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Unrelated cord blood transplantation in children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome: a retrospective comparative study from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) between Real-World Data and previously reported results of a Randomized Clinical Trial
Teyssier, A. C., Michel, G., Jubert, C., Rialland, F., Visentin, S., Ouachée, M., Bilger, K., Gandemer, V., Beguin, Y., Marie-Cardine, A., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality (TRM), engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality (TRM), engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n = 137) to a Francophone population-based registry of patients (real-world (RW) group) fulfilling the eligibility criteria used in our RCT and transplanted with one or two UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n = 141). The primary endpoint was the two-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, p < 0.001) and to receive a radiation-free regimen (39.0% vs. 60.6%, p < 0.001). The two-year CI of transplantation strategy failure, TRM, and the two-year probability of OS were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%, p = 0.01), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%, p = 0.047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used. OBJECTIVES AND STUDY DESIGN We compared the characteristics and outcomes of RCT participants (n = 137) to a Francophone population-based registry of patients (real-world (RW) group) fulfilling the eligibility criteria used in our RCT and transplanted with one or two UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n = 141). The primary endpoint was the two-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. RESULTS The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, p < 0.001) and to receive a radiation-free regimen (39.0% vs. 60.6%, p < 0.001). The two-year CI of transplantation strategy failure, TRM, and the two-year probability of OS were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%, p = 0.01), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%, p = 0.047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). CONCLUSION The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.
PICO Summary
Population
Children, adolescents and young adults with acute leukaemia or myelodysplastic syndrome
Intervention
Participants in a randomised controlled trial (RCT) (n=137)
Comparison
Patients from a real-world cohort reported to a Francohpone regisistry, receiving onr or two cord blood units after myeloablative conditioning (RW group, n=141)
Outcome
The two groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%) and to receive a radiation-free regimen (39.0% vs. 60.6%). The two-year CI of transplantation strategy failure, Transplant related mortality, and the two-year probability of overall survival were similar between the two groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% vs. 20.4% ± 6.8%), resulting in a significantly lower DFS (59.2% ± 8.4% vs. 69.3% ± 8.0%). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg).
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Umbilical cord blood transplants facilitated by the French cord blood banks network. On behalf of the Agency of Biomedicine, Eurocord and the French society of bone marrow transplant and cell therapy (SFGM-TC)
Rafii, H., Garnier, F., Ruggeri, A., Ionescu, I., Ballot, C., Bensoussan, D., Chabannon, C., Dazey, B., De Vos, J., Gautier, E., et al
Bone marrow transplantation. 2021
Abstract
The public French Cord Blood Banks Network was established in 1999 with the objective of standardizing the practices governing umbilical cord blood (UCB) banking in France. The Network adopted a strategy to optimize its inventory and improve the quality of its banked units based on a quality improvement process using outcome data regularly provided by Eurocord. This study aimed to describe the results, over 10 years, of UCBT facilitated by a national network that used the same criteria of UCB collection and banking and to assess how modifications of banking criteria and unit selection might influence transplant outcomes. Nine hundred and ninety-nine units (593 single-unit and 203 double-unit grafts) were released by the Network to transplant 796 patients with malignant (83%) and non-malignant (17%) diseases. Median cell dose exceeded 3.5?×?10(7) TNC/kg in 86%. There was a trend to select units more recently collected and with higher cell dose. Neutrophil engraftment was 88.2% (85.7-90.7) and 79.3% (72.6-86.5) respectively for malignant and non-malignant diseases with a trend to faster recovery with higher cell doses. The respective 3-year transplant-related mortality were 31.1% (27.5-35.1) and 34.3% (27.0-43.5). OS was 49%?±?4 in malignant and 62%?±?4 in non-malignant disorders. In multivariate analysis, cell dose was the only unit-related factor associated with outcomes. Our results reflect the benefit on clinical outcomes of the strategy adopted by the Network to bank units with higher cell counts.
