Biol Blood Marrow Transplant 26 (2020) 2098 2104 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org Cord Blood Reduced-Intensity versus Myeloablative Conditioning in Cord Blood Transplantation for Acute Myeloid Leukemia (40-60 years) across Highly Mismatched HLA Barriers—On Behalf of Eurocord and the Cellular Therapy & Immunobiology Working Party (CTIWP) of EBMT Vipul Sheth1, Fernanda Volt2, Jaime Sanz3, Laurence Clement4, Jan Cornelissen5, Didier Blaise6, Jorge Sierra7, Mauricette Michallet8, Riccardo Saccardi9, Vanderson Rocha2, Eliane Gluckman2, Christian Chabannon10, Annalisa Ruggeri2,11,* 1 Clinical Research Division, Program in Immunology, Fred Hutchison Cancer Research Centre, Seattle, Washington 2 Eurocord, Hopital Saint Louis—EA3518, Paris, France 3 Department of Stem Cell Transplant and Immunotherapy, Hospital Universitario La Fe, Valencia, Spain 4 Department of Stem Cell Transplant and Immunotherapy, Haut-Lev^eque, Bordeaux, France 5 Department of Stem Cell Transplant and Immunotherapy, Erasmus MC-Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands 6 Department of Stem Cell Transplant and Immunotherapy, Paoli Calmettes, Marseille, France 7 Department of Stem Cell Transplant and Immunotherapy, Hospital Santa Creu i Sant Pau, Barcelona, Spain 8 Department of Stem Cell Transplant and Immunotherapy, Service d'Hematologie, Centre Leon Berard, Lyon, France 9 Department of Stem Cell Transplant and Immunotherapy, Azienda Ospedaliero Universitaria Meyer—Ospedale di Careggi, Firenze, Italy 10 Centre de Therapie Cellulaire, Departement de Biologie du Cancer, Institut Paoli-Calmettes, & Inserm CBT-1409, Aix-Marseille Universite, Marseille, France 11 Haematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Article history: A B S T R A C T Received 18 May 2020 The use of myeloablative conditioning (MAC) in umbilical cord blood transplantation (UCBT) has been associated Accepted 20 July 2020 with high nonrelapse mortality (NRM) in patients aged >40 years, especially those having a high HLA disparity, thus limiting wider applications. We hypothesized that the NRM advantage of reduced-intensity conditioning Keywords: (RIC) and higher graft-versus-leukemia effect associated with greater HLA disparities would expand its use for Reduced intensity patients (aged 40 to 60 years) without compromising efficacy and compared outcomes between RIC and MAC reg- Myeloablative imens. In total, 288 patients aged 40 to 60 years, with de novo acute myeloid leukemia, receiving UCBT with at Umbilical cord transplant least 2 HLA mismatches with RIC (n = 166) or MAC (n = 122) regimens were included. As compared to RIC, the Mismatched MAC cohort included relatively younger patients, having received more single UCBT, with lower total nucleated cell counts and more in vivo T cell depletion. Median time to neutrophil engraftment, infections (bacterial, viral, and fungal), and grade II to IV acute and chronic graft-versus-host disease were similar in both groups. In the mul- tivariate analysis, overall survival (hazard ratio [HR], 0.98; P = .9), NRM (HR, 0.68; P = .2), and relapse (HR, 1.24; P = .5) were not different between RIC and MAC. Refractory disease was associated with worse survival. Outcomes of UBCT for patients aged 40 to 60 years having 2 HLA mismatches are comparable after the RIC or MAC regimen. