Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;

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1 Mobilized Peripheral Blood Stem Cells Compared with Bone Marrow as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced-Intensity Conditioning in Patients with Acute Myeloid Leukemia in Complete Remission: An Analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation Arnon Nagler, 1 Myriam Labopin, 2 Avichai Shimoni, 1 Dietger Niederwieser, 3 Ghulam J. Mufti, 4 Axel R. Zander, 5 Renate Arnold, 6 Hildegard Greinix, 7 Jan J. Cornelissen, 8 Graham H. Jackson, 9 Charles Craddock, 10 Donald W. Bunjes, 11 Arnold Ganser, 12 Nigel H. Russell, 13 Slawomira Kyrcz-Krzemien, 14 Vanderson Rocha, 15, * Mohamad Mohty 16, * Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient s age was higher in the PBSC versus BM groups 57 (range, years) and 51 (range, years), respectively (P \.0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (agvhd) grade.ii was significantly higher in the PBSC group: 27% versus 12% in the BM group (P \.002). Similarly, chronic graft-versus-host disease (cgvhd; at 2 years) was somewhat higher in the PBSC group with 43% 6 3% versus 35% 6 6% in the BM group, respectively (P 5.04). The 2-year probabilities of leukemia-free survival (LFS) were 46% 6 3% for the PBSC group in comparison to 43% 6 6% for the BM transplant group (P 5 NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% 6 6% versus 32% 6 3%, respectively (P 5.014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% 6 2% From the 1 Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 2 Hospital Saint-Antoine, and EBMT ALWP Office Universite Pierre et Marie Curie Paris 6, Paris, France; 3 Department of Hematology/Oncology and Hemostasiology, University of Leipzig, Leipzig, Germany; 4 Department of Haematological Medicine, King s College London, London, United Kingdom; 5 Stem Cell Transplantation, University Medical Center Hamburg, Hamburg, Germany; 6 Department of Hematology and Oncology, Charite - University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany; 7 Internal Medicine I, Bone Marrow Transplantation, Medical University of Vienna, Vienna, Austria; 8 Department of Hematology, Erasmus Medical Center/Daniel den Hoed, Rotterdam, the Netherlands; 9 Department of Haematology, University of Newcastle-Upon- Tyne, R.V.I., Queen Victoria Road, Newcastle-Upon-Tyne, United Kingdom; 10 Haematology, University Hospital Birmingham, Birmingham, United Kingdom; 11 Universitatsklinikum Ulm, Ulm, Germany; 12 Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 13 Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, United Kingdom; 14 Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland; 15 Bone Marrow Transplantation Unit, Hospital Saint Louis APHP, EBMT ALWP and University of Paris VII, Paris, France; and 16 Hematology Department, CHU de Nantes, Nantes, France. Financial disclosure: See Acknowledgment on page * Vanderson Rocha and Mohamad Mohty share senior authorship. Correspondence and reprint requests: Arnon Nagler, MD, MSc, Hematology Division and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel ( a.nagler@sheba.health.gov.il). Received October 25, 2011; accepted February 26, 2012 Ó 2012 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt

2 Biol Blood Marrow Transplant 18: , 2012 PB versus BM in RIC-alloSCT 1423 versus 13% 6 4%, respectively (P 5.004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of agvhd (grade II-IV; hazard ratio [HR] ; P 5.06), higher NRM (HR 5 2.3; P 5.015), and a decreased relapse incidence (HR, 0.61; P 5.02) with no statistical difference of LFS between the 2 groups (P 5.88). In conclusion, our results indicate significantly higher incidence of agvhd and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT. Biol Blood Marrow Transplant 18: (2012) Ó 2012 American Society for Blood and Marrow Transplantation KEY WORDS: Acute myelogenous leukemia, Allogeneic stem cell transplant, Reduced-intensity conditioning, Stem cell mobilization, Remission INTRODUCTION Allogeneic hematopoietic stem cell transplant (allosct) is a potentially curative treatment for advanced or high-risk acute myeloid leukemia (AML) [1]. However, myeloablative conditioning may be associated with unacceptably increased toxicity in elderly, medically unfit, or heavily pretreated patients. The introduction of allosct with reduced-intensity conditioning (RIC) allowed extension of allosct to a much wider patient population by reducing the toxicity and exploiting the graft-versus-lymphoma (GVL) effect as the primary curative approach [2-5]. As engraftment post-allosct has been shown to correlate with dose intensity, the engraftment post-ric is mainly based on strong, but transient immunosuppression and high cell dose [6-9]. Indeed, most of the RIC alloscts are performed with mobilized peripheral blood stem cell (PBSC) grafts rather than bone marrow (BM) grafts [10], as PBSCs have been demonstrated to contain significantly higher numbers of CD341 hematopoietic stem cells compared with BM grafts [11-15]. However, the stem cell source and type of graft may have different implications on transplantation outcome in the RIC setting compared to the myeloablative setting. In the myeloablative setting with BM grafts, the infusion of high doses of progenitor cells has a favorable impact on transplantation outcome, due to faster hematopoietic and immune recovery [16]. In contrast, when using granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs in the context of myeloablative allosct, the infusion of a high number of CD341 cells increased the incidence of extensive chronic graft-versus-host disease (cgvhd), which adversely affected outcome due to higher transplantrelated mortality (TRM) [17-19]. In contrast to the availability of extensive literature comparing mobilized PBSC grafts to BM grafts in sibling myeloablative allosct [13,17-22], data in the unrelated setting is still sparse [23]. In the study by Eapen et al. [24], the authors compared the outcome after 331 PBSC and 586 transplants in adults with leukemia and myelodysplastic syndrome. Rates of acute graft-versus-host disease (agvhd) and cgvhd were significantly higher with PBSC than with BM transplants [13,17-22], whereas TRM, relapse, leukemia-free survival (LFS), and overall survival were similar [23]. Similar results were also observed recently in another analysis from the Center for International Blood and Marrow Transplant Research that compared the effect of graft source in unrelated donor (URD) hematopoietic stem cell transplant in adults with acute leukemia [24]. In both analyses, patients were conditioned with myeloablative preparative regimens [23,24]. With this background, and given the increased usage of both URDs and RIC allosct in patients with acute leukemia [25,26], this report aimed to compare outcomes of PBSC versus BM in the setting of RIC allosct in patients with AML in remission undergoing allosct from matched unrelated donors (MUDs). PATIENTS AND METHODS Study Design and Data Collection This was a retrospective multicenter analysis. Data of adult patients with AML receiving RIC allosct using PBSC or BM from an MUD were provided by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) group. The EBMT registry is a voluntary working group of more than 500 transplantation centers, participants of which are required once a year to report all consecutive stem cell transplants and follow-up. The Acute Leukemia Working Party of the EBMT group approved this study. Selection Criteria The study included patients with AML receiving first RIC allosct in complete remission (CR) from an MUD using PBSCs or BM, who: (1) were age $16 years at time of transplantation; (2) were transplanted between the years 2000 and 2007; (3) had received an RIC regimen defined as the use of fludarabine associated with low-dose total body irradiation (TBI; #6 Gy) or busulfan (total dose #8 mg/kg) or other immunosuppressive or cytotoxic drugs such as melphalan or cyclophosphamide as defined by the

3 1424 A. Nagler et al. Biol Blood Marrow Transplant 18: , 2012 EBMT criteria [27,28]; and (4) were patients whose clinical data on outcomes were adequate. A total of 602 allosct recipients from 123 transplantation centers met these eligibility criteria. Exclusion criteria were: previous allogeneic transplant, cord blood transplant, and myeloablative conditioning allosct. URDs were selected on the basis of serological typing at class I (HLA-A and HLA-B) and molecular typing of class II (DRB1) alleles. An MUD was defined as the absence of an antigenic mismatch at class I or a molecular mismatch at class II. Statistical Analysis and Study Endpoints The primary endpoint was LFS. Secondary endpoints were non-relapse mortality (NRM), engraftment, agvhd, cgvhd, and relapse incidence (RI). Patient, disease, and transplant-related variables of both groups were compared, using the chi-square statistic for categorical and the Mann-Whitney test for continuous variables. Characteristics considered were recipient age at transplantation, recipient and donor sex, recipient and donor cytomegalovirus (CMV) status, disease features (WBC at diagnosis, AML French, American, British [FAB] subtype, cytogenetics, disease stage at transplantation), and allosct characteristics (year of transplantation, interval between diagnosis and transplantation, conditioning regimen). LFS was defined as survival without evidence of relapse or progression. Relapse was defined as any event related to the reoccurrence of the disease. NRM was defined as death from any cause without previous relapse or progression. The agvhd and cgvhd were graded and staged by standard criteria. Cumulative incidence curves were used for RI and NRM in a competing risk setting [29]. For estimation of cgvhd, death was considered as a competing event. Probabilities of LFS were calculated using the Kaplan-Meier method, and the log-rank test was used for univariate comparisons. For all prognostic analyses, the median value of continuous variables was used as a cutoff point. All factors differing between the 2 groups with a P value less than.15 were included in the final model. Associations of patient and graft characteristics with outcomes were evaluated in multivariate analyses using Cox proportional hazards. All tests are 2-sided. The type I error rate was fixed at 0.05 for determination of factors associated with time-to-event outcomes. Statistical analyses were performed with the SPSS (IBM Inc., Chicago, IL) and Splus (MathSoft, Inc., Seattle, WA) software packages. RESULTS Patient Characteristics Six hundred two patients with AML were included in this analysis. Five hundred eight patients underwent transplantation with G-CSF-mobilized PBSCs grafts and 94 with BM grafts. This BM/ PBSC ratio reflects the current practice in favor of PBSCs in this population of patients. The median age of the PBSC group was 57 years (range, years) and of the BM group 51 years (range, years), respectively (P \.0001; Table 1). Fifty-five percent of the PBSC group were men and 45% were women, whereas in the BM group, it was 69% and 31%, respectively (P 5.72). Patients in the PBSC group underwent transplantation in 2006 (range, ), whereas patients in the BM group underwent transplantation in 2005 ( ), respectively (P \.001; Table 1). Median follow-up of the whole study group was 17 months (range, months). All patients were in CR at allosct, per study inclusion criteria. In the PBSC group, 61% of the patients were in first complete remission (CR1) and 39% in second complete remission (CR2), respectively, whereas in the BM group, 60% of the patients were in CR1 and 40% at CR2, respectively (P 5.79). Disease characteristics also did not differ between the 2 study groups. As outlined in Table 1, WBC at diagnosis and FAB classification were not statistically significantly different between the PBSC and BM groups. Similarly, cytogenetic scores (ie, good, intermediate, and poor risk groups) did not differ between the 2 groups (P 5.79; Table 2). Median time from diagnosis to allosct was longer in BM allosct in comparison to the PBSC transplants: 324 and 325 days versus 253 days, respectively (P \.015 in Table 2). Both groups were comparable for CMV status of patients and donors, donor characteristics, and gender (Table 2). The RIC protocols included fludarabine and melphalan in 39% of the transplantations, or fludarabine and busulfan in 54% of the transplantations in both groups (Table 2; P 5 NS). However, more patients received low-dose TBI in the PBSC group (36%) as compared to only 5% in the BM group (P ; Table 2). The details of the GVHD prophylaxis regimen were available for 377 patients (62 BM and 315 PBSC). Association of cyclosporine A and mycophenolate mofetil was used in 146 patients who received PBSCs, but in only 8 patients who received BM (P \.0001). Thus, it was not possible to adjust the comparison on this variable. Engraftment Ninety-seven percent and 96% of patients in the BM and peripheral blood (PB) groups engrafted, respectively. Twenty patients (4%) in the PBSC group and 2 patients (3%) in the BM group did not engraft (P 5 NS). Only 1 patient from each group had a late loss of the graft (Table 3).