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Myeloablative unrelated cord blood transplantation in adolescents and young adults with acute leukemia
Hayashi, H., Volt, F., Sanz, J., Petersen, E., Dhedin, N., Hough, R., Milpied, N., Angelucci, E., Yakoub-Agha, I., Michallet, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Outcomes for adolescents and young adults (AYA) with leukemia differ from other age groups but are still underrepresented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA with acute leukemia reported to Eurocord/EBMT. Patients (n=504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15-25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. Primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (HR 2.74, p <0.001) and more recent UCBT (HR 1.43, p=0.01) were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT (HR 1.65, p =0.02) and decreased with more recent transplantation period (HR 0.65, p=0.02) and ATG use (HR 0.55, p =0.01). Outcomes of AYA UCBT improved in more recent years becoming comparable to pediatric results. Demonstrating the feasibility of UCBT in AYA facilitates stem cell source selection and provides the basis for future prospective studies.
PICO Summary
Population
Adolescents and young adults with acute leukaemia (n=504)
Intervention
Unrelated cord blood transplantation after myeloablative conditioning
Comparison
None
Outcome
Three-year overall survival (OS) was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIF) of non-relapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute GVHD grade II-IV at day-100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT and more recent UCBT were associated with increased OS and a similar effect of these factors was observed on LFS. Contrastingly, the use of ATG had a negative effect in LFS. The risk of acute GVHD grade II-IV increased with the use of double UCBT and decreased with more recent transplantation period and ATG use.
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Low Body Mass Index Is Associated with Increased Risk of Acute GVHD after Umbilical Cord Blood Transplantation in Children and Young Adults with Acute Leukemia: A Study on Behalf of Eurocord and the EBMT Pediatric Disease Working Party
Paviglianiti, A., Dalle, J. H., Ayas, M., Boelens, J. J., Volt, F., Iori, A. P., de Souza, M. P., Diaz, M. A., Michel, G., Locatelli, F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(4):799-805
Abstract
Body mass index (BMI) may influence outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of BMI on survival in children undergoing HSCT is not well defined, with conflicting results being reported on this issue. We analyzed 855 patients age 2 to 20 years with diagnosis of acute leukemia who underwent umbilical cord blood transplantation (UCBT) from 1990 to 2015. Patients were classified according to BMI as normal (fifth to 85th percentile), underweight (less than fifth percentile), overweight (85th to 95th percentile), and obese (>95th percentile) using growth charts for age and sex. All patients received single-unit UCBT after a myeloablative conditioning regimen. Diagnosis was acute lymphoblastic leukemia in 68% of the patients. Sixty-one percent of patients (n = 523) were in the normal BMI category, 11% (n = 96) were underweight, 16% (n = 137) overweight, and 12% (n = 99) obese. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was 35% (32% to 38%). According to pretransplantation BMI, aGVHD was 46% (33% to 59%) for underweight, 34% (31% to 42%) for normal, 36% (18% to 38%) for overweight, and 27% (15% to 37%) for obese (P = .04). In multivariate analysis, a BMI less than the fifth percentile was associated with higher incidence of acute grade II to IV GVHD compared with normal-BMI patients (hazard ratio, 1.61; 95% confidence interval, 1.15 to 2.26; P = .006). Our results show that being underweight at the time of transplantation is associated with an increased risk of aGVHD, highlighting the importance of nutritional status before UCBT.
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Unrelated cord blood transplantation in patients with acquired refractory aplastic anemia: a nationwide phase II study
Peffault de Latour, R., Chevret, S., Jubert, C., Sirvent, A., Galambrun, C., Ruggeri, A., Gandemer, V., Cornillon, J., Rialland, F., Dalle, J. H., et al
Blood. 2018
Abstract
Outcomes remain poor for patients with refractory severe aplastic anemia (SAA). Alternative donor transplantation may be considered, but results from previous studies have not been encouraging. We conducted a prospective nationwide phase II study to assess the efficacy and safety of unrelated cord blood transplantation (CBT) in patients with refractory SAA (APCORD protocol, NCT 01343953). To demonstrate a significant difference in one-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients. Twenty-six patients (median age: 16 years) were therefore included. Eligibility criteria required one or two unrelated CB units, containing separately or together more than 4x10(7) frozen nucleated cells/kg recipient body weight. The conditioning regimen comprised fludarabine, cyclophosphamide, thymoglobulin and 2-Gy total body irradiation. With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic GvHD were 45.8% and 36%, respectively. Twenty-three patients were alive at one year, with an overall survival rate of 88.5%, differing significantly from the expected 20% (p<0.0001) (84% overall survival at 2 years). CBT with units containing at least 4x10(7) frozen nucleated cells/kg is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors.