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. Allogeneic hematopoietic stem cell transplantation from transplantation, particularly for patients at high risk of disease HLA identical sibling is the treatment of choice for selected relapse who urgently need a transplantation [3-6]. patients with acute myeloid leukemia with high-risk features During the past 2 decades, there has been an increase in the as well as in relapsed settings [1,2]. However, for patients who use of the reduced-intensity conditioning (RIC) regimen, lack a suitable HLA identical donor, unrelated cord blood trans- which mainly relies on the graft-versus-leukemia (GVL) effect plantation (UCBT) is a valid alternative to HLA-matched unre- rather than conditioning intensity to eradicate the disease. On lated bone marrow or peripheral blood stem cell (PBSC) the basis of a prospective study, the myeloablative condition- ing (MAC; including reduced toxicity) regimen is still generally preferred for younger individuals [7] while using PBSCs both Financial disclosure: See Acknowledgments on page 2103. related and unrelated donors, but it is limited by high nonre- *Correspondence and reprint requests: Annalisa Ruggeri, MD, PhD, Euro- lapse mortality (NRM) in older patients, thereby promoting cord, Hopital Saint Louis, 1, avenue Claude Vellefaux, 75010, Paris, France. the usage of novel RIC regimens in this subgroup of patients E-mail address: Annalisaruggeri80@hotmail.com (A. Ruggeri). https://doi.org/10.1016/j.bbmt.2020.07.025 1083-8791/© 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 2099 [8,9]. Due to cord blood stem cell properties, a strong GVL 4.7, P  .001), and more in vivo T cell depletion using ATG effect is reported in UBCT recipients [10]. This could suggest (86.6% versus 27.6, P .001). More patients in the RIC group that conditioning intensity might be proportionally less impor- received standard cyclosporine/MMF-based prophylaxis tant following UCBT in regards to the risk of relapse [5,11,12]. (82.5% versus 43.4%, P < .001) (Table 1). However, large registry data in UCBT showed no advantage of using RIC over MAC (reduced NRM was counterbalanced by an Engraftment and GVHD increased incidence of relapses) [13]. Also, very similar to There was no difference between the 2 groups for median PBSCs, the use of MAC in UCBT was associated with a higher time to neutrophil engraftment (RIC, 21 [3 to 54] versus MAC, risk of NRM in patients older than 40 years, especially in case 22 [11 to 50] days; P = .3) (Table 2). Seventeen patients (13.9%) of higher HLA disparity (allele level) [14-18], thus restricting in the MAC group had engraftment failure as compared to 29 wider applications due to limitations of finding a nearly (17.5%) in the RIC group (P = .62). Grade II to IV acute GVHD matched cord donor [5,17]. (aGVHD) and all grade chronic GVHD (cGVHD) were compara- ble between the groups (30.6% versus 37.6%, P = .221, and PATIENTS AND METHODS 31.8% versus 27.2%, P = .28, for MAC versus RIC, respectively). This study was approved by Eurocord and the Cellular Therapy & Immu- Among patients with GVHD, the proportion of patients with nobiology Working Party (CTIWP) of European Society for Blood and Marrow Transplantation (EBMT). Patients and donors treated at EBMT-affiliated cen- grade III to IV aGVHD and extensive cGVHD was also similar ters routinely provide informed consent authorizing the use of their personal (37% versus 42% and 67% versus 48%, MAC versus RIC, respec- information for research purposes. tively). Factors predicting lower aGVHD in multivariate analy- sis (MVA) were the use of ATG and TNC <4.3 £ 107/kg. Factors Patient Selection and Treatment Characteristics Inclusion criteria for this analysis were patients with de novo acute mye- predicting a higher incidence of cGVHD were use of busulfan- loid leukemia (any disease status), 40 to 60 years of age, undergoing single or based regimens, which were mainly myeloablative (Table 3). double UCBT with 2 or more HLA mismatches in EBMT centers between 2005 and 2018. In total, 134 (54.5%) patients received in vivo T cell depletion with NRM and Relapse anti-thymocyte globulin (ATG). Patients were conditioned with either RIC or The 3-year cumulative incidence of NRM was significantly MAC [19]. Both groups received HLA mismatched cords (at least at 2 loci— HLA A/B at antigen level and