RESEARCH ARTICLE. Introduction Wiley Periodicals, Inc.

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1 Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older AJH Takaaki Konuma, 1 * Nobuhiro Tsukada, 2 Junya Kanda, 3 Naoyuki Uchida, 4 Yuju Ohno, 5 Shigesaburo Miyakoshi, 6 Heiwa Kanamori, 7 Michihiro Hidaka, 8 Toru Sakura, 9 Makoto Onizuka, 10 Naoki Kobayashi, 11 Masashi Sawa, 12 Tetsuya Eto, 13 Yoshiko Matsuhashi, 14 Koji Kato, 15 Tatsuo Ichinohe, 16 Yoshiko Atsuta, 17,18 Koichi Miyamura, 19 and Donor/Source Working Group of the Japan Society for Hematopoietic Cell Transplantation Older recipient and donor age were associated with higher incidences of severe graft-versus-host disease (GVHD) and mortality after allogeneic hematopoietic stem cell transplantation from matched sibling donors (MSDs) and matched unrelated donors. Since a lower incidence of severe GVHD is advantageous in unrelated cord blood transplantation (CBT), a higher incidence of GVHD using older MSDs could be overcome using cord blood for older patients. We retrospectively analyzed Japanese registration data of 2,091 patients with acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome aged 50 years or older who underwent MSD bone marrow transplantation (BMT) (n 5 319), MSD peripheral blood stem cell transplantation (PBSCT) (n 5 462), or unrelated CBT (n 5 1,310) between 2007 and Median age of MSD was 56 (range, 38 74) years. Compared with CBT, the risk of developing extensive chronic GVHD was higher after BMT (hazard ratio [HR], 2.00; P ) or PBSCT (HR, 2.38; P < 0.001), and transplant-related mortality was lower after BMT (HR, 0.61; P < 0.001) or PBSCT (HR, 0.63; P < 0.001). Relapse rates were not significant difference between three groups. Although overall mortality was lower after BMT (HR, 0.67; P < 0.001) or PBSCT (HR, 0.75; P ) compared with CBT, the rates of a composite endpoint of GVHD-free, relapse-free survival (GRFS) were not significant difference between three groups. These data showed that MSDs remain the best donor source for older patients, but CBT led to similar GRFS to BMT and PBSCT. Am. J. Hematol. 91:E284 E292, VC 2016 Wiley Periodicals, Inc. Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective therapeutic modalities for patients with intractable hematological malignancies. Although human leukocyte antigen (HLA)-matched sibling donors (MSDs) have been a frontline donor source for this treatment, alternative donors have increasingly been used for patients lacking MSDs. Recent advances in HLA matching between donor and recipient, and improvements in supportive care could continue to provide almost similar results in MSDs and matched unrelated donors (MUDs) [1 7]. Cord blood (CB) has been considered an acceptable alternative to donor type and source of stem cells in unrelated allogeneic HSCT for pediatric and adult patients without MSDs or MUDs [8 19]. Several studies have shown that the survival rate and relapse incidence after cord blood transplantation (CBT) from unrelated donors were almost comparable to those after bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) from MUDs in adult patients [8,9]. Older donor age has been shown to be associated with higher incidences of severe acute and chronic graft-versus-host disease (GVHD) [20,21] and mortality [22 25] after allogeneic HSCT from MSDs and MUDs. In allogeneic HSCT from MSDs, the exact role of donor age has been Additional Supporting Information may be found in the online version of this article. 