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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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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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Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children
Benadiba, J., Ansari, M., Krajinovic, M., Vachon, M. F., Duval, M., Teira, P., Cellot, S., Bittencourt, H.
PloS one. 2018;13(4):e0193862
Abstract
Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.