DRB1 at allelic level). The most common MAC higher in the MAC group (MAC, 45.3% versus RIC, 23%; used was fludarabine, busulfan, and thiotepa (70%), while the commonest P = .001) (Figure 2A and Table 2). However, MVA did not con- RIC regimen consisted of cyclophosphamide, fludarabine, and total body irra- firm a statistically significant difference between the 2 groups diation (TBI) less than 6 Gy (70%). Graft-versus- host disease (GVHD) prophy- (P = .2; HR, 0.68; 95% CI, 0.3 to 1.2; reference MAC) (Table 3). laxis consisted of calcineurin inhibitors and mycophenolate (MMF) in 190 (66%) patients. The choice of conditioning regimen and GVHD prophylaxis Disease relapse was the main cause of death in the RIC group was dependent on transplant center protocols. (56%) as compared to MAC (33%). Patients receiving the MAC Cytogenetic abnormalities were classified according to the Medical regimen succumbed more often to transplant-related compli- Research Council classification [20]. Leukemia-free survival (LFS) was defined cations (64%) (GVHD, 30%; infections, 36% [bacterial infection, as the interval from the time of transplant to either relapse or death while in remission. Overall survival (OS) was defined as the time to death from any 14%; unknown infections, 12%; viral infections, 8%; parasitic cause. Engraftment was defined as the first 3 consecutive days with an abso- infections, 2%]). There was no difference in infective (bacterial, lute neutrophil count over 0.5 £ 109/L. Acute and chronic GVHD was diag- viral, or fungal) episodes/complications between the 2 groups. nosed and graded according to standard criteria, respectively [21]. Veno-occlusive disease and idiopathic pneumonia were reported in MAC recipients only (MAC, 6%, 2% versus RIC, no Statistical Methods veno-occlusive disease, no idiopathic pneumonia). The Kruskal-Wallis test was used to assess continuous variables and chi- square was used for categorical variables. Univariate analyses were per- At 3 years, the cumulative incidence of relapse was signifi- formed using Gray’s test for cumulative incidence functions and the log-rank cantly higher in the RIC group (41% versus 27%, P = .019) test for OS and LFS. To study acute and chronic GVHD, we considered relapse (Table 2 and Figure 2B). However, in MVA shown in Table 3, and death to be competing events. Variables considered in univariate analy- the difference no longer remained significant (P = .48; HR, ses were type of conditioning regimen (RIC versus MAC), median year of UCBT, recipient weight, median age, age group (50 or >50), sex, graft type 1.24; 95% CI, 0.47 to 2.3, reference MAC). (double of single UCBT), disease status (remission versus no remission), cyto- genetic risk, cytomegalovirus serology, performance status, ABO matching, OS and LFS TBI, ATG, use of busulfan, GVHD prophylaxis (cyclosporine + MMF § other There was no difference in 3-year OS or LFS between the 2 versus other), median total nucleated cell count (TNC), and median CD34. Probabilities of OS and LFS were calculated using the Kaplan-Meier esti- groups, OS (MAC, 31% versus RIC, 41%; P = .073) and LFS (MAC, mate. A Cox proportional hazard models was used for multivariate regres- 28% versus RIC, 36%; P = .28) (Figure 1A,B). In multivariate sions. Variables differing significantly between the 2 groups or factors analyses, disease status prior to transplant (complete remis- associated with significant outcome in the univariate analysis were included sion versus no remission) was the only factor that remained in the multivariate Cox models. Results were expressed as the hazard ratio (HR) with the 95% confidence interval (CI). All tests were 2-sided. The type I significant for OS and LFS (P < .0001; HR, 2.7; 95% CI, 1.7 to error rate was fixed at 0.05 for the determination of factors associated with 4.08; P  .0001; HR, 3.03; 