ASBMT and Marrow Transplantation

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1 Biol Blood Marrow Transplant 19 (2013) 898e903 Ex Vivo T CelleDepleted versus Unmodified Allografts in Patients with Acute Myeloid Leukemia in First Complete Remission American Society for Blood ASBMT and Marrow Transplantation Ulas D. Bayraktar 1, Marcos de Lima 1, Rima M. Saliba 1, Molly Maloy 2, Hugo R. Castro-Malaspina 2, Julianne Chen 1, Gabriela Rondon 1, Alexander Chiattone 1, Ann A. Jakubowski 2, Farid Boulad 2,3, Nancy A. Kernan 2,3,RichardJ.O Reilly 2,3, Richard E. Champlin 1, Sergio Giralt 2, Borje S. Andersson 1, Esperanza B. Papadopoulos 2, * 1 Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, Houston, Texas 2 Adult Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York 3 Pediatric Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, New York Article history: Received 4 October 2012 Accepted 23 February 2013 Key Words: AML Stem cell transplantation T cell depletion GVHD Transplant outcomes abstract This study was conducted to retrospectively compare the clinical outcomes after transplantation of Tcelledepleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N ¼ 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)þthiotepaþfludarabine; HFTBIþthiotepaþcyclophosphamide; or i.v. busulfanþmelphalanþfludarabine. TCD was performed by 1 of 2 immunomagnetic CD34 þ cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood celle rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N ¼ 181) after conditioning with busulfanþfludarabine and GVHD prophylaxis with tacrolimusþmini-methotrexate. Patients with unrelated or human leukocyte antigenemismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P ¼ not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD. Ó 2013 American Society for Blood and Marrow Transplantation. INTRODUCTION A substantial number of patients with acute myeloid leukemia (AML) relapse after achieving first hematologic complete remission (CR1) [1]. Allogeneic hematopoietic stem cell transplantation (SCT) is a powerful tool to reduce the risk of leukemia relapse. SCT is currently recommended for AML patients in CR1 with poor-risk cytogenetics and should be considered for those with intermediate risk [2,3]. However, preparative regimen-related toxicities and graft-versus-host disease (GVHD) associated with SCT have limited its widespread use. GVHD can be effectively prevented by ex vivo T cell depletion of the donor graft without the morbidity associated with immunosuppressive drugs [4]. The early observation of immune-mediated graft rejection with the use of T celledepleted (TCD) grafts was overcome with antithymocyte globulin (ATG) at the expense of delayed immune reconstitution [5]. Financial disclosure: See Acknowledgments on page 902. * Correspondence and reprint requests: Esperanza B. Papadopoulos, M.D., Adult Bone Marrow Transplantation Unit, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY address: papadope@mskcc.org (E.B. Papadopoulos) /$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. Despite the use of TCD grafts for over 3 decades, studies comparing SCT with TCD versus SCT with unmodified grafts are scarce. In a retrospective study including 146 patients with diverse hematological malignancies transplanted between 1997 and 1999, survival, GVHD rates, and quality of life were found to be similar between patients who received TCD and those who received unmodified grafts [6]. In a multi-center, randomized phase 2/3 trial, although acute GVHD incidence was found to be lower after SCT with TCD grafts, there was no difference in survival [7]. However, in both studies, T cell depletion was accomplished by a physical method or by treatment of the graft with antibodies achieving only 1 to 2 logs of depletion compared with 3 to 5 logs of depletion that is achieved with the currently available magnetic selection methods [8]. To compare the efficacy of both approaches in a more homogenous patient population and with current day practices and technology, we retrospectively evaluated the outcomes of patients with AML, who underwent SCT with either TCD grafts at Memorial-Sloan Kettering Cancer Center (MSKCC) or unmodified grafts at the University of Texas M.D. Anderson Cancer Center (MDACC), while in CR1.