1 Department of Hematology/Oncology, the Institute of Medical Science, the University of Tokyo, Tokyo, Japan; 2 Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan; 3 Division of Hematology, Jichi Medical University, Saitama Medical Center, Saitama, Japan; 4 Department of Hematology, Toranomon Hospital, Tokyo, Japan; 5 Department of Internal Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan; 6 Department of Hematology, Tokyo Metropolitan Geriatric Hospital, Tokyo; 7 Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan; 8 Department of Hematology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; 9 Saiseikai Maebashi Hospital, Leukemia Research Center, Gunma, Japan; 10 Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan; 11 Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan; 12 Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan; 13 Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan; 14 Division of Hematology, Kawasaki Medical School, Kurashiki, Japan; 15 Department of Hematology and Oncology, Children s Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan; 16 Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; 17 Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan; 18 Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; 19 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan Conflict of interest: Nothing to report *Correspondence to: Takaaki Konuma, Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-Ku, Tokyo , Japan. tkonuma@ims.u-tokyo.ac.jp Received for publication: 7 January 2016; Revised: 2 February 2016; Accepted: 17 February 2016 Am. J. Hematol. 91:E284 E292, Published online: 22 February 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh VC 2016 Wiley Periodicals, Inc. E284 American Journal of Hematology, Vol. 91, No. 5, May 2016 doi: /ajh.24340

2 discussed since older patients could usually receive allogeneic HSCT from older donors. Since the lower incidence of severe GVHD is one of the advantages of CBT [8,10,11,26,27], the higher incidence of GVHD using older MSDs could be overcome using CB for older patients. In addition, the absence of risk to donors may also be advantageous with CBT because the risk of adverse events during donation increases with the age of the donor [26]. However, there has been no comparative study between CBT, BMT, and PBSCT from MSDs in patients 50 years or older. Therefore, we retrospectively analyzed the Japanese registry data of 2,091 patients with acute myeloid leukemia (AML) (n 5 1,346), acute lymphoblastic leukemia (ALL) (n 5 308), and myelodysplastic syndrome (MDS) (n 5 437) aged 50 years or older who underwent MSD BMT (n 5 319), MSD PBSCT (n 5 462), or unrelated CBT (n ) between 2007 and Methods Data collection. Clinical data were obtained from the Transplant Registry Unified Management Program (TRUMP) of the Japan Society of Hematopoietic Cell Transplantation (JSHCT) [29]. Included in this retrospective analysis were patients aged 50 years or older with AML, ALL, or MDS who received first allogeneic HSCT using bone marrow (BM) or peripheral blood stem cell (PBSC) from MSDs, or a single HLA 0-2 antigen-mismatched unrelated CB unit between January 2007 and December 2012 in Japan. Because HLA-DR mismatches were previously evaluated at the low-resolution level at CB unit selection in Japan [30], the number of HLA disparities between recipient and MSD or between recipient and CB unit was defined as a low-resolution for HLA-A, HLA-B, and HLA-DR loci in this study. CB units were obtained from the Japan Cord Blood Bank Network. We excluded those lacking data of survival status (n 5 2) and donor status (n 5 9), those who received double unit CBT (n 5 6) and both BM and PBSC in their graft (n 5 5) or were conditioned with antithymocyte globulin (ATG) (n 5 77), and those whose grafts were depleted of T cells (n 5 1) or expanded stem cells ex vivo (n 5 1). We also excluded surviving patients, whose period of follow-up was less than 2 months (n 5 8). The Institutional Review Board of the Institute of Medical Science, The University of Tokyo, where this study was carried out, approved this retrospective study. Endpoints and definitions. The primary endpoint was to compare overall survival (OS) among stem cell sources. Secondary endpoints were hematological recovery, GVHD, relapse, transplant-related mortality (TRM), and a composite endpoint GVHD-free, relapse-free