95% CI, 1.9 to 4.5, reference complete time-to-event outcomes. Statistical analysis was performed using R 3.4.0 (R remission, for OS and LFS, respectively) (Table 3). There was no Core Team, Vienna, Austria) and SPSS 22 (SPSS, Inc., Chicago, IL). difference in impact of intensity of conditioning regimen when considering the use of TBI or ATG (data not shown). RESULTS Patients DISCUSSION A total of 288 patients (122 MAC and 166 RIC) were Results of UCBT and related HLA haploidentical grafts have included in the analysis. Median follow-up was 33 (3.2 to shown comparable outcomes to HLA matched or mismatched 155.2) and 47 (3.2 to 149.9) months for the MAC and RIC unrelated PBSC donors [3-5]. The use of myeloablative UCBT is groups (P = .21), respectively. Baseline demographic and clini- standard for young patients but still highly limited by substan- cal data are outlined in Table 1. As compared to RIC, the MAC tially increased NRM associated with HLA disparity (especially group included relatively younger patients (median age 47 at the allele level) and increasing age [13]. There is a need to versus 53 years, P  .001), having had received more single expand the utilization of UCBT across such barriers without UCBT (73.8% versus 28.9%, P  .001), a lower TNC (3.9 versus compromising efficacy. Recently, it was shown that in case of 2100 V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 Table 1 Demographic Characteristics of the Study Population Characteristic Table 1 MAC (n = 122) RIC (n = 166) P Value Follow-up for survi- Median (range) 33 (3.3-155.2) 47.9 (3.2-149.9) .215 vors in months Year UCBT Median (range) 2011 (2005-2018) 2010 (2005-2018) .034 Patient sex, No. (%) Male 55 (45.1) 76 (45.8) .906 Female 67 (54.9) 90 (54.2) Age at UCBT, yr Median (range) 47.8 (40.0-59.9) 53.2 (40.3-60.0) <.001 Type of graft (graft Single 90 (73.8) 48 (28.9) <.001 type), No. (%) Double 32 (26.2) 118 (71.1) Disease status, No. First CR 74 (61.7) 89 (54.6) NP (%) Second CR 30 (25.0) 48 (29.4) >Second CR 1 (0.8) 5 (3.1) Active or advanced 15 (12.5) 21 (12.9) disease Missing 2 6 Remission, No. (%) CR 105 (87.5) 142 (87.1) .924 No CR 15 (12.5) 21 (12.9) Missing 2 6 Cytogenetic risk, No. Good or 65 (78.3) 111 (82.2) .477 (%) intermediate Poor 18 (21.7) 24 (17.8) Missing 39 31 Performance status KPS 80 21 (20.8) 19 (19.0) .75 at transplant, No. (%) KPS >80 80 (79.2) 81 (81.0) Missing 21 66 Delay in months Median (range) 6.5 (3.19-52.9) 7.3 (3.13-247.5) .036 from diagnosis to UCBT (considering only patients in CR) HLA matching (HLA 2 mismatches 111 (92.5) 148 (94.3) NP STUDY), No. (%) 3 mismatches 8 (6.7) 7 (4.5) 4 mismatches 1 (0.8) 2 (1.3) At least 2 mis- 2 9 matches, but miss- ing information for the second CB CMV (donor), No. (%) Negative 34 (29.3) 60 (38.2) .126 Positive 82 (70.7) 97 (61.8) Missing 69 ABO match, No. (%) Compatible or 48 (60.0) 78 (57.4) .703 minor Major 32 (40.0) 58 (42.6) incompatibility Missing 42 30 TBI in conditioning, No 83 (80.6) 28 (17.6) <.001 No. (%) Yes 20 (19.4) 131 (82.4) Missing 19 7 Busulfan in condi- No 24 (19.7) 149 (89.8) <.001 tioning, No. (%) Yes 98 (80.3) 17 (10.2) ATG, No. (%) No 15 (13.4) 97 (72.4) <.001 Yes 97 (86.6) 37 (27.6) Missing 10 32 GVHD prophylaxis, Other GVHD 69 (56.6) 29 (17.5) <.001 No. (%) prophylaxis CSA + MMF § other 53 (43.4) 137 (82.5) Median TNC Median (IQR) 3.9 (3.1-5.1) 4.7 (3.8-5.7) <.001 (continued) V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 2101 Table 1 (Continued) Characteristic Table 1 MAC (n = 122) RIC (n = 166) P Value Missing 12 21 Median CD34 Median (IQR) 1.9 (0.5-7.0) 1.8 (1.4-2.7) .903 Missing 13 28 CR indicates complete remission; KPS, Karnofsky performance status; CB, cord blood; CMV, cytomegalovirus; CSA, cyclosporine; IQR, interquartile range. Table 2 mismatched unrelated donor transplants, the reduced NRM Univariate Analysis for RIC