2 U.D. Bayraktar et al. / Biol Blood Marrow Transplant 19 (2013) 898e PATIENTS AND METHODS After approval by MSKCC and MDACC respective institutional review boards, AML patients older than 18 years, who underwent SCT between 2001 and 2010 with ablative preparative regimens while in CR1, were identified through the institutional bone marrow transplantation (BMT) registries. At MDACC, only those who received fludarabine-busulfan conditioning were included in the study to preserve the homogeneity of the cohort. At MSKCC, all consecutively transplanted patients with AML CR1 over this time period were included in the analysis. Demographics, disease characteristics, treatment, GVHD, and survival data were retrieved from departmental databases at the respective institutions. Complete remission was defined as 5% blasts in bone marrow, absence of blasts in peripheral blood, platelet count 100 K/mL, and absolute neutrophil count 1000/mL. Cytogenetic risk stratification considered complex cytogenetics, -5, -5q, -7, -7q, 11q23 aberrations, inv(3), t(3;3), t(6;9), t(9;22) as poor risk; and t(8;21), t(16;16), inv(16), t(15;17) as good risk [9]. Donorerecipient human leukocyte antigen (HLA) matching was established by DNA sequence-specific oligonucleotide typing for HLA-A, -B, -Cw, -DQB1, and -DRB1 loci, in both institutions. Patients at MSKCC received TCD grafts (TCD graft group, N ¼ 115) after conditioning with 1 of the following preparative regimens as previously reported [10-12]: (1) hyperfractionated total body irradiation (HFTBI) 1375 centigray (cgy) over 4 days followed by thiotepa 5 mg/kg/day i.v. for 2 days and fludarabine 25 mg/m 2 /day i.v. for 5 days beginning on the first day of thiotepa (n ¼ 29); (2) HFTBI 1375 cgy over 4 days followed by thiotepa 5 mg/kg/day and cyclophosphamide 60 mg/kg/day i.v. for 2 days (n ¼ 25); or (3) busulfan.8 mg/kg i.v. every 6 hours for 10 doses (n ¼ 42) or 12 doses (n ¼ 19), with doses of busulfan adjusted according to pharmacokinetics, melphalan 70 mg/m 2 /day i.v. for 2 days, and fludarabine 25 mg/m 2 /day i.v. for 5 days (total n ¼ 61). Six patients in the HFTBIþthiotepaþcyclophosphamide group were also enrolled on BMT CTN 0303 [13]. Patients >60 years of age and those patients with therapy related or secondary AML received the regimen without total body irradiation. Peripheral blood grafts underwent CD34 þ cell selection using the ISOLEX 300i magnetic cell selection system (Baxter, Deerfield, IL), followed by sheep red blood cellerosette depletion (n ¼ 85); or CD34 þ cell selection using the CliniMACS cell selection system (Miltenyi Biotech, Gladbach, Germany) alone (n ¼ 22). Bone marrow (BM) grafts were used upon donor preference and were depleted of T cells by sequential soybean lectin agglutination and sheep red blood cellerosette depletion (n ¼ 8). All patients received equine (total 60 mg/kg) or rabbit (2.5 mg/kg to 5 mg/kg) ATG to prevent graft rejection, except for those patients receiving a transplant from an HLAmatched related donor and conditioned with HFTBIþthiotepaþfludarabine [10]. No GVHD prophylaxis was administered post-transplantation. Patients at MDACC received unmodified grafts (unmodified graft group, N ¼ 181) after an ablative, reduced-toxicity preparative regimen consisting of fludarabine 40 mg/m 2 /day over 1 hour and busulfan 130 mg/m 2 /day i.v. over 3 hours for 4 days (days -6 to -3) [14]. Patients with unrelated or HLA-mismatched donors received equine (total 60 mg/kg) or rabbit (total 2.5 mg/kg to 5 mg/kg) ATG. Tacrolimus and mini-methotrexate (5 mg i.v. on days 1, 3, 6, and 11) were used for GVHD prophylaxis. Fifteen patients also received pentostatin under an investigational protocol on days 8, 15, 22, and 30 at 1 mg/m 2 or 1.5 mg/m 2. Patients were managed clinically according to MSKCC and MDACC standard guidelines including infection prophylaxis for Pneumocystis carinii, herpes viruses, and fungus. Patients received no cytomegalovirus (CMV)- specific prophylaxis and were regularly monitored for CMV reactivation by CMV pp65 antigenemia assay of peripheral blood in both institutions. Preemptive therapy was instituted in patients with documented CMV viremia. Patients in the TCD cohort were also monitored regularly for Epstein-Barr virus reactivation in the peripheral blood by polymerase chain reaction, per institutional