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Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial
Sykora, K. W., Beier, R., Schulz, A., Cesaro, S., Greil, J., Gozdzik, J., Sedlacek, P., Bader, P., Schulte, J., Zecca, M., et al
Bone marrow transplantation. 2023
Abstract
Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m(2)/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.
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Acute Lymphoblastic Leukemia in Children: Better Transplant Outcomes After Total Body Irradiation-based Conditioning
Styczynski, J., Debski, R., Czyzewski, K., Gagola, K., Marquardt, E., Roszkowski, K., Winiecki, J., Irga-Jaworska, N., Hennig, M., Muszynska-Roslan, K., et al
In vivo (Athens, Greece). 2021;35(6):3315-3320
Abstract
BACKGROUND/AIM: Comparison of transplant outcomes in long-term follow-up of children after total body irradiation (TBI)- or chemotherapy-based conditioning allogeneic hematopoietic cell transplantation (allo-HCT). PATIENTS AND METHODS Patients undergoing allo-HCT for Acute lymphoblastic leukemia (ALL) conditioned either with TBI (n=55) or chemotherapy (n