versus MAC associated with the RIC regimen [8,9] and increased GVL effect Outcomes Variables Events EFS at 4 yr P Value associated with HLA disparity could be harnessed to expand LFS MAC 82 28% .285 indications in patients older than 40 years [22]. Since GVL may RIC 107 36% increase with the degree of HLA disparity, we took advantage OS MAC 78 31% .073 of the large EBMT and Eurocord registries to determine whether the utility of highly HLA mismatched UCBT could be RIC 96 41% similarly expanded in patients aged 40 to 60 years by using % 60 days 95% CI P Value the RIC regimen. Engraftment MAC 86.1 (80-92.6) .629 Unlike previous studies comparing RIC and MAC regimens RIC 82.5 (76.9-88.6) for UCBT [13], wherein RIC was associated with substantially % 3 years (95% CI) P Value increased relapses and reduced NRM in comparison to MAC, NRM MAC 45.4 (36.9-56.0) <.001 our study showed no statistical difference in outcomes RIC 23 (17.3-30.6) between the 2 cohorts when adjusting in the multivariate % 3 years (95% CI) P Value analyses. In a large retrospective Center for International Blood Relapse MAC 27.8 (20.5-37.7) .019 and Marrow Transplant Research and Eurocord analysis, NRM RIC 41.3 (34.2-49.8) increased exponentially with every degree of high-resolution % 100 days (95% CI) P Value HLA disparity [14]. Similarly, the effects of high-resolution aGVHD MAC 30.6 (23.3-40.1) .221 allele-level HLA mismatches and association with higher NRM RIC 37.6 (30.8-45.8) and increased GVL [15,16] were shown in a large Japanese reg- % 3 years (95% CI) P Value istry study, separately for pediatric and adult cohorts. cGVHD MAC 31.8 (23.8-42.4) .280 The OS and LFS in the present study were similar for both RIC 27.2 (21-35.3) groups and comparable to other studies [14-16]. A Japanese EFS indicates Event-free survival. group [16] showed significant reduction in OS after 5 or greater degree of allele-level HLA mismatches in a cohort of Table 3 Multivariate Analysis of Factors Affecting OS, EFS, NRM, Relapse, and GVHD Characteristic P Value HR 95% CI, Exp(B) Inferior Superior OS RIC (RIC versus MAC) .931 .983 .663 1.458 Graft type (double versus single) .060 .697 .479 1.015 Remission (no CR versus CR) .000 2.703 1.791 4.080 ATG (ATG versus no ATG) .774 1.063 .699 1.617 LFS RIC (RIC versus MAC) .838 1.040 .713 1.517 Graft type (double versus single) .125 .749 .518 1.083 ATG (ATG versus no ATG) .726 1.075 .718 1.609 Remission (no CR versus CR) .000 3.003 1.990 4.531 NRM RIC (RIC versus MAC) .202 .685 .383 1.225 ATG (ATG versus no ATG) .533 1.235 .636 2.397 Graft type (double versus single) .235 .699 .387 1.263 Year of transplant (>2010 or 2010) .193 1.370 .853 2.201 CSA § MMF versus others .751 .917 .539 1.562 Relapse RIC (RIC versus MAC) .476 1.244 .682 2.268 Remission (no CR versus CR) .000 5.384 3.295 8.796 TBI (yes versus no) .625 1.204 .572 2.535 Bu (yes versus no) .703 1.182 .500 2.795 CSA_MMF (CSA + MMF § other versus other) .458 1.232 .710 2.136 Year of transplant (>2010 or 2010 .268 .791 .523 1.198 Acute GVHD RIC (RIC versus MAC) .350 .755 .418 1.362 (continued) 2102 V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 Table 3 (Continued) Characteristic P Value HR 95% CI, Exp(B) Inferior Superior Sex (female versus male) .099 .676 .425 1.076 CMV (yes versus no) .906 .972 .609 1.551 ATG (ATG versus no ATG) .002 .382 .210 .696 TNC (>4.3 versus 4.3) .013 1.819 1.136 2.914 Chronic GVHD RIC (RIC versus MAC) .907 .965 .528 1.763 Year of transplant (>2010 versus 2010) .026 1.685 1.063 2.671 Bu (yes versus no) .058 1.781 .980 3.238 Bu indicates busufan. Figure 1. (A) NRM between RIC (n = 166; NRM, 23%) and MAC (n = 122; NRM, 45.4%; P  .001). (B) Relapse RIC (n = 166; relapse, 41.3%) versus MAC (n = 122; relapse, 27.8%; P = .019). Figure 2. (A) OS between RIC (n = 166; OS, 41%) and MAC (n = 122; OS, 31%; P = .073). (B) LFS between RIC (n = 166; LFS, 36%) and MAC (n = 122; LFS, 28%; P = .28). 