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Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT
Baron, F., Ruggeri, A., Peczynski, C., Labopin, M., Bourhis, J. H., Michallet, M., Chevallier, P., Sanz, J., Forcade, E., Saccardi, R., et al
Bone marrow transplantation. 2023
Abstract
Graft failure has remained a limitation of umbilical cord blood transplantation (CBT). Here, we assessed the outcomes of patients who experienced graft failure after CBT. Inclusion criteria were patients (age ≥ 18 years) experiencing graft failure after unrelated CBT (single or double) between 2005 and 2016, for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), no prior allogeneic or autologous transplantation, no other stem cell product. The study included 87 patients. At 1-year, cumulative incidence of relapse and nonrelapse mortality (NRM) was 35% and 37%, respectively. One-year overall survival (OS) and progression-free survival (PFS) was 40% and 29%, respectively. Forty-six patients underwent a salvage second transplantation with 1-year and 2-year OS and PFS from second transplantation 41% and 34% for OS, and 37% and 34% for PFS, respectively. In multivariate analysis, complete remission (CR) at CBT (HR = 0.45, 95% CI 0.25-0.83, P = 0.01) and reduced-intensity conditioning (HR = 0.51, 95% CI 0.29-0.91, P = 0.023) were associated with better OS. In conclusion, in this retrospective study, we observed that approximately one-quarter of patients experiencing graft failure after CBT remained alive without relapse 2 years later.
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Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Nagler, A., Labopin, M., Cornelissen, J. J., Forcade, E., Chevallier, P., Fegueux, N., Sierra, J., Desmier, D., Labussière-Wallet, H., Byrne, J. L., et al
Bone marrow transplantation. 2022
Abstract
We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar.
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3.
Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT
Baron, F., Ngoya, M., Labopin, M., Cornelissen, J. J., Ganser, A., Forcade, E., Sengeloev, H., Socié, G., Blaise, D., Bornhäuser, M., et al
Bone marrow transplantation. 2021
Abstract
Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P?=?0.36) and 84% in UD 9/10 patients (P?=?0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P?0.001), male gender (P?0.001), second complete remission (CR2) versus CR1 (P?=?0.05), secondary AML (P?=?0.01), antecedent of chronic GVHD (P?0.001) and poor-risk cytogenetics (P?=?0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
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4.
Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia
Dholaria, B., Labopin, M., Sanz, J., Ruggeri, A., Cornelissen, J., Labussière-Wallet, H., Blaise, D., Forcade, E., Chevallier, P., Grassi, A., et al
Journal of hematology & oncology. 2021;14(1):76
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia. METHODS Patients who underwent a first CBT without PTCy (N?=?902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N?=?280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk. RESULTS The incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p?=?0.07) and 15% versus 11% (p?=?0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p?0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p?0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR?=?2.09, 95% CI 1.46-2.99, p?0.0001), and relapse (HR?=?1.35, 95% CI 1-1.83, p?=?0.05), which resulted in worse leukemia-free survival (LFS) (HR?=?1.68, 95% CI 1.34-2.12, p?0.0001), overall survival (OS) (HR?=?1.7, 95% CI 1.33-2.17, p?0.0001), and GVHD-free, relapse-free survival (GRFS) (HR?=?1.49, 95% CI 1.21-1.83, p?0.0001) compared to MMUD. The risk of grade II-IV acute GVHD (p?=?0.052) and chronic GVHD (p?=?0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis. CONCLUSIONS CBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT.
PICO Summary
Population
Patients with acute myeloid leukaemia (n=1182)
Intervention
First cord blood transplant without post-transplant cyclophosphamide (CBT, n=902)
Comparison
Allogeneic haematopoietic stem cell transplantation usinga mismatched unrelated donor with post-transplant cyclophosphamide (MMUD, n=280)
Outcome
The incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% and 15% versus 11% for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR=2.09), and relapse (HR=1.35), which resulted in worse leukemia-free survival (LFS) (HR=1.68), overall survival (OS) (HR=1.7), and GVHD-free, relapse-free survival (GRFS) (HR=1.49) compared to MMUD. The risk of grade II-IV acute GVHD and chronic GVHD did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis.