survival (GRFS) [31]. The OS (inverse of overall mortality) was defined as the time from the date of HSCT to the date of death or last contact. Neutrophil engraftment was defined as being achieved on the first of three consecutive days during which the absolute neutrophil count was at least /L. Platelet engraftment was defined as being achieved on the first of three consecutive days when the platelet count was higher than /L without transfusion support. Both acute GVHD and chronic GVHD were graded according to the previously published criteria [32,33]. The incidence of acute GVHD was evaluated in all engrafted patients, whereas the incidence of chronic GVHD was evaluated in engrafted patients surviving more than 100 days. Relapse was defined by hematological evidence of disease. Patients who never achieved remission after HSCT were considered to have had a relapse on day 1. TRM was defined as death during a remission. GRFS (inverse of treatment failure as defined by GRFS) was defined as the time from the date of HSCT to the date of grade III to IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, relapse, or death due to any cause [31,34]. The myeloablative conditioning (MAC) regimen was defined according to the criteria of the Center for International Blood and Marrow Transplant Research (CIBMTR) [35], and others were classified as reducedintensity conditioning (RIC). The disease status at HSCT was assessed according to the disease risk index, which is determined by disease type, disease status, and cytogenetic risk [36]. The pre-existing comorbidities were assessed according to the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) [37]. Statistical analysis. The baseline patient and transplant characteristics were compared using the chi-square test or Fisher s exact test for categorical variables and the Kruskal Wallis test for continuous variables. The probabilities of OS and GRFS were estimated according to the Kaplan Meier method, and the groups were compared using the log-rank test. The probabilities of neutrophil and platelet engraftment, acute GVHD and chronic GVHD, relapse, and TRM were estimated based on a cumulative incidence method to accommodate competing risks, and the groups were compared using Gray s test. Multivariate analysis was performed with a Cox proportional hazard model using all these variables: stem cell source (CBT vs. BMT vs. PBSCT), recipient age (50 59 vs. 60 years), HCT-CI score (0 2 vs. 3), disease (AML vs. ALL vs. MDS), disease risk index (low/intermediate vs. high/ very high), conditioning regimen (MAC vs. RIC), GVHD prophylaxis (cyclosporine-based vs. tacrolimus-based), the interval time from diagnosis to HSCT (<6 months vs. 6 months), sex compatibility between donor and recipient (female donor to male recipient vs. other vs. unknown), ABO compatibility between donor and recipient (match vs. mismatch), and year of HSCT ( vs ). All P-values were two-sided. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for the R software program (R Foundation for Statistical Computing, Vienna, Austria) [38]. Results Characteristics of patients and grafts The characteristics of patients, donors, grafts, and transplant procedures are summarized in Table I. CBT recipients were older than BMT or PBSCT recipients (P < 0.001). The proportion of HCT- CI 3 was higher in CBT recipients (P < 0.001). The proportions of disease type significantly differed among the three groups (P ). CBT recipients were more likely to have high and very high of the disease risk index (P < 0.001). The proportion of interval time from diagnosis to HSCT of more than six months was higher in CBT recipients (P < 0.001). Higher proportions of CBT recipients received RIC (P < 0.001), tacrolimus-based GVHD prophylaxis (P < 0.001), and ABO-mismatched HSCT (P < 0.001). CBTs were more frequently performed in recent years (P ). The median donor age was 56 years (range, years) for BMT and 56 years (range, years) for PBSCT (P ). Among the CBT recipients, the median number of cryopreserved nucleated cells was /kg (range, /kg to /kg) and the median number of cryopreserved CD341 cells was /kg (range, /kg to /kg). The median period of follow-up for survivors after HSCT was 28 months (range, 2 75 months) for BMT recipients, 27 months (range, 2 77 months) for PBSCT recipients, and 25 months (range, 2 79 months) for CBT recipients (P ). Neutrophil and platelet recovery The cumulative incidence of neutrophil recovery significantly differed among the three groups in univariate analysis (Gray s test for the entire group, P < 0.001) (Fig. 1a). In multivariate analysis, the hazard risk of neutrophil engraftment was significantly higher in BMT (hazard risk [HR], 2.10, 95% confidence interval [CI], 1.79 to 2.47; P < 0.001) or PBSCT (HR, 3.59, 95% CI, 3.10 to 4.16; P < 0.001) recipients compared with CBT recipients (Table II). The cumulative incidence of platelet recovery significantly differed among the three groups in univariate analysis (Gray s test for the entire group, P < 0.001) (Fig. 1b). In multivariate analysis, the hazard risk of platelet recovery was also significantly higher in BMT (HR, 2.60, 95% CI, ; P < 0.001) or PBSCT (HR, 3.41, 95% CI, ; P < 0.001) recipients compared with CBT recipients (Table II). Acute and chronic GVHD Matched Sibling BMT/PBSCT vs Unrelated CBT for Older In univariate analysis, the cumulative incidences of Grades II to IV acute GVHD significantly differed among the three groups (Gray s test for the entire group, P ) (Fig. 1c), but not grades III to IV acute GVHD among the three groups (Gray s test for the entire group, P ) (Fig. 1d). In multivariate analysis, the hazard risk of Grades II to IV acute GVHD was lower in BMT (HR, 0.53, 95% CI, ; P < 0.001) or PBSCT (HR, 0.64, 95% CI, 0.50 to 0.80; P < 0.001) recipients compared with CBT recipients. Similarly, compared with CBT recipients, the hazard risk of Grades III to IV acute GVHD was also lower in BMT (HR, 0.42, 95% CI, 0.25 to 0.69; P < 0.001) or PBSCT recipients (HR, 0.62, 95% CI, 0.42 to 0.91; P ) (Table II). The cumulative incidences of chronic GVHD (Gray s test for the entire group, P < 0.001) (Fig. 1e) and extensive chronic GVHD doi: /ajh American Journal of Hematology, Vol. 91, No. 5, May 2016 E285

3 Konuma et al. RESEARCH ARTICLE TABLE I. Characteristics of Patients, Grafts, and Transplant Procedures BMT PBSCT CBT P Number of patients Recipient age at HSCT < years 231 (72%) 298 (64%) 560 (42%) 60 years 88 (27%) 164 (35%) 750 (57%) Median recipient age at HSCT, years (range) 57 (50 73) 58 (50 74) 61 (50 82) <0.001 Recipient sex 0.07 Male 195 (61%) 261 (56%) 819 (62%) Female 124 (38%) 201 (43%) 491 (37%) HCT-CI score < (84%) 354 (84%) 914 (76%) 3 45 (15%) 63 (15%) 289 (24%) Unknown Disease AML 185 (57%) 282 (61%) 879 (67%) ALL 60 (18%) 70 (15%) 178 (13%) MDS 74 (23%) 110 (23%) 253 (19%) Disease Risk Index <0.001 Low 5 (1%) 7 (1%) 15 (1%) Intermediate 198 (64%) 253 (55%) 526 (41%) High 88 (28%) 157 (34%) 597 (46%) Very high 15 (4%) 36 (7%) 146 (11%) Unknown Diagnosis to HSCT <0.001 <6months 157 (49%) 251 (54%) 569 (43%) 6months 162 (50%) 210 (45%) 736 (56%) Unknown Conditioning regimen <0.001 MAC 246 (77%) 313 (67%) 669 (51%) RIC 73 (22%) 149 (32%) 641 (48%) GVHD prophylaxis <0.001 CSP-based 268 (84%) 366 (81%) 370 (28%) TAC-based 49 (15%) 85 (18%) 930 (71%) Unknown Median donor age, years, (range) 56 (39 74) 56 (38 72) NA 0.81 HLA compatibility < (100%) 462 (100%) 83 (6%) (20%) (73%) ABO compatibility <0.001 Match 180 (56%) 282 (61%) 486 (37%) Mismatch 139 (43%) 180 (39%) 820 (62%) Unknown Sex compatibility <0.001 Female donor to male recipient 86 (27%) 129 (27%) 315 (24%) Other 233 (73%) 333 (72%) 603 (46%) Unknown (29%) Year of HSCT (49%) 199 (43%) 512 (39%) (50%) 263 (56%) 798 (60%) Median follow-up of survivors, months (range) 28(2 75) 27(2 77) 25(2 79) 0.52 HSCT, hematopoietic stem cell