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Reduced-toxicity myeloablative conditioning regimen using fludarabine and full doses of intravenous busulfan in pediatric patients not eligible for standard myeloablative conditioning regimens: Results of a multicenter prospective phase 2 trial
Rialland, F., Grain, A., Labopin, M., Michel, G., Gandemer, V., Paillard, C., Pochon, C., Clement, L., Brissot, E., Jubert, C., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Data regarding the safety and efficacy of reduced-toxicity conditioning regimen (RTC) prior to allogeneic stem cell transplantation (allo-SCT) to treat hematological malignancies in pediatric patients are limited. This prospective multicenter, phase 2 trial investigated a RTC regimen based on the combination of intravenous busulfan (3.2 mg/kg/d x 4 days), fludarabine (30 mg/m(2)/d x 5 days) and antithymocyte globulin (Thymoglobulin®, Genzyme; 5 mg/kg total dose) with the aim of delivering high dose myeloablation that would allow optimal disease control while minimizing toxicity, in a subgroup of children at very high risk of non-relapse mortality (NRM). The primary endpoint was NRM at 1 year after allo-SCT. A total of 48 high risk patients were included (median age, 13 years; range, 3-24). At 1 year, the cumulative incidence of recurrence/disease progression and NRM were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively. We conclude that the RTC regimen used in this prospective trial is safe, with a < 10% NRM rate noted among high-risk children and adolescents, paving the way for larger phase 3 trials incorporating novel agents pre- and post-allo-SCT.(ClinicalTrials.gov Identifier: NCT01572181).
PICO Summary
Population
Children and adolescents with haematological malignancies, but not eligible for standard myeloablative conditioning regimens, in 16 centres in France (n=48)
Intervention
30 mg/m2/d fludarabine for 5 consecutive days (day -6 to -2), 3.2 mg/kg/day IV Busulfan administered four times daily in a 2 h infusion for 4 consecutive days (day -5, -4, -3, and -2), and 2.5 mg/Kg/d antithymocyte globulin for 2 consecutive days (day -2 and -1).
Comparison
None
Outcome
At 1 year, the cumulative incidence of recurrence/disease progression and non-relapse mortality (NRM) were 33% and 8%, respectively. With a median follow-up of 23 months, the Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) at 1 year were 69% and 58%, respectively.
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Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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Gonadal function after Busulfan compared to Treosulfan in children and adolescents undergoing allogeneic hematopoietic stem cell transplantation. On Behalf of the Pediatric and Transplant Complications Working Parties of EBMT
Faraci, M., Diesch, T., Labopin, M., Dalissier, A., Lankester, A., Gennery, A., Sundin, M., Uckan-Cetinkaya, D., Bierings, M., Peters, A. M. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
INTRODUCTION Gonadal impairment is an important late effect having a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after Busulfan (Bu) or Treosulfan (Treo) conditioning regimens in pre and post-pubertal children. MATERIAL AND METHODS This is a retrospective, multicenter study including children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemo-radiotherapy before the transplant. RESULTS We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range 5-18); 89 patients were males and 48 were females. Eighty-nine patients were pre-pubertal at transplant, while 48 were post-pubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of females treated with Treo in pre-pubertal stage reached spontaneous puberty compared to those treated with Bu (p=0.02). Spontaneous menarche was more frequent after Treo than after Bu (p< 0.001). Post-pubertal males and females treated with Treo had significantly lower luteinizing hormone (LH) levels (p=0.03 and p=0.04, respectively) compared to the Bu group. CONCLUSIONS Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.
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Factors Associated with Long-Term Risk of Relapse after Unrelated Cord Blood Transplantation in Children with Acute Lymphoblastic Leukemia in Remission
Page, K. M., Labopin, M., Ruggeri, A., Michel, G., Diaz de Heredia, C., O'Brien, T., Picardi, A., Ayas, M., Bittencourt, H., Vora, A. J., et al
Biology of Blood & Marrow Transplantation. 2017;23(8):1350-1358
Abstract
For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n=257, 40%) or second complete remission (CR2; n=383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2+ (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (>=30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated.
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Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation
Gluckman, E., Cappelli, B., Bernaudin, F., Labopin, M., Volt, F., Carreras, J., Pinto Simoes, B., Ferster, A., Dupont, S., de la Fuente, J., et al
Blood. 2017;129(11):1548-1556
Abstract
Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.
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More chronic GvHD and non-relapse mortality after peripheral blood stem cell compared with bone marrow in hematopoietic transplantation for paediatric acute lymphoblastic leukemia: a retrospective study on behalf of the EBMT Paediatric Diseases Working Party
Simonin, M., Dalissier, A., Labopin, M., Willasch, A., Zecca, M., Mouhab, A., Chybicka, A., Balduzzi, A., Volin, L., Peters, C., et al
Bone Marrow Transplantation. 2017;52(7):1071-1073
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Impact of Conditioning Regimen on Outcomes for Children with Acute Myeloid Leukemia Undergoing Transplantation in First Complete Remission. An Analysis on Behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation
Lucchini, G., Labopin, M., Beohou, E., Dalissier, A., Dalle, J. H., Cornish, J., Zecca, M., Samarasinghe, S., Gibson, B., Locatelli, F., et al
Biology of Blood & Marrow Transplantation. 2017;23(3):467-474
Abstract
Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients>2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P<.01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P=.04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P<.01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P=.79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS. Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.