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Impact of detectable measurable residual disease on umbilical cord blood transplantation
Baron, F., Labopin, M., Ruggeri, A., Sierra, J., Robinson, S., Labussiere-Wallet, H., Potter, M., Ribera, J. M., Deconinck, E., Rambaldi, A., et al
American journal of hematology. 2020
Abstract
The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity versus 33% in those with MRD positivity at transplantation (P<0.001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, versus 38% (P<0.001) and 48% (P=0.004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (i.e. ALL versus AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR=1.8, P=0.003), comparable non-relapse mortality (P=0.44), worse LFS (HR=1.4, P=0.008) and a trend towards worse OS (HR=1.3, P=0.065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT. This article is protected by copyright. All rights reserved.
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Prognostic factors for adult single cord blood transplantation among European and Japanese populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT collaborative study
Kanda, J., Hayashi, H., Ruggeri, A., Kimura, F., Volt, F., Takahashi, S., Labopin, M., Kako, S., Tozatto-Maio, K., Yano, S., et al
Leukemia. 2019
Abstract
Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations. Thus, we performed a collaborative study between Eurocord/ALWP-EBMT and JSHCT/JDCHCT. Adults with acute leukaemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included. The median ages of the Japanese and European cohorts were 51 and 38 years, respectively. Three or more HLA mismatches were more frequently observed in the Japanese cohort. The median total nucleated cell (TNC) counts were 2.58 and 3.51 x 10(7)/kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. The 3-year overall survival (OS) was 41% in JSHCT/JDCHCT and 33% in Eurocord/ALWP-EBMT. In the multivariate analysis, TNC dose and HLA matching had no significant effect on OS in either cohort, whereas year of transplantation, age, and refined disease risk index affected OS in both cohorts. Despite considerable differences in characteristics between the Japanese and European cohorts, we observed similar prognostic factors affecting UCBT outcomes in adult patients with acute leukaemia in both registries.
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Umbilical cord blood versus unrelated donor transplantation in adults with primary refractory or relapsed acute myeloid leukemia: a report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the EBMT
Baron, F., Labopin, M., Ruggeri, A., Ehninger, G., Bonifazi, F., Stelljes, M., Sanz, J., Stuhler, G., Bosi, A., Kroger, N., et al
Blood cancer journal. 2019;9(4):46
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Editor's Choice
Abstract
The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated. In this study, we compared transplantation outcomes of 2963 patients with primary refractory or relapsed AML given CBT, 10/10 HLA-matched UD, or 9/10 HLA-matched UD allo-HCT from 2004 to 2015 at EBMT-affiliated centers. Neutrophil engraftment and complete remission rates in CBT, UD 10/10, and UD 9/10 recipients were 75 and 48%, 93 and 69%, and 93 and 70%, respectively. In multivariate Cox analyses, in comparison with CBT (n = 285), UD 10/10 recipients (n = 2001) had a lower incidence of relapse (HR = 0.7, P = 0.001), a lower incidence of non relapse mortality (HR = 0.6, P < 0.001), better GVHD-free and leukemia-free survival (GRFS, HR = 0.8, P < 0.001) and better survival (HR = 0.6, P < 0.001). Further, in comparison with CBT, 9/10 UD recipients (n = 677) also had a lower incidence of relapse (HR = 0.8, P = 0.02), a lower incidence of nonrelapse mortality (HR = 0.7, P = 0.008), better GRFS (HR = 0.8, P = 0.01) and better survival (HR = 0.7, P < 0.001). In summary, these data suggest that in AML patients with active disease at transplantation, allo-HCT with UD results in better transplantation outcomes than CBT.
PICO Summary
Population
Patients with primary refractory or relapsed acute myeloid leukaemia (n=2963)
Intervention
Cord blood transplant (n=285)
Comparison
Allo-HCST with 10/10 (n=2001) or 9/10 HLA matched unrelated donor (n=677)
Outcome
In comparison with CBT, UD 10/10 recipients had a lower incidence of relapse, a lower incidence of no- relapse mortality, better GVHD-free and leukemia-free survival, and better survival. Further, in comparison with CBT, 9/10 UD recipients also had a lower incidence of relapse, a lower incidence of nonrelapse mortality, and better survival.