transplantation; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; GVHD, graft-versushost disease; CSP, cyclosporine A; TAC, tacrolimus; BMT, bone marrow transplantation; PBSCT, peripheral blood stem cell transplantation; CBT, cord blood transplantation. (Gray s test for the entire group, P < 0.001) (Fig. 1f) differed among the three groups according to univariate analysis. In multivariate analysis, the hazard risk of chronic GVHD was significantly higher in PBSCT recipients (HR, 1.76, 95% CI, 1.34 to 2.33; P < 0.001), but was similar to BMT recipients (HR, 1.33, 95% CI, ; P ) compared with CBT recipients. The hazard risk of extensive chronic GVHD was significantly higher in BMT (HR, 2.00, 95% CI, ; P ) or PBSCT (HR, 2.38, 95% CI, ; P < 0.001) recipients compared with CBT recipients (Table II). Relapse, TRM, survival, and GRFS Although the cumulative incidences of relapse differed among the three groups in univariate analysis (Gray s test for the entire group, P ) (Fig. 2a), there was no significant difference in relapse between CBT and both BMT (HR, 1.11, 95% CI, ; P ) and PBSCT (HR, 1.13, 95% CI, ; P ) in multivariate analysis (Table II). In univariate analysis, the cumulative incidence of TRM significantly differed among the three groups (Gray s test for the entire group, P < 0.001) (Fig. 2b). In multivariate analysis, the hazard risk of TRM was significantly lower in BMT (HR, 0.61, 95% CI, ; P < 0.001) or PBSCT (HR, 0.63, 95% CI, ; P < 0.001) recipients compared with CBT recipients (Table II). In univariate analysis, the probabilities of OS significantly differed among the three groups (log-rank test for the entire group, P < 0.001) (Fig. 2c). In multivariate analysis, the hazard risk of overall mortality E286 American Journal of Hematology, Vol. 91, No. 5, May 2016 doi: /ajh.24340

4 Matched Sibling BMT/PBSCT vs Unrelated CBT for Older Figure 1. The cumulative incidences of neutrophil (a) and platelet recovery (b), Grades II2IV acute GVHD (c), Grades III2IV acute GVHD (d), chronic GVHD (e), and extensive chronic GVHD (f) after HSCT according to stem cell source. (a) The cumulative incidences of neutrophil recovery at 60 days after BMT, PBSCT, and CBT were 96.3% (95% confidence interval [CI], 93.4%298.0%), 94.8% (95% CI, 92.2%296.5%), and 80.2% (95% CI, 77.7%282.4%), respectively (Gray s test for the entire group, P < 0.001). (b) The cumulative incidences of platelet recovery at 100 days after BMT, PBSCT, and CBT were 87.7% (95% CI, 83.4%291.0%), 83.7% (95% CI, 79.8%286.9%), and 68.0% (95% CI, 65.0%270.8%), respectively (Gray s test for the entire group, P < 0.001). (c) The cumulative incidences of Grades II2IV acute GVHD at 100 days after BMT, PBSCT, and CBT were 34.9% (95% CI, 29.6%240.2%), 38.2% (95% CI, 33.7%242.8%), and 42.1% (95% CI, 39.1%245.1%), respectively (Gray s test for the entire group, P ). (d) The cumulative incidences of Grades III2IV acute GVHD at 100 days after BMT, PBSCT, and CBT were 10.4% (95% CI, 7.3%214.2%), 13.7% (95% CI, 10.7%217.1%), and 15.1% (95% CI, 13.0%217.3%), respectively (Gray s test for the entire group, P ). (e) The cumulative incidences of chronic GVHD at two years after BMT, PBSCT, and CBT were 47.4% (95% CI, 40.8%253.7%), 55.0% (95% CI, 49.3%260.3%), and 33.0% (95% CI, 29.4%236.5%), respectively (Gray s test for the entire group, P < 0.001). (f) The cumulative incidences of extensive-type chronic GVHD at two years after BMT, PBSCT, and CBT were 31.7% (95% CI, 25.7%237.7%), 36.1% (95% CI, 30.7%241.5%), and 14.4% (95% CI, 11.9%217.2%), respectively (Gray s test for the entire group, P < 0.001). was significantly lower in BMT (HR, 0.67, 95% CI, ; P < 0.001) or PBSCT (HR, 0.75, 95% CI, ; P ) recipients compared with CBT recipients (Table II). Although the probabilities of GRFS significantly differed among the three groups in univariate analysis (log-rank test for the entire group, P ) (Fig. 2d), there was no significant difference in treatment failure as defined by GRFS between CBT and both BMT (HR, 0.94, 95% CI, ; P ) and PBSCT (HR, 1.12, 95% CI, ; P ) in multivariate analysis (Table II). doi: /ajh American Journal of Hematology, Vol. 91, No. 5, May 2016 E287