4 Biol Blood Marrow Transplant 18: , 2012 PB versus BM in RIC-alloSCT 1425 Table 1. Patient and Disease Characteristics Patient Characteristics PBSC BM P Value Number of patients Median age in years (range) 57 (17-77) 51 (17-76) <.0001 Gender M: 281 (55.4%) M: 63 (69.2%).72 F: 226 (44.6%) F: 28 (30.8%) CMV status Neg (33.9%) Neg 5 19 (29.7%).51 Pos (66.1%) Pos 5 45 (70.3%) Transplantation year 2006 ( ) 2005 ( ).001 Disease status* CR (61%) CR (60%).79 CR (39%) CR (40%) WBC (10 9 /L) median (range) 10.0 ( ) 10.9 ( ).79 FAB classification M1 M2-M % M1 M2-M %.33 M4-M % M4-M % M0 M6 M % M0 M6 M7 5 10% PBSC indicates peripheral blood stem cells; BM, bone marrow; CMV, cytomegalovirus; CR1, first complete remission; CR2, second complete remission; Neg, negative; Pos, positive; FAB, French, American, British. *At transplantation. At diagnosis. NRM NRM at 2 years was significantly higher in patients with AML who underwent transplantation with PBSC grafts (cumulative incidence, 28% 6 2%) in comparison with those transplanted with BM grafts (13% 6 4%; P Gray test 5.004; P Cox 5.015; Figure 1). Other parameters including age (above or below 55 years), disease status (CR2 versus CR1), conditioning regimen (yes or no low dose TBI), year of allosct, and interval from diagnosis to allosct (longer or shorter than 262 days) were not found as independent predictive factors for NRM in multivariable analysis (Table 4). Table 2. Disease and Transplant Characteristics Patients Characteristics PBSC BM P Value Number of patients Cytogenetic classification.79 Good risk 16 (7.7%) 4 (8.5%) Intermediate risk 148 (70.8%) 35 (74.5%) Poor risk 45 (21.5%) 8 (17%) Donor characteristics Gender M: 358 (72%) M: 63 (69.2%).59 F: 139 (28%) F: 28 (30.8%) Female donor to male recipient 53 (10.7%) 10 (11%).93 CMV status Neg (56.9%) Neg 5 33 (52.4%).51 Pos (43.1%) Pos 5 30 (47.6%) Conditioning No TBI 324 (64.4%) 87 (94.6%).0001 With TBI 179 (35.6%) 5 (5.4%) If chemotherapy alone: Flu + Melfalan 37% 39% Flu + Busulfan 51% 55% Cy + other 12% 6%.22 Median time from diagnosis to transplantation (days) <.015 PBSC indicates peripheral blood stem cells; BM, bone marrow; CMV, cytomegalovirus; Neg, negative; Pos, positive; TBI, total body irradiation; Flu, fludarabine; Cy, cyclophosphamide. Relapse Rate Relapse rate was significantly higher (46% 6 6%) in patients who underwent transplantation with BM grafts as compared with those who underwent transplantation with PBSC grafts (32% 6 3%), respectively (P Gray test 5.014; P Cox 5.019; Figure 2). Other parameters including age (above or below 55 years; P 5.053), disease status (CR2 versus CR1), conditioning regimen (yes or no low dose TBI), year of allosct, and interval from diagnosis to allosct (longer or shorter than 262 days) were not found as independent predictive factors for relapse rate in multivariable analysis (Table 4). GVHD Incidence of agvhd was significantly higher in patients with AML who underwent transplantation from mobilized PBSC grafts in comparison with those who underwent transplantation with BM grafts (Table 3). Because BM recipients were younger, the comparison between the PBSC and BM groups was adjusted for recipient age. The frequency of grades II to IV agvhd was significantly lower in patients who underwent transplantation Table 3. Transplantation Outcome Patients Characteristics PBSC BM P Value Number of patients Engraftment 473 (96%) 89 (97%) NS No engraftment 20 (4%) 2 (3%) Lost graft 1 (0.1%) 1 (0.02%) agvhd Grades II-IV 131 (27.1%) 11 (12.1%).002 Grades III-IV 44 (9.1%) 2 (2.2%).03 cgvhd, 2 years 43% ± 3% 35% ± 6%.04 Median follow-up in months (range) 16 (1-94) 24 (1-104).07 PBSC indicates peripheral blood stem cells; BM, bone marrow; NS, not significant; agvhd, acute graft-versus-host disease; cgvhd, chronic graft-versus-host disease.