guidelines. Patients received granulocyte colonystimulating factor beginning at day þ7 after transplantation. GVHD was diagnosed clinically, confirmed pathologically whenever possible, and classified according to standard criteria [15]. GVHD diagnosed after day 100 post-transplantation was classified as chronic GVHD. Only patients who engrafted were evaluable for GVHD assessment. Data were updated as of July Patients characteristics were compared between the TCD and unmodified graft groups using the chi-square test and Wilcoxon s rank sum test. Overall survival (OS) and relapse-free survival (RFS) were defined as the time from SCT until death from any cause, and disease relapse or death, respectively. Non relapse mortality (NRM) was defined as death in a patient without leukemia relapse. Univariate probabilities of OS and RFS were estimated using the Kaplan-Meier method with 95% confidence intervals (95% CI) calculated using log transformed intervals. Predictors of OS and RFS by 3 years post-transplantation were assessed in univariate and multivariate analyses using Cox s proportional hazards regression analysis. The proportionality of the hazards assumption was tested on the basis of Schoenfeld Table 1 Comparison of Demographic and Clinical Characteristics of Patients Who Underwent Transplantation with T CelleDepleted (TCD) or Unmodified Grafts Characteristics TCD N ¼ 115, n (%) Unmodified P Value N ¼ 181, n (%) Age, yr* 52 (19-71) 48 (18-63) <.001 >50 66 (57) 76 (42).010 Female 58 (50) 90 (50) NS Time CR1 to transplantation, d* 83 (12-304) 97 (8-455).040 Etiology <.001 de novo 60 (52) 144 (80) Secondary 38 (33) 24 (13) Therapy-related 17 (15) 13 (7) Cytogenetic risk status NS Good 1 (1) 2 (1) Intermediate 72 (63) 103 (57) Poor 42 (37) 76 (42) Donor type <.001 Matched related 56 (49) 103 (57) Matched unrelated 32 (28) 64 (35) Mismatch 27 (23) 14 (8) Donor/recipient gender NS Match 54 (47) 89 (49) Mismatch 61 (53) 92 (51) Stem cell source <.001 Bone marrow 8 (7) 57 (32) Peripheral blood 107 (93) 124 (68) CR1 indicates first complete remission; NS, not significant. * Data presented as median (range). residuals and was found to be met when assessed overall and by 3 years post-transplantation. Predictors considered included type of graft (TCD versus unmodified), age (older than 50 years), donor/recipient gender (female to male versus all other), leukemia etiology (primary, secondary, therapy-related), cytogenetic risk group, donor type (HLA-matched related versus HLA-matched unrelated, or HLA-mismatched), and stem cell source (bone marrow versus peripheral blood). Predictors significant on univariate analysis were evaluated in multivariate analysis. Potential interaction effects by graft type were assessed by stratified analysis, and were tested statistically using firstdegree interaction-effect terms in Cox s regression analysis. When indicated, interaction effects were adjusted for in multivariate analysis. The cumulative incidence of NRM, leukemia relapse, and GVHD was estimated based on the cumulative incidence method to account for competing risks. Leukemia relapse, death in the absence of leukemia relapse, and relapse or death in the absence of GVHD were considered competing risks for NRM, leukemia relapse, and GVHD, respectively. Cox s regression analysis was used to compare the rate of NRM, disease relapse, and GVHD according to graft type in univariate analysis. Statistical significance was determined at the.05 level. Statistical analysis was performed using STATA RESULTS Patient demographic and clinical characteristics are summarized in Table 1. TCD graft recipients were significantly older, less likely to have de novo AML, and more likely to have HLA-mismatched donors. Peripheral blood was almost exclusively the graft source used in the TCD graft group. Time from achievement of CR1 to transplantation was longer in patients who received unmodified grafts. Overall Survival and Relapse-Free Survival As of July 2011, the median (range) follow-up among surviving patients was 32 months (.5 to 108 months) and 29 months (2 to 104 months) for the TCD and unmodified graft groups, respectively. Accordingly, outcomes in the TCD and unmodified groups were compared within 3 years posttransplantation. A total of 43 deaths (37%) and 18 relapses (16%) occurred in the TCD graft group, and a total of 54 deaths (30%) and 42 relapses (23%) occurred in the