5 Konuma et al. RESEARCH ARTICLE TABLE II. Multivariate Analysis of Transplant Cutcomes a Outcomes Variables HR (95% CI) P Neutrophil engraftment Platelet engraftment Grades II IV acute GVHD Grades III IV acute GVHD Chronic GVHD Extensive chronic GVHD Relapse Transplant-related mortality BMT 2.10 ( ) <0.001 PBSCT 3.59 ( ) < ( ) 0.04 High/very high 0.72 ( ) <0.001 ABO compatibility Match 1.00 Mismatch 0.88 ( ) 0.01 BMT 2.60 ( ) <0.001 PBSCT 3.41 ( ) < ( ) Disease AML 1.00 ALL 0.87 ( ) 0.11 MDS 0.86 ( ) 0.03 High/very high 0.60 ( ) <0.001 GVHD prophylaxis CSP-based 1.00 TAC-based 1.16 ( ) 0.02 Year of HSCT ( ) 0.01 BMT 0.53 ( ) <0.001 PBSCT 0.64 ( ) <0.001 Conditioning regimen MAC 1.00 RIC 0.78 ( ) GVHD prophylaxis CSP-based 1.00 TAC-based 0.71 ( ) <0.001 BMT 0.42 ( ) <0.001 PBSCT 0.62 ( ) ( ) 0.03 GVHD prophylaxis CSP-based 1.00 TAC-based 0.55 ( ) <0.001 BMT 1.33 ( ) 0.06 PBSCT 1.76 ( ) < ( ) 0.04 High/very high 1.36 ( ) Diagnosis to HSCT <6months months 0.82 ( ) 0.04 Conditioning regimen MAC 1.00 RIC 0.80 ( ) 0.03 Sex compatibility Female donor to male recipient 1.00 Other 0.94 ( ) 0.63 Unknown 0.68 ( ) 0.04 BMT 2.00 ( ) PBSCT 2.38 ( ) < ( ) BMT 1.11 ( ) 0.47 PBSCT 1.13 ( ) 0.35 High/very high 2.71 ( ) <0.001 BMT 0.61 ( ) <0.001 PBSCT 0.63 ( ) <0.001 E288 American Journal of Hematology, Vol. 91, No. 5, May 2016 doi: /ajh.24340

6 Matched Sibling BMT/PBSCT vs Unrelated CBT for Older TABLE II. Continued Outcomes Variables HR (95% CI) P ( ) < ( ) <0.001 Disease AML 1.00 ALL 1.11 ( ) 0.38 MDS 1.33 ( ) High/very high 1.87 ( ) <0.001 GVHD prophylaxis CSP-based 1.00 TAC-based 0.83 ( ) 0.04 ABO compatibility Match 1.00 Mismatch 0.84 ( ) 0.03 Sex compatibility Female donor to male recipient 1.00 Other 0.81 ( ) 0.02 Unknown 1.03 ( ) 0.76 Overall mortality BMT 0.67 ( ) <0.001 PBSCT 0.75 ( ) ( ) ( ) <0.001 High/very high 2.12 ( ) <0.001 ABO compatibility Match 1.00 Mismatch 0.84 ( ) Treatment failure as defined by GRFS BMT 0.94 ( ) 0.53 PBSCT 1.12 ( ) ( ) <0.001 High/very high 1.90 ( ) <0.001 ABO compatibility Match 1.00 Mismatch 0.88 ( ) 0.02 GVHD, graft-versus-host disease; GRFS, GVHD-free/relapse-free survival; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; HSCT, hematopoietic stem cell transplantation; CBT, cord blood transplantation; BMT, bone marrow transplantation; PBSCT, peripheral blood stem cell transplantation; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; CSP, cyclosporine A; TAC, tacrolimus; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; HR, hazard ratio; CI, confidence interval. a In addition to the results of stem cell source, the only significant variables other than stem cell source and their results were described in each endpoint. Subset analyses of transplant outcomes Given that disease type, disease risk index, conditioning regimen, and recipient and donor age were important factors for transplant outcomes, we performed subgroup analyses to identify in which patient population comparable outcomes between CBT and both BMT and PBSCT could be observed. Although the probabilities of OS significantly differed among the three groups in patients with each subgroup in univariate analysis (Supporting Information Figures 1 4), multivariate analysis showed that the hazard risk of overall mortality was not significantly different between CBT and both BMT and PBSCT in patients with ALL, low/intermediate-disease risk index, and recipient age of years (Supporting Information Table I). In these subgroups, the improved OS after CBT was mainly due to the lower TRM, but not relapse incidence. Similar to entire cohort, there were no significant differences in treatment failure as defined by GRFS among the three groups in patients with each subgroup analysis. Cause of death Among the entire 2,091 patients, 1,254 patients