5 1426 A. Nagler et al. Biol Blood Marrow Transplant 18: , 2012 RIC in MUD SCT for AML in remission: NRM RIC in MUD SCT for AML in remission: chronic GVHD P Gray=0.004 Cox : ± 2% PB n= ± 4% BM n= P Gray= days 43 ± 3% PB n=508 BM n=94 35 ± 6% 730 years Figure 1. Probability of 2-year non-relapse mortality (NRM) after reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allosct) with mobilized peripheral blood stem cell graft (PBSC; n 5 508) versus bone marrow (BM) graft (n 5 94; P Gray test 5.004; P Cox 5.015). with BM grafts (12%) as compared with 27% in those who underwent transplantation from mobilized PBSC grafts (P 5.002; Table 3). Furthermore, severe agvhd grades III to IV was significantly higher in PBSC allosct versus BM allosct: 9.1% versus 2.2%, respectively (Table 3; P 5.03). No patient in the BM group had grade IV agvhd in comparison with 17 patients (3%) in the PBSC group, respectively. Similarly, the incidence of cgvhd was significantly higher in the PBSC group (43% 6 3%) as compared with the BM group (35% 6 6%; P 5.04; Figure 3). Transplantation Outcome LFS rates at 2 years were similar between both groups: 46% 6 3% in patients who underwent transplantation from mobilized PBSC grafts versus 43% 6 6% in patients who underwent transplantation Figure 3. Probability of chronic graft-versus-host disease (cgvhd) at 2 years after reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allosct) with mobilized peripheral blood stem cell (PBSC) graft (n 5 508) versus bone marrow (BM) graft (n 5 94; P Gray 5.04). from BM grafts (Figure 4; P log-rank 5.70; P Cox 5.88). In multivariable analysis, the type of graft (PBSC versus BM), disease status (CR2 versus CR1), conditioning regimen (with or without low-dose TBI), year of transplantation (after or before 2005), and time from diagnosis to allosct (longer or shorter than 262 days) were not found as predictive factors for LFS. However, age (above or below 55 years) reached statistical significance (P 5.02) (Table 4). DISCUSSION In the current study, we have compared G-CSFmobilized PBSC and BM as a graft source for unrelated allosct post-ric preparative regimens for patients with AML in remission. Our data indicates that PBSC grafts are associated with higher incidence of both agvhd and cgvhd and NRM, but with a lower incidence of relapse, with LFS being comparable between the PBSC and BM groups. Unfortunately, RIC in MUD SCT for AML in remission: Relapse P Gray=0.014 Cox : ± 6% BM n=94 32 ± 3% PB n= years Figure 2. Probability of relapse after reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allosct) with mobilized peripheral blood stem cell graft (PBSC; n 5 508) versus bone marrow (BM) graft (n 5 94; P Gray 5.014; P Cox 5.019). Figure 4. Probability of leukemia-free-survival (LFS) at 2 years after reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allosct) with mobilized peripheral blood stem cell (PBSC) graft (n 5 508) versus bone marrow (BM) graft (n 5 94; P log-rank 5.70; P Cox 5.88).

6 Biol Blood Marrow Transplant 18: , 2012 PB versus BM in RIC-alloSCT 1427 Table 4. Multivariable Analysis NRM P Value HR 95% CI PBSC versus BM Age >55 years CR2 versus CR TBI versus no Year $ Diag to tx >262 days RI PBSC versus BM Age >55 years CR2 versus CR TBI versus no Year $ Diag to tx >262 days cgvhd PBSC versus BM Age >55 years CR2 versus CR TBI versus no Year $ Diag to tx >262 days LFS PBSC versus BM Age >55 years CR2 versus CR TBI versus no Year $ Diag to tx >262 days NRM indicates non-relapse mortality; PBSC, peripheral blood stem cells; BM, bone marrow; CR2, second complete remission; CR1, first complete remission; TBI, total body irradiation; RI, relapse incidence; Diag to tx, time from diagnosis to transplantation; cgvhd, chronic graft-versus-host disease; LFS, leukemia-free survival; HR, hazard ratio; CI, confidence interval; Inf, inferior limit of 95% Confidence Interval; Sup, superior limit of 95% CI. Inf Sup this study was not able to assess the impact of stem cell source according to disease status at transplantation, given the relatively small number of BM recipients. Also, other weaknesses of this study were the lack of full cytogenetic data and the diversity of the so-called RIC regimens. Previous studies comparing PBSC to BM in allo- SCT differ from the current study in several aspects: (1) the donors were mostly HLA matched siblings; (2) the conditioning was a standard myeloablative one; (3) patients with various hematological malignancies were usually included; and (4) disease status was heterogeneous, including patients in remission as well as patients with active disease [13,17-22,30]. Except for 2 studies [21,31], in most of these comparisons on sibling donor allosct after myeloablative conditioning, incidence of either agvhd [21] or cgvhd [18,22,32,33] or both [17,19,29,34] was higher posttransplantation from PBSC grafts as compared with BM grafts. In this respect, our study in the RIC setting and with URDs suggested a higher incidence of GVHD ($grade II 27%; severe grade III-IV 8.7%; and chronic %) post-pbsc transplantation as compared with 12%, 2%, and 35% 6 6%, respectively, post-bm transplantation. Interestingly, GVHD incidence in our cohort was not different from the incidence published in previous