3500 adult patients receiving UCBT. Similarly, Eapen et al. [14] Graft rejection has been a major barrier in UCBT, especially showed survival differences with a higher degree of HLA mis- when using HLA-mismatched cords [14] in comparison to fully matches at high resolution among patients receiving UCBT. As matched UCBT. HLA matching is an important factor to the expected, OS and LFS in both groups were lower in comparison success of the UCBT and should be carefully considered during to other recent studies in UCBT (RIC versus MAC), including the donor searching process. younger patients. In a prospective multicenter study in 57 Several strategies to improve engraftment and decrease patients having received standard MAC UCBT, the 3-year dis- graft failure have been described with promising results, ease-free survival was 50% [23], and 2-year disease-free sur- including different platforms for progenitor cell expansion vival in a prospective study of 79 patients using standard RIC or the use of agents to enhance homing, among others. UCBT was 35% [12]. Although some of the approaches are still under V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 2103 investigation, they offer hope for improved outcomes after ACKNOWLEDGMENTS UCBT, including for patients at a higher risk of graft failure The authors thank the data managers and biostatisticians of such as those receiving HLA-mismatched UCBT. Surpris- the EBMT-CTIWP/Eurocord and participating EBMT centers. ingly, in our study, there was no difference in engraftment Financial disclosure: The authors have nothing to disclose. kinetics and graft rejection between the 2 groups. This can Conflict of interest statement: There are no conflicts of inter- be explained by a significantly higher use of double cords est to report. and higher median TNC count [23,24] in the RIC group as compared to MAC, which could have counterbalanced the reduction in the intensity of conditioning. GVHD has not REFERENCES been a major obstacle for UCBT. Similar to reported litera- 1. Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared with autologous ture [15,17], we reported comparable and low acute and stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission chronic GVHD incidences in the RIC and MAC groups. This (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. could possibly be explained by a predominantly naive rep- Blood. 2003;102(4):1232–1240. ertoire of cord blood donors [25]; however, data on 2. Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute immune recovery were not available in our study. myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115 Historically, the use of RIC in UCBT has been associated (3):453–474. with the double cord blood platform as developed by investi- 3. Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of gators from the University of Minnesota. In line with these unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Lancet. 2007;369(9577):1947– findings, the group of RIC patients in our study more fre- 1954. quently received double UCBT to overcome the cell dose limi- 4. Ruggeri A, Labopin M, Sanz G, et al. Comparison of outcomes after unre- tation when a single UCB unit with adequate TNC count was lated cord blood and unmanipulated haploidentical stem cell transplanta- tion in adults with acute leukemia. Leukemia. 2015;29(9):1891–1900. not available [26]. Importantly, we confirmed similar out- 5. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation comes between single and double UCBT for older patients, as after reduced intensity conditioning: results of parallel phase 2 trials using previously reported in prospective trials accruing children and partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118(2):282–288. young adults [27]. Similar to all previous studies, disease status 6. Ruggeri A, Sanz G, Bittencourt H, et al. Comparison of outcomes after sin- prior to transplant was significantly associated with overall gle or double cord blood transplantation in adults with acute leukemia outcome [12,13,23]. using different types of myeloablative conditioning regimen, a retrospec- tive study on behalf of Eurocord and the Acute Leukemia Working Party Previous studies showed a detrimental impact of ATG on of EBMT. Leukemia. 2014;28(4):779–786. NRM and OS in patients given double UCBT after MAC [28] or 7. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced- RIC [29], despite the association with in vivo T cell depletion intensity hematopoietic cell transplantation for acute myeloid leukemia with a reduced risk of aGVHD. The use of ATG in patients and myelodysplastic syndromes. J Clin Oncol. 2017;35(11):1154–1161. 8. Sheth V, Labopin M, Canaani J, et al. Comparison of FLAMSA-based receiving UCBT should be done cautiously, preferably in the reduced intensity conditioning with treosulfan/fludarabine conditioning setting of clinical trials. Studies of individualized ATG dosing for patients with acute myeloid leukemia: an ALWP/EBMT analysis. Bone could be helpful in investigation of the optimal dose schedule Marrow Transplant. 2019;54(4):531–539. 9. Nagler A, Labopin M, Beelen D, et al. Long-term outcome after a treosul- of ATG to improve outcomes. fan-based conditioning regimen for patients with acute myeloid leuke- Our study is limited by its design being retrospective and mia: a report from the Acute Leukemia Working Party of the European the imbalance of the 2 groups for risk factors known to be Society for Blood and Marrow Transplantation. Cancer. 2017;123 (14):2671–2679. associated with outcome: RIC patients more frequently 10. Hiwarkar P, Qasim W, Ricciardelli I, et al. Cord blood T cells mediate received double UCBT without ATG. These differences were enhanced antitumor effects compared with adult peripheral blood T cells. carefully adjusted for in the multivariate analysis. Also, differ- Blood. 2015;126(26):2882–2891. 11. Somers JA, Braakman E, van der Holt B, et al. Rapid induction of single ences in practices as regards to conditioning regimen as well donor chimerism after double umbilical cord blood transplantation pre- as GVHD prophylaxis across various centers need to be taken ceded by reduced intensity conditioning: results of the HOVON 106 phase into account. Although considering mismatches at standard II study. Haematologica. 2014;99(11):1753–1761. 12. Rio B, Chevret S, Vigouroux S, et al. Decreased nonrelapse mortality after HLA A/B and DRB1 is standard practice in most of the centers, unrelated cord blood transplantation for acute myeloid leukemia using our study is limited by the fact that we have not taken into reduced-intensity conditioning: a prospective phase II multicenter trial. account additional and clinically relevant mismatches such as Biol Blood Marrow Transplant. 2015;21(3):445–453. for HLA C [16]. 13. Baron F, Ruggeri A, Beohou E, et al. RIC versus MAC UCBT in adults with AML: a report from Eurocord, the ALWP and the CTIWP of the EBMT. How these results will compare with hematopoietic cell Oncotarget. 2016;7(28):43027–43038. transplantation from haploidentical or unrelated donor should 14. Eapen M, Klein JP, Ruggeri A, et al. Impact of allele-level HLA match- be further investigated. So far, data available in literature from ing on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014;123(1):133– single centers and registry studies [3,4] revealed comparable 140. outcomes of UCBT and mismatched related or unrelated donor 15. Yabe T, Azuma F, Kashiwase K, et al. HLA-DPB1 mismatch induces a graft- transplantation, but this should be carefully considered in a versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation. Leukemia. 