had died at the last follow-up. The causes of death before and after 100 days in each stem cell source group are summarized in Supporting Information Table II. The most frequent cause of death was relapse among the three groups. Compared with BMT and PBSCT, infection, hemorrhage, and graft failure were more common causes of early death after CBT. Among causes of late death, infection was comparable among the three groups, and GVHD was less common after CBT. Discussion Recent advances in allogeneic HSCT techniques have led to expansion of indications for allogeneic HSCT for older patients. However, it is unclear whether older MSDs or alternative donors provide better outcomes for older patients, although MSDs are generally a first-line donor source in younger patients. Several studies investigated whether older MSDs or younger MUDs provides better outcomes for older patients [22,23,39 42]. Although these data were controversial, MUD is an alternative donor source for older patients. On the other hand, the outcome of CBT has improved over the past decades. In patients 50 years or older, there have been two retrospective comparative studies between CBT and MUD HSCT, which showed that OS was significantly lower after CBT than HSCT from MUDs, but that survival was similar between CBT and HSCT from one-allele- doi: /ajh American Journal of Hematology, Vol. 91, No. 5, May 2016 E289

7 Konuma et al. RESEARCH ARTICLE Figure 2. The cumulative incidences of relapse (a) and TRM (b), and the unadjusted probabilities of OS (c) and GRFS (d) after HSCT according to stem cell source. (a) The cumulative incidences of relapse at two years after BMT, PBSCT, and CBT were 30.0% (95% CI, %), 32.8% (95% CI, %), and 26.8% (95% CI, %), respectively (Gray s test for the entire group, P ). (b) The cumulative incidences of TRM after BMT, PBSCT, and CBT were 6.3% (95% CI, %), 8.1% (95% CI, %), and 25.2% (95% CI, %) at 100 days, and 25.5% (95% CI, %), 26.2% (95% CI, %), and 40.5% (95% CI, %) at two years, respectively (Gray s test for the entire group, P < 0.001). (c) The probabilities of OS at 2 years after BMT, PBSCT, and CBT were 53.5% (95% CI, %), 47.0% (95% CI, %), and 36.1% (95% CI, %), respectively (log-rank test for the entire group, P < 0.001). (d) The probabilities of GRFS at two years after BMT, PBSCT, and CBT were 25.3% (95% CI, %), 17.2% (95% CI, %), and 24.9% (95% CI, %), respectively (log-rank test for the entire group, P ). mismatched unrelated donors [43,44]. In addition, several recent studies demonstrated highly similar survival results between CBT and MSD recipients [12 14,27,45,46]. However, in this study, the rate of OS after CBT was significantly inferior to that after BMT or PBSCT from MSDs. This significantly inferior OS was partly due to the high early TRM within 100 days, which might be associated with the low incidence of hematopoietic recovery, because infection, hemorrhage, and graft failure were more common causes of early death after CBT, except for relapse. These findings indicated the need for enhancement of hematopoietic recovery to improve survival after CBT particularly in older patients. The incidence of Grades II IV and Grades III IV acute GVHD was higher after CBT compared with BMT from MSDs in our study. Although the reason for this remains unclear, our data showed GVHD was not a common cause of early death after CBT. Murata et al. reported a higher response of Grades II IV acute GVHD to systemic corticosteroid treatment in CBT recipients than in BMT and PBSCT recipients [47], suggesting that the higher incidence of severe acute GVHD might not have contributed to the higher early TRM after CBT in our study. On the other hand, chronic GVHD was a less common cause of late death after CBT compared with BMT and PBSCT in our study. Since chronic GVHD and its treatment were one of the common causes of late death after allogeneic HSCT, the higher incidence of chronic GVHD might have contributed