studies comparing PBSC to BM in the sibling setting reporting, in general, an incidence of 30% to 40% for grade II to IV agvhd, 14% to 20% for grade III to IV agvhd, and 30% to 50% for cgvhd in PBSC transplants versus 25% to 30%, 5% to 15%, and 15% to 30%, respectively, for BM transplants [17,19,30,32,34,35]. Such similarities with the sibling myeloablative setting is of high interest and may indicate the improvement in unrelated transplantations on one hand [30,36], but also the fact that incidence of GVHD may be reduced in RIC versus myeloablative allosct [37,38] and that GVHD incidence is lower in patients with remission as compared with patients in relapse [37]. As for NRM, we observed a significantly lower incidence of NRM with BM (13% 6 4%) as compared to 28% 6 2% with PBSC. The lower incidence of NRM with BM grafts is likely related to the lower incidence of agvhd and cgvhd. Indeed, similar results were observed in other comparisons in the sibling myeloablative setting. Champlin et al. [20] reported an incidence of 18% versus 28% with BM versus PBSC grafts, respectively, for 1 year NRM. Similar results were also reported by Couban et al. [34] and Nagafugi et al. [29], who observed a trend for lower NRM with BM grafts. In contrast, Ringden et al. [18], Schmitz et al. [22], and the Stem Cell Trialists Collaborative Group [19], as well as the Spanish cooperative group [33], found no difference in NRM between transplantations with PBSC versus BM grafts. The difference between the various comparisons in the myeloablative sibling setting may be due to differences in disease categories, disease status (remission versus active disease), and conditioning regimens (with or without TBI). The relatively low 2-year TRM in our comparison, especially with BM grafts, confirms the potential benefit of RIC conditioning regimens that have resulted in a significant reduction of NRM in most, if not all, studies reporting allosct with RIC [2-6,36,39]. Interestingly, in multivariable analysis, no other transplant variable was found to be predictive of NRM. As for relapse, we observed a lower relapse rate with PBSC grafts as compared with BM grafts, which is suggestive of a stronger graft-versus-leukemia (GVL) effect with PBSC grafts that are known to contain about 20- to 25-fold more cytotoxic T cells and natural killer cells compared with BM grafts [11,12]. This, most probably, is also the reason for the higher incidence of GVHD, and especially cgvhd, observed with PBSC grafts, especially those with a higher number of CD341 cells [17,19,30,34,37]. As for the relapse rate post-pbsc versus BM in myeloablative transplants from HLA matched donors, conflicting results were reported previously. Couban et al. [34] and others [22,40-43] reported a lower relapse rate with

7 1428 A. Nagler et al. Biol Blood Marrow Transplant 18: , 2012 PBSC, whereas others did not find differences between the 2 groups [18,20,21,30,34]. Such discrepancies might again be related to the type of malignancy and disease status at transplantation [19,21,31,44]. Also, the observed correlation between decreased relapse and higher incidence of cgvhd in the RIC setting supports a close correlation between cgvhd and the GVL effect after RIC allosct, as described previously [37,45,46]. Most important, in multivariable analysis, the graft source (ie, PBSC versus BM) was the only significant factor predictive for relapse. Comparison between PBSC and BM in the URD transplant setting was previously reported in 2 studies performed by the Center for International Blood and Marrow Transplant Research [23,24] in adults with acute (AML and ALL) and chronic leukemia, as well as myelodysplastic syndrome, in remission or relapse who received myeloablative conditioning, and in another pediatric small study including mainly acute leukemias after myeloablative conditioning [47]. In the latter studies [23,24,47], the main differences found between BM and PBSC groups (aside from kinetics of engraftment), was the incidence of agvhd and cgvhd. As for the RIC setting, there is only 1 previously published comparison of PBSC versus BM grafts conducted in patients with myeloma who received allosct from sibling donors [48]. The authors observed a reduced incidence of cgvhd in BM versus PBSC transplants but NRM, relapse rate, and progression-free survival were not different between the groups. In conclusion, despite its retrospective nature, the current study comparing PBSC and BM grafts in a homogeneous group of patients with AML in remission receiving an RIC allosct from an MUD suggests similar final survival in the results; only LFS has shown outcomes between PBSC and BM. Whether PBSC should be the preferred stem cell source in patients with advanced disease needs to be further investigated. Randomized studies comparing G-CSF-mobilized PBSC versus BM grafts for patients with AML in remission undergoing RIC allosct are indicated. ACKNOWLEDGMENT Financial disclosure: The authors have nothing to disclose. REFERENCES 1. Gale RP, Champlin RE. How does bone-marrow transplantation cure leukaemia? Lancet. 1984;2: Slavin S, Nagler A, Naparstek E, et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. 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