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Intrabone transplant provides full stemness of cord blood stem cells with fast hematopoietic recovery and low GVHD rate: results from a prospective study
Bonifazi, F., Dan, E., Labopin, M., Sessa, M., Guadagnuolo, V., Ferioli, M., Rizzi, S., De Carolis, S., Sinigaglia, B., Motta, M. R., et al
Bone marrow transplantation. 2018
Abstract
Umbilical Cord Blood (UCB) represents a valid option for patients with hematopoietic malignancies lacking an HLA matched donor. To overcome the limitation of the low stem cell dose of UCB, the intrabone (IB) route has been proposed. We report the results of a prospective study on a poor-prognosis cohort of 23 patients receiving intrabone single UCB transplant (Clinicaltrials.gov NCT00886522). Cumulative incidence of hematological recovery at day 90 was 82 +/- 9% (ANC > 0.5 x 10(9)/L) and 70 +/- 10% (platelet > 50 x 10(9)/L) and correlated with CD34 + cells in the graft. NRM was 20 +/- 9%. No severe aGVHD and only one extensive cGVHD occurred, with fast immune reconstitution. To test the hypothesis that the direct IB injection could affect the expression of stem cells regulatory pathways, CD34 + cells from BM aspirates at day + 10, + 20, + 30, processed in hypoxic conditions mimicking the BM-microenvironment (7%pO2), were studied for the expression of c-Mpl, Notch1 and CXCR4. We found that the expression of c-Mpl in CD34 + cells at day + 10 significantly correlated with hematological recovery. In conclusion, IB-UCB transplant success is associated with low incidence of GVHD and high-speed platelet recovery; intrabone route may preserve full hematopoietic stemness by direct delivery of UCB stem cells into the hypoxic HSC niche.
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Cord blood transplantation is associated with good outcomes in secondary Acute Myeloid Leukemia in first remission
Baron, F., Labopin, M., Ruggeri, A., Volt, F., Mohty, M., Blaise, D., Chevallier, P., Sanz, J., Fegueux, N., Cornelissen, J. J., et al
Journal of internal medicine. 2018
Abstract
BACKGROUND We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary acute myeloid leukemia (sAML). METHODS Inclusion criteria consisted of ≥ 18 years of age, sAML, first CBT between 2002 and 2016, and either first complete remission (CR) or active disease at CBT. RESULTS One hundred forty six patients met the study inclusion criteria. Status at transplantation was first CR (n=97), primary refractory sAML (n=30) or relapsed (n=19) sAML. Neutrophil engraftment was achieved in 118 patients while the remaining 25 patients (17%) failed to engraft. This include 13% of patients transplanted in first CR versus 30% of those transplanted with active disease (P=0.008)). Two-year incidences of relapse were 25% in first CR patients versus 36% in those with advanced disease (P=0.06) while 2-year incidences of nonrelapse mortality were 35% and 49% (P=0.03), respectively. At 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse free survival were 42% versus 19% (P<0.001), 40% versus 16% (P<0.001), and 26% versus 12% (P=0.002) in first CR patients versus those with advanced disease, respectively. CONCLUSIONS We report here the first study of CBT in a large cohort of sAML patients. Main observation was that CBT rescued approximately 40% of patients with sAML in first CR. This article is protected by copyright. All rights reserved.
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10.
Cord Blood Unit Dominance Analysis and Effect of the Winning Unit on Outcomes after Double Unit Umbilical Cord Blood Transplantation in Adults with Acute Leukaemia: a Retrospective Study on Behalf of Eurocord, the Cord Blood Committee of Cellular Therapy, Immunobiology Working Party and the Acute Leukaemia Working Party of the EBMT
Tozatto-Maio, K., Giannotti, F., Labopin, M., Ruggeri, A., Volt, F., Paviglianiti, A., Kenzey, C., Hayashi, H., Cornelissen, J., Michallet, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
Usually, after double umbilical cord blood transplant (DUCBT) only one of the transplanted units persists long term. The characteristics of the winning cord blood unit (W-CBU) that determine unit dominance and how they influence the outcomes of DUCBT remain unclear. We retrospectively analysed 347 patients with acute leukaemia transplanted with a DUCBT (694 CBU) from 2005 to 2013 who had documented neutrophil engraftment and a W-CBU identified by chimerism analysis, in order to identify unit characteristics impacting on dominance. Median age at DUCBT was 40 years and median follow-up was 35 months. Among W-CBUs, 41% were ≥5/6 human leukocyte antigen (HLA)-matched to the recipient and 59% were ≤4/6. Multivariate analysis indicated that ≤4/6 HLA-matched W-CBUs led to lower leukaemia-free survival (44% vs 56%, HR 1.5, p=0.032) and overall survival (49% vs 62%, HR 1.5, p=0.028), increased non-relapse mortality (26% vs 18%, HR 1.9, p=0.027) and acute graft versus-host disease (46% vs 35%, HR 1.7, p=0.013). We were unable to predict unit dominance, but we demonstrated that outcomes were strongly influenced by the degree of HLA mismatch between W-CBU and recipient. Therefore, selection of both units with the lower number of HLA mismatches with the recipient is indicated.