3 900 U.D. Bayraktar et al. / Biol Blood Marrow Transplant 19 (2013) 898e903 Table 2 Comparison of Outcomes in the T CelleDepleted (TCD) and Unmodified Graft Groups Based on Univariate Analysis Using Cox s Proportional Hazards Regression Outcome TCD (95% CI) Unmodified (95% CI) P Value Relapse-free survival 1 yr 62% (51-70) 65% (57-72).6 3 yr 58% (47-67) 60% (51-67).7 Overall survival 1 yr 68% (58-76) 74% (66-80).3 3 yr 57% (47-67) 66% (58-74).2 Relapse incidence 1 yr 17% (11-26) 21% (15-28).4 3 yr 18% (12-27) 25% (19-33).3 Nonrelapse mortality 100 d 8% (4-15) 3% (1-7).07 1 yr 18% (12-27) 13% (9-19).2 3 yr 24% (17-34) 16% (11-23).1 Acute GVHD (grade 2-4) 100 d 5% (2-11) 18% (13-24).005 Chronic GVHD 3 yr 13% (8-22) 53% (46-62) <.001 GVHD indicates graft-versus-host disease. unmodified graft group, during the study period. Comparison of outcomes within 3 years (Table 2) showed no significant differences between TCD and unmodified graft recipients in regard to OS (57% versus 66%, P ¼.2, Figure 1), RFS (58% versus 60%, P ¼.7), or rate of relapse (18% versus 25%, P ¼.3). Table 3 Predictors of Overall Survival (OS) and Relapse-free Survival (RFS) Evaluated by Univariate Analyses Value RFS, HR at 3 years (95% CI) Age, yr 50 OS, HR at 3 years (95% CI) > (.7-1.4) 1.1 (.8-1.7) Gender Male Female 1.1 (.7-1.7) 1.1 (.7-1.5) Etiology de novo Secondary 1.4 (.9-2.2) 1.7 ( )* Therapy-related.9 (.4-1.7).9 (.4-2.0) Cytogenetic risk Good/intermediate Poor 1.1 (.7-1.6).9 (.6-1.4) Donor type Matched related Matched unrelated 1.1 (.8-1.7) 1.2 (.8-1.9) Mismatch 1.0 (.5-1.7) 1.2 (.7-2.2) Stem cell source Bone marrow Peripheral blood 1.4 (.8-2.5) 1.6 (.9-2.9) Graft type T celledepleted Unmodified.9 (.6-1.4).7 (.5-1.1) * P ¼.02. Nonrelapse Mortality The cumulative incidence of NRM at day 100, 1 year, and 3 years were 8%,18%, and 24% in the TCD graft group compared with 3%,13%, and 16% in the unmodified graft group. There was no significant difference in the rate of NRM between the TCD and unmodified groups (P ¼.1). Causes of death in the TCD graft group included relapsed leukemia (n ¼ 17, 40%), infection (n ¼ 11, 26%), GVHD (n ¼ 5, 12%), organ toxicities (n ¼ 5, 12%), graft failure (n ¼ 2, 4%), solid malignancies (n ¼ 2, 4%), and post-transplantation lymphoproliferative disease (n ¼ 1, 2%). In the unmodified graft group, causes of death included relapsed disease (n ¼ 27, 50%), infection (n ¼ 6, 11%), GVHD (n ¼ 12, 22%), organ toxicities (n ¼ 3, 6%), graft rejection/failure (n ¼ 4, 7%), and solid malignancies (n ¼ 1, 2%). Overall, there was no significant difference in the distribution of the causes of death between the TCD and unmodified groups. Within 100 days post-transplantation, 6 (5%) and 2 (1%) patients died of infections in the TCD and unmodified groups (P ¼.04), respectively. Graft-versus-Host Disease The rate of grade 2 to 4 acute GVHD occurring within 100 days post-transplantation was significantly lower in the TCD graft group compared with the unmodified graft group (5% versus 18%, P ¼.005). There was no significant difference in the rate of grade 3 to 4 acute GVHD between the 2 groups (1% versus 3%, P ¼.3). Within 3 years post-transplantation, 14 and 78 patients developed chronic GVHD, of which 5 and 55 were extensive, in the TCD and unmodified graft groups, respectively. The rate of chronic GVHD was lower in the TCD graft group (13% versus 53%, P <.001). Figure 1. Probabilities of overall (top) and relapse-free (bottom) survival among recipients of T celledepleted (TCD) and unmodified grafts. Prognostic Factors None of the prognostic factors evaluated (listed in methods section), including the type of graft, were significantly associated with OS or RFS, except for etiology of AML (Table 3). Compared with primary AML, secondary AML