2018;32(1):168–175. homogeneous cohort and uniform conditioning regimen and 16. Yokoyama H, Morishima Y, Fuji S, et al. Impact of HLA allele mismatch at GVHD prophylaxis (ie, with post-transplant cyclophospha- HLA-A, -B, -C, and -DRB1 in single cord blood transplantation. Biol Blood mide). Marrow Transplant. 2020;26(3):519–528. 17. Brunstein CG, Cutler CS, DeFor TE, et al. Matching at human leukocyte In summary, the use of UCBT with 2 or greater HLA mis- antigen-C improved the outcomes after double umbilical cord blood matches is still limited, and in this setting, RIC showed compa- transplantation for recipients of two to four of six human leukocyte anti- rable outcomes to MAC in patients aged 40 to 60 years. There gen-matched grafts. Biol Blood Marrow Transplant. 2017;23(1):126–133. 18. Sanz J, Jaramillo FJ, Planelles D, et al. Impact on outcomes of human leuko- is a need to find other means of reducing NRM without cyte antigen matching by allele-level typing in adults with acute myeloid increasing relapses by achieving better disease control prior to leukemia undergoing umbilical cord blood transplantation. Biol Blood transplant, designing better pretransplant strategies, avoiding Marrow Transplant. 2014;20(1):106–110. use of ATG, and not solely relying on modulation of the inten- 19. Spyridonidis A, Labopin M, Savani BN, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute mye- sity of conditioning. loid leukemia patients. Bone Marrow Transplant. 2020;55(6):1114– 1125. 2104 V. Sheth et al. / Biol Blood Marrow Transplant 26 (2020) 2098 2104 20. Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic clas- Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study. Leukemia. sification in acute myeloid leukemia: determination of prognostic signifi- 2020;34(1):128–137. cance of rare recurring chromosomal abnormalities among 5876 younger 25. Baron F, Ruggeri A, Beohou E, et al. Occurrence of graft-versus-host dis- adult patients treated in the United Kingdom Medical Research Council ease increases mortality after umbilical cord blood transplantation for trials. Blood. 2010;116(3):354–365. acute myeloid leukaemia: a report from Eurocord and the ALWP of the 21. Vigorito AC, Campregher PV, Storer BE, et al. Evaluation of NIH consensus EBMT. J Intern Med. 2018;283(2):178–189. criteria for classification of late acute and chronic GVHD. Blood. 2009;114 26. Ruggeri A. Optimizing cord blood selection. Hematology Am Soc Hematol (3):702–708. Educ Program. 2019;2019(1):522–531. 22. Savani BN, Labopin M, Kroger N, et al. Expanding transplant options to 27. Wagner Jr JE, Eapen M, Carter S, et al. One-unit versus two-unit cord- patients over 50 years: improved outcome after reduced intensity condi- blood transplantation for hematologic cancers. N Engl J Med. 2014;371 tioning mismatched-unrelated donor transplantation for patients with (18):1685–1694. acute myeloid leukemia: a report from the Acute Leukemia Working Party 28. Pascal L, Mohty M, Ruggeri A, et al. Impact of rabbit ATG-containing mye- of the EBMT. Haematologica. 2016;101(6):773–780. loablative conditioning regimens on the outcome of patients undergoing 23. Barker JN, Fei M, Karanes C, et al. Results of a prospective multicentre myeloa- unrelated single-unit cord blood transplantation for hematological malig- blative double-unit cord blood transplantation trial in adult patients with nancies. Bone Marrow Transplant. 2015;50(1):45–50. acute leukaemia and myelodysplasia. Br J Haematol. 2015;168(3):405–412. 29. Pascal L, Tucunduva L, Ruggeri A, et al. Impact of ATG-containing reduced- 24. Kanda J, Hayashi H, Ruggeri A, et al. Prognostic factors for adult single cord intensity conditioning after single- or double-unit allogeneic cord blood blood transplantation among European and Japanese populations: the transplantation. Blood. 2015;126(8):1027–1032.