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Single vs double-unit cord-blood transplantation in children and young adults with residual leukemic disease
Balligand, L., Galambrun, C., Sirvent, A., Roux, C., Pochon, C., Bruno, B., Jubert, C., Loundou, A., Esmiol, S., Yakoub-Agha, I., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 does not decrease the risk of transplantation failure but may enhance alloreactivity. We present here the influence of pre-transplant minimal residual disease (MRD) on leukemia relapse and survival after single versus double-UCB transplantation. Among 137 children and young adults who were transplanted in the randomized study, 115 had available MRD assessment immediately before their conditioning regimen. MRD was considered positive when ≥ 10(-4), which was the case of 43 out of 115 patients. Overall, the 3-year survival probability was 69.1+/-4.4% and it was not significantly influenced by the MRD level: 70.7+/-5.4% in MRD- (<10(-4)) patients (n=72), 71.1+/-9.4% in MRD+ with 10(-4)≤MRD<10(-3) (n=26), and 58.8+/-11.9% in MRD+ ≥ 10(-3) patients (n=17). In the MRD+ group, we found a significantly lower risk of relapse in the double- versus single-unit arm (10.5+/-7.2% vs 41.7+/-10.4%; p=0.025) leading to a higher 3-year survival rate (82.6+/-9.3% vs 53.6+/-10.3%, p=0.031). This difference was only observed in patients who had not received anti-thymocyte globulin (ATG) during their conditioning regimen. In the MRD- group, no difference was found between the single- and the double-unit arms. We conclude that, even in case of positive pre-transplant MRD, UCB transplantation in children and young adults with acute leukemia results in a high cure rate and that a double-unit strategy may enhance graft-vs-leukemia effect and survival in these patients.
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Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis
Ruggeri, A., Volt, F., Locatelli, F., Michel, G., Diaz de Heredia, C., Abecasis, M., Zecca, M., Vora, A., Yakouben, K., O'Brien, T. A., et al
Biology of Blood & Marrow Transplantation. 2017;23(1):96-102
Abstract
Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n=157) or acute myelogenous leukemia (AML; n=95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40%+/-3% and of 4-year chronic GVHD was 13%+/-2%. CIF of 1-year transplant-related mortality was 23%+/-3% and of 4-year relapse was 27%+/-3%. Leukemia-free-survival (LFS) at 4 years was 50%+/-3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P=.001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P=.001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P=.012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis
Eapen, M., Wang, T., Veys, P. A., Boelens, J. J., St Martin, A., Spellman, S., Bonfim, C. S., Brady, C., Cant, A. J., Dalle, J. H., et al
The Lancet Haematology. 2017;4(7):e325-e333
Abstract
BACKGROUND The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation. METHODS We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model. FINDINGS Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1.55, 95% CI 1.08-2.21, p=0.018), three (2.04, 1.44-2.89, p=0.0001), and four or more alleles (3.15, 2.16-4.58, p<0.0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1.18, 95% CI 0.80-1.72, p=0.39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1.40, 95% CI 1.13-1.74, p=0.0020), reduced intensity compared with myeloablative conditioning regimens (HR 1.36, 1.10-1.68, p=0.0041), transplantation of units with total nucleated cell dose of more than 21 x 107 cells per kg compared with 21 x 107 cells per kg or less (HR 1.47, 1.11-1.95, p=0.0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1.64, 1.31-2.04, p<0.0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality. INTERPRETATION These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1. FUNDING National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.
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Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience
Alloin, A. L., Leverger, G., Dalle, J. H., Galambrun, C., Bertrand, Y., Baruchel, A., Auvrignon, A., Gandemer, V., Ragu, C., Loundou, A., et al
Bone Marrow Transplantation. 2017;52(4):516-521
Abstract
We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.
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Unrelated cord blood transplantation for childhood acute myelogenous leukemia: The influence of cytogenetic risk group stratification
Michel, G., Cunha, R., Ruggeri, A., O'Brien, T. A., Bittencourt, H., Dalle, J. H., Locatelli, F., Iori, A. P., Mauad, M., Oudin, C., et al
Leukemia. 2016;30(5):1180-3