4 U.D. Bayraktar et al. / Biol Blood Marrow Transplant 19 (2013) 898e was associated with significantly lower OS (hazard ratio [HR] ¼ 1.7, P ¼.02), but did not impact RFS (HR ¼ 1.4, P ¼.1). To determine if the factors evaluated had the same impact in the TCD and unmodified groups, we performed a stratified analysis evaluating the association between the prognostic factors and outcomes separately in these 2 groups. This stratified analysis showed that the impact of recipient gender on OS and RFS differed according to the type of graft. Female gender was associated with significantly lower OS (HR ¼ 2.2, P ¼.01) and RFS (HR ¼ 2.3, P ¼.01) in the TCD group, but not in the unmodified group (HR ¼.7, P ¼.2; HR ¼.6, P ¼.07). This association was independent of the donor s gender. All other factors considered had the comparable impact on OS and RFS in the TCD and unmodified groups. On multivariate analysis, secondary AML was significantly associated with lower OS (HR ¼ 1.7, P ¼.02), and female gender in the TCD group was significantly associated with lower OS (HR ¼ 1.9, P ¼.004) and RFS (HR ¼ 1.7, P ¼.01). There was no independent effect for graft type on OS or RFS in multivariate analysis. Subset Analysis Because the distribution of age >60 years, HLA compatibility, and AML etiology differed significantly between the TCD and unmodified groups, we compared outcomes by graft type in a relatively homogeneous group that included patients <60 years of age who received a graft from a 10/10 HLA compatible donor, and who did not have secondary AML. Results of this subset analysis were comparable with those obtained overall, showing no significant difference in OS (HR ¼.6, P ¼.1) or RFS (HR ¼.8, P ¼.4) in the TCD group (n ¼ 42) compared with the unmodified group (n ¼ 135). Comparable results were obtained when analysis was restricted to younger patients with primary AML and 10/10 compatible donors. DISCUSSION Ex vivo T cell depletion of the graft is the most effective method to prevent GVHD after SCT. However, approaches to T cell depletion have varied greatly in the levels of T cell depletion achieved, and most have also incorporated post-transplantation immunosuppression. As a consequence, the role of T cell depletion alone in transplantation for hematologic malignancies has not been well established and only a minority of centers in the United States use this procedure. However, significant changes have also occurred in T cell depletion technology with CD34 þ selection, including methods that provide a 1-2 log 10 greater T cell depletion replacing monoclonal or polyclonal antibodies directed against T cell epitopes [8,16]. Significant changes have also been made to traditional conditioning regimens primarily substituting fludarabine for cyclophosphamide and the introduction of intravenous busulfan [14,17,18]. Furthermore, advances in molecular diagnostic and supportive care have greatly reduced transplantation-related mortality due to viral infections. To compare the outcomes of TCD grafts using positive CD34 selection technology to calcineurin inhibitorebased GVHD prophylaxis when used with more tolerable conditioning regimens employing fludarabine and/or busulfan, we analyzed the clinical outcomes of 115 and 181 patients with AML who were transplanted while in CR1 with TCD and unmodified grafts at MSKCC and MDACC, respectively. Survival rates were similar, albeit with significantly lower incidence of acute and chronic GVHD in those who received TCD grafts. None of the TCD grafts were rejected with the use of ATG and ablative conditioning. Though T cell depletion has been associated with a higher risk of relapse in patients with chronic myeloid leukemia [19-22], this has not been the case for patients with acute leukemia. Soiffer and colleagues [23] reported their results using a monoclonal antibody for T cell depletion in patients with AML undergoing transplantation in first CR. The majority of these patients had adverse clinical features or poor-risk cytogenetics. The 4-year estimated incidence rates of relapse and event-free survival were 25% and 63%, respectively. Similarly, Wagner et al. [7] reported on results of a prospective randomized trial comparing T cell depletion to unmodified transplants in patients with hematologic malignancies undergoing unrelated donor transplantations. In this report, there was no statistical difference between the 2 cohorts with respect to the incidence of relapse for patients with AML, though there was a statistically lower incidence of grade 2 through 4 GVHD. Our own results again did not demonstrate an increased risk of relapse in the recipients of TCD grafts. However, the more intense preparative regimen used in the TCD group may have offset any reduction in graft-versus-leukemia effect. More recently, in the prospective Blood and Marrow