistics, University of Leiden; Depart- ment of Hematology, Leiden University Medical Center, Leiden; Department of Hematology, Radboud University Medi- cal Center Nijmegen, the Netherlands; Division of Clinical Hematology; Hospi- tal de la Sant Creu i Sant Pau, Autono- mous University of Barcelona, Spain; Department of Medicine, Hematology and Oncology, University of Freiburg; Department of Bone Marrow Transplan- tation, University Hospital, Essen; Department of Internal Medicine, University Hospital Leipzig; Department of Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Hematology, Ospedale San Martino, Genova; Policlinico San Matteo Instituti di Ricovero e Cura a Carattere Scienti- fico, Pavia; Centro Trapianti Midollo, Azienda Ospedaliera S. Giovanni, Torino, Italy; Department of Hematol- ogy, Hospital St Louis, Paris; Service de Maladies du Sang, Hospital Claude Huriez, Lille, France; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; and Depart- ment of Hematology, University Hospi- tal of Leuven, Belgium. Submitted January 16, 2009; accepted August 13, 2009; published online ahead of print at www.jco.org on December 14, 2009. Written on behalf for the Myelodysplas- tic Syndromes subcommittee of the Chronic Leukemia Working Party of the European Group for Blood, and Marrow Transplantation. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: ZiYi Lim, MRCP, FRCPath, Department of Haematologi- cal Medicine, Kings College London and Kings College Hospital, Denmark Hill, London, United Kingdom SE5 9RS; e-mail: ziyi.lim@kcl.ac.uk. © 2009 by American Society of Clinical Oncology 0732-183X/10/2803-405/$20.00 DOI: 10.1200/JCO.2009.21.8073 A B S T R A C T Purpose This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. Patients and Methods We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). Results The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P � .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P � .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P � .01), use of an unrelated donor (P � .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P � .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P � .01) was the major independent variable associated with an inferior 4-year overall survival. Conclusion Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes. J Clin Oncol 28:405-411. © 2009 by American Society of Clinical Oncology INTRODUCTION Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for patients withmyelodysplastic syndromes (MDS) or second- ary acute myeloid leukemia (sAML). Early registry studies demonstrated an adverse association be- tween advanced age and increased nonrelapsemor- tality (NRM).1-7 However, recent improvements in conditioning regimens, supportive care, as well as the introduction of reduced intensity conditioning (RIC) regimens, have allowed the transplantation of older patients.8,9 Concurrent improvements in the resolution of HLA typing have facilitated the in- creased use of unrelated donor transplantationwith comparable results to sibling allografts. These devel- opments have led to a significant increase in the number of elderly patients withMDSbeing referred for allogeneic transplantation.10 While much of the drive toward allografting older patients has been made possible by the use of RIC regimens, it remains unclear as to whether it confers an improved overall survival (OS) in elderly patients with MDS. Some studies have suggested that the dose intensity of the conditioning regimen appears to play an important role in relapse-free JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28 � NUMBER 3 � JANUARY 20 2010 © 2009 by American Society of Clinical Oncology 405 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved. Downloaded from jco.ascopubs.org by Lei Zhang on January 17, 2010 from 116.226.213.172. survival post-transplantation for MDS or AML11,12 and recent Euro- pean Group for Blood andMarrow Transplantation (EBMT) studies in MDS and multiple myeloma have indicated that while the use of RIC is associated with a lower NRM, this is offset by a significantly higher relapse incidence when compared with conventional myeloa- blative conditioning regimens.6,13 With improvements in the quality of life and longevity of the generalpopulation, increasingnumbersofpatientsolder than50years are now being actively treated for MDS. Concurrent with these changes in treatment expectations,many older patients now ask to be considered for an allogeneic HSCT. The challenges facing transplant physicians at present include deciding which older MDS patients should be eligible for allografting, and whether certain older patients may derive greater benefit from receiving an increased dose regimen. Herein, we report on a retrospective multicenter analysis of 1,333 patients with MDS 50 years or older who received transplantation within the EBMT since 1998. The main aims of this study were to examine the characteristics of transplant activity for patients with MDS older than 50 years within EBMT, and additionally to study the factors predicting outcome within this group of patients. PATIENTS AND METHODS Patient details are presented in Table 1. Included in the studywere 1,333 patients from 202 centers, with a primary diagnosis of MDS. Only data from patients who underwent a first allogeneic transplantation between January 1998 and October 2006 andwhowere registered in the EBMT registry were included in this analysis. Data from 295 patients with HLA-matched sibling donors have been reported in apreviousEBMTanalysis.6All patientswere 50years orolder at time of their first allogeneic transplantation. Disease morphology was clas- sified according to the French-American-British (FAB) classification and was documented as separate variables for time of initial diagnosis as well as at time of transplantation. Patients with a diagnosis of chronic myelomonocytic leu- kemia (CMML) were excluded from the analysis. Three hundred thirteen patients (24%) had refractory anemia/refractory anemia with ringed sider- oblasts, 471 (35%) had refractory anemia with excess blasts, 215 (16%) had refractory anemia with excess blasts in transition, and 334 secondary acute myeloid leukemia (25%) at initial diagnosis. Disease status at transplantation was defined as either early (� 5% marrow blasts) or advanced (� 5% mar- row blasts). The median recipient age was 56 years (range, 50 to 74 years) with 884 patients (66%) age 50 to 60 years and449 (34%) ageolder than60 years. There were 811 HLA-matched sibling (67%) and 522 unrelated donor transplants (33%). Four hundred nine were matched unrelated donors and 113 were mismatchedunrelateddonors.Fivehundredpatients (38%)received standard myeloablative conditioning (SMC) and 833 (62%) received RIC as previously defined.6 Briefly, RIC included fludarabine plus intermediate doses of one or two alkylating agents or low-dose total body irradiation (2 to 4 Gy), with or without anti-thymocite globulin or alemtuzumab. Intermediate doses of alky- lating agents were defined as busulphan (8 to 10 mg/kg orally), intravenous melphalan (80 to 140 mg/m2), intravenous cyclophosphamide (600 to 1,200 mg/m2), or intravenous thiotepa (5 to 10mg/kg). Themedian ageof theolder than60 cohortwas 63 years (range, 60 to 75) comparedwith54years (range, 50 to60) for the50 to60cohort. Patients in the older than 60 cohort were more likely to receive a volunteer unrelated donor transplant (37% v 32%; P � .03), as well as a RIC regimen (78% v 55%; P � .01), while patients in the 50 to 60 cohort were more likely to have advanced stage MDS at transplant. Patients receiving RIC were older when compared with SMC recipients (median age, 59 years [range, 50.0 to 74.7 years] v54years [range, 50.0 to73.7 years];P� .02).However, SMCrecipients had more advanced disease stage at both time of diagnosis (60% v 49%; P� .03) and at time of transplantation. Therewas no difference in donor type between RIC and SMC (P� .15). For graft versus host disease prophylaxis, this variablewas not uniformly entered into the EBMT database in most patients, and thus its impact on transplantation outcomes has not been estimated. Fifty-one percent of pa- tients received some form of in vivo T-cell depletion. Due to the retrospective natureof the study, the reason(s) for inclusion in aRICprotocol andexclusion fromaSMCineach transplantationgroupwerenotknown. Informedconsent was obtained locally in accordance with the principles laid out in the Declara- tion of Helsinki and based on specific protocols approved by the respective local and national ethics committees for each transplant center. Statistical Methods End points were assessed on the date of last patient contact, and the final database was updated in October 2006. Analysis focused on NRM, disease relapse, or progression, relapse-free survival (RFS), and OS. Transplantation outcomes were tabulated at 4-years after transplantation, although outcomes at earlier time points are shown in Figure 1 where cumulative incidence estimates are shown in a competing risk context. The probabilities of RFS andOS estimates from the time of transplanta- tion are identical to the usual Kaplan-Meier estimates and groups were com- pared using the two-tailed log-rank test. The probability of occurrence of graft Table 1. Patient Characteristics Characteristic No. % Median recipient age, years Range 50-60 884 66 � 60 449 34 Conditioning Myeloablative 500 38 Reduced intensity 833 62 Donor type HLA-matched sibling 811 61 HLA-matched unrelated 409 31 HLA-mismatched unrelated 113 8 Stem-cell source Bone marrow 256 19 Peripheral blood 1077 81 Transplant period 1998-2001 395 30 2001 onward 938 70 Interval from diagnosis to transplantation, months � 6 455 34 6-12 428 32 � 6 450 34 Disease stage at diagnosis RA/RARS 313 24 RAEB 471 35 RAEB-t 215 16 sAML 334 25 Disease status at transplantation Early 557 42 Advanced 688 52 Unavailable 88 6 Cytogenetics Poor 89 7 Standard 91 7 Good 225 17 Unavailable 928 69 Abbreviations: RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transition; sAML, secondary acute myeloid leukemia. Lim et al 406 © 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved. Downloaded from jco.ascopubs.org by Lei Zhang on January 17, 2010 from 116.226.213.172. versus host disease, NRM, and disease relapse or progression was calculated using cumulative incidence estimates, taking into account the appropriate competing risk structure(s). (Cause specific) effect estimates for risk factors were obtained using Cox regression models. The main variables analyzed included donor age, donor status, recipient age group (50 to 60 v� 60 years), FAB disease classification at presentation, disease status at transplantation, type of conditioning regimen, time period of transplantation (1998 to 2001 v 2001-present), time from diagnosis to transplantation (� 6 month, 6 to 12 months, and� 12months), lines of prior intensive chemotherapy, cytogenet- ics,donor-recipient cytomegalovirus status, graft type (bonemarrowvperiph- eral blood stemcells). Therewas sufficient data on cytogenetics in 378patients (31%). As such, International Prognostic Scoring System (IPSS) was not included as a variable in this study. Formultivariate analyses, themain covariateswere first entered together into the model; with covariates found not to be significant at the .10 level removed from theCoxmodel in a stepwise backwardway. Type of condition- ing regimen was held in the model at each step irrespective of its significance since it was themain parameter of interest. Potential interactions between the covariate type of conditioning regimen and the other remaining covariates were tested, adding cross-product terms to the model in a forward stepwise way. Significance tests for all outcomes are based on the usual Cox models which estimate cause-specific hazards and test hazard ratios (HRs) using a likelihood ratio test.However,whenweproduced survival curves (cumulative incidence estimates) these were based on uni- or bivariate competing risk estimates without underlying model assumptions, but with unbiased curve estimates. When groups were compared according to continuous covariates, the Mann-WhitneyU test or Kruskal-Wallis one-way analysis of variance on ranks testwere used for differences inmedians. According to the group sizes, a �2 analysisorFisher’s exact testwasused tocompare categoric covariates. SPSS version 11 (SPSS, Chicago, IL) was used for all statistical analyses. RESULTS OS The 4-year estimate OS of the whole cohort was 31% (Fig 1). At the time of data censure, there were 642 deaths in total. The main identifiable causes of death were relapse in 235 (37%), secondary malignancy in three (0.5%), transplant-related causes 359 (56%), and other causes 45 (7%). The 4-year OS estimate of the 50 to 60 years and older than 60 years cohort was 34% and 27%, respectively, corresponding to aHR of 0.87 (P� .23). In addition, 4-year estimate OS for patients receivingRICor SMCwas 32%versus 30%(HR, 0.97; P� .73; Fig 2). Nonrelapse Mortality The 4-year estimate NRM was 36% for all patients. However, patients undergoing RIC had a significantly lower 4-year NRMwhen comparedwith those receiving SMC (32% v 44%;HR, 0.84; P� .05). While patients older than 60 years had a higher NRM, this was not significantly different from the 50 to 60 age group (4-year estimate: 36% v 39%; HR, 1.11; P� .39). When compared with the use of an HLA-matched sibling donor, an HLA-matched or HLA-mismatched Pr ob ab ili ty Time Since Transplant (months) 50403020100 1.0 0.8 0.6 0.4 0.2 0 OS (overall survival) Relapse Incidence Nonrelapse death Dead after relapse Alive after relapse Fig 1. Stacked cumulative incidence curves from a competing risk model evaluating the proportion of patients in a particular state with respect to the presence or absence of relapse, as a function of time after transplant. OS, overall survival. Nonrelapse death Dead after relapse Alive after relapse SMC 50-60 yrs SMC > 60 yrs RIC 50-60 yrs RIC > 60 yrs Nonrelapse death Dead after relapse Alive after relapse Nonrelapse death Dead after relapse Alive after relapse Nonrelapse death Dead after relapse Alive after relapse Pr ob ab ili ty Time Since Transplant (months) 50403020100 1.0 0.8 0.6 0.4 0.2 0 Pr ob ab ili ty Time Since Transplant (months) 50403020100 1.0 0.8 0.6 0.4 0.2 0 Pr ob ab ili ty Time Since Transplant (months) 50403020100 1.0 0.8 0.6 0.4 0.2 0 Pr ob ab ili ty Time Since Transplant (months) 50403020100 1.0 0.8 0.6 0.4 0.2 0 A B C D Fig 2. Stacked cumulative incidence curves from a competing risk model with relapse and death as competing risks, with the study population substratified according to (A) age 50 to 60 years, stan- dard myeloablative conditioning (SMC), (B) age � 60 years, SMC, (C) age 50 to 60 years, reduced intensity conditioning (RIC), and (D) age � 60 years, RIC. Allogeneic HSCT for MDS or sAML Patients Older Than 50 www.jco.org © 2009 by American Society of Clinical Oncology 407 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved. Downloaded from jco.ascopubs.org by Lei Zhang on January 17, 2010 from 116.226.213.172. unrelated donor was both associated with a higher NRM (4-year estimate: 34% v 40% v 54%; P� .02; Fig 3). Relapse There were 368 relapses in the cohort at time of data censure. Despite more patients with advanced disease receiving SMC, patients with RIC had a higher 4-year relapse rate (41% v 33%; HR, 1.39; P� .01). In addition, patients with advanced age had a higher relapse rate (50 to 60 years: 32% v� 60 years: 41%;HR, 1.32;P� .02). There was no significant difference in relapse incidence between patients with either an HLA-matched sibling, HLA-matched or mismatched unrelated donor (4-year estimate: 36% v 34% v 38%; P� .96). Cytogenetics Based on the IPSS cytogenetic classification, 89 patients were poor risk, 91 standard risk, and 225 favorable risk. There was no significant difference in the choice of conditioning regimens between different cytogenetic risk groups. Patients with available cytogenetic data were more likely to be 50 to 60 years, have an HLA-matched sibling donor, and have less advanced disease stage at time of trans- plant. On univariate analysis, patients with poor risk cytogenetics had a significantly increased 4-year relapse incidence (71% v 39% v 37%; P� .01) and reducedmedian OS (8.1 v 19.4 v 30.5 months; P� .01) whencomparedwithpatientswith standardor favorable cytogenetics. There was no significant difference in 4-year NRM among groups (42% v 35% v 36%; P� .24). Multivariate Analysis On multivariate analysis of 4-year outcomes (Table 2), use of RIC (HR, 1.44; 95%CI, 1.13 to 1.84; P� .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P � .01) were associated with an increased relapse rate. In contrast, ad- vanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P� .01), use of RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P� .03) and use of an unrelated donor (P� .03) were independent variables associatedwithNRM.Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P � .01) was the major independent variable associated with an inferior 4-year OS. DISCUSSION The contribution of recipient age toward the outcomes of allogeneic hematopoietic stem-cell transplantation has been a subject of signifi- cant debate in recent years. The incidenceof poor riskMDS is propor- tionally greater in eld