to higher late TRM after BMT and PBSCT compared with CBT in our study. These data suggested that the lower incidence of chronic GVHD after CBT might improve late TRM, resulting in that similar GRFS was observed between CBT and both BMT and PBSCT recipients. Several studies demonstrated that the use of ATG was associated with increased TRM and decreased survival in CBT, which was mainly due to the higher incidence of infection [48,49]. Therefore, patients who received ATG in conditioning regimen were excluded in this study. Recently, the addition of ATG to the conventional MAC has been shown in a prospective randomized study to reduce the risk of chronic GVHD in MSD PBSCT recipients [50]. Of course, although the impact of ATG might differ depending on the graft type, conditioning regimen, or disease type, the use of ATG might be an alternative to decrease the incidence of chronic GVHD after MSD BMT and PBSCT in older patients. In subgroup analysis, we found that the survival rate was similar between CBT and both BMT and PBSCT only in patients with low/ intermediate-disease risk index, ALL, and recipient age of E290 American Journal of Hematology, Vol. 91, No. 5, May 2016 doi: /ajh.24340

8 years. In CBT recipients, the cumulative incidence of neutrophil recovery at 60 days was much higher in patients with low/intermediate-disease risk index (86.4%) compared to those with high/very high-disease risk index (76.3%), which might contribute to the lower early TRM after CBT, resulting in comparable survival between CBT and both BMT and PBSCT in patients with low/intermediate-disease risk index. As for ALL, there were no significant differences of OS between CBT and both BMT and PBSCT in our study. This is consistent with the previous studies, which also demonstrated that CBT led to similar survival to HSCT from either MSDs or MUDs for adult ALL [51 53]. The upper age limit of MSD for BM and mobilized PBSC harvest is unclear [54]. In general, increasing recipient age is frequently accompanied by increased donor age in MSDs. It has been reported that the risk of acute adverse events associated with BM and mobilized PBSC harvest was higher in older donors in an unrelated setting [28]. Moreover, increasing donor age has also been reported to be associated with both the lower numbers of BM nucleated cells in grafts of BM collection and the lower numbers of CD341 cells in products of mobilized PBSC harvest [55 57]. Further studies are required to confirm the suitability criteria for older MSDs for donation. Our study had several limitations. First, patient selection bias should be considered when selecting a graft source because this study was a retrospective multicenter analysis which might have included heterogeneous populations and physician or institute preference. Therefore, we adjusted for possible confounders by multivariate analysis to take into account the different backgrounds of patients according to stem cell source type. Second, although this study was a nationwide study, almost all patients were Japanese. HLA or non- HLA immune genetics are relatively homogeneous [58], which contributes to sufficient CB units in view of HLA disparities. In conclusion, MSD BMT and PBSCT remain the best graft and donor source for older patients compared with CBT, if MSDs are available. However, CBT led to similar GRFS to MSD BMT and PBSCT in older patients. Acknowledgments Matched Sibling BMT/PBSCT vs Unrelated CBT for Older The authors thank all of the physicians and staff at the centers who provided the clinical data to the Transplant Registry Unified Management Program (TRUMP) of the Japan Society of Hematopoietic Cell Transplantation (JSHCT). They also thank the Japan Cord Blood Bank Network for their help in this study. Author Contributions TK designed the research, analyzed the data, performed the statistical analysis and wrote the first draft of the manuscript. 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