Transplantation Clinical Trials Network (BMT-CTN) 0303 trial of TCD transplants in AML [13], the relapse incidence was reported as 17% at 3 years among those in CR1, similar to those reported in prospective trials of T cell replete transplants [24-26]. Furthermore, Pasquini et al. compared the outcomes of patients treated on the BMT-CTN 0303 TCD trial to similar patients who received unmodified grafts between 2003 and 2006 on BMT-CTN 0101 protocol. No significant differences in relapse incidence, NRM, or survival were observed between the 2 patient groups [27]. In our study cohort, both acute and chronic GVHD rates were lower in the recipients of TCD grafts compared with the recipients of unmodified grafts, despite the higher prevalence of mismatched donors in the former group. Ex vivo T cell depletion of the donor graft has been consistently associated with reduced GVHD and is considered the most effective method for prevention of GVHD [7,28,29]. However, the degree of T cell depletion and methods used may influence the incidence of GVHD [4,28,30-32]. With 1 to 2 logs of T cell depletion, Lee et al. reported no difference in GVHD rates between TCD and T cell replete transplants from unrelated donors. With the T cell depletion techniques utilized by the MSKCC group, 3 to 4 logs of T cell depletion were achieved resulting in the significantly lower incidence of both acute and chronic GVHD seen in this group. In our cohort, ex vivo T cell depletion was not associated with improved OS or RFS rates when compared with those for recipients of unmodified grafts, despite having lower rates of acute and chronic GVHD and similar relapse risk. OS in both groups were comparable to that previously reported in AML patients in CR1 [26,33]. Likewise, previous reports comparing TCD with unmodified grafts did not demonstrate any difference in survival [6,7], suggesting that advances in SCT affected both methods equally. Though there was a trend toward a higher NRM at day 100 in the TCD cohort, there were no differences between the 2 groups in 1-year and 3-year NRM. The early NRM in the TCD cohort was attributed to infectious deaths, most of which were in the early peritransplantation period and bacterial in nature. Therefore, they could not be attributed to delayed quantitative and functional recovery of T cells [5,34-37]. However, the

5 902 U.D. Bayraktar et al. / Biol Blood Marrow Transplant 19 (2013) 898e903 difference in intensities of the TCD cytoreductive regimens compared with the MDACC busulfan and fludarabine regimen could potentially explain the trend toward a higher early NRM in the TCD group. Relapse was the most important cause of treatment failure in both groups, and strategies aimed at preventing post-transplantation relapse will be essential to improve transplantation outcomes regardless of graft source. Moving forward, the ability to deliver post-transplantation therapies will need to be carefully assessed when comparing TCD with other GVHD-prevention strategies. Our study has several limitations, with the retrospective nature of data collection being the foremost. This has led to significantly different patient/donor characteristics between the 2 groups. Second, some of the patients were treated under investigational trials that may have led to selection bias. Moreover, comparing transplant procedures between the 2 different centers may have introduced confounding variables for which we may have not accounted (ie, patient selection and differences in supportive therapy). It appears from this retrospective study that survival is similar between patients receiving TCD transplants and those receiving conventional transplants, with a reduced GVHD rate after the former. Our results support the need for a randomized prospective trial comparing TCD with unmodified grafts in homogeneous populations. ACKNOWLEDGMENTS Financial disclosure: The authors have nothing to disclose. Part of this study was presented at 2011 ASH Annual Meeting on December 10, This work was supported in part by PO1 CA23766 from the National Cancer Institute and the Major Family Fund for Cancer Research. MDACC authors had no acknowledgements. Conflict of interest statement: There are no conflicts of interest to report. REFERENCES 1. Lowenberg B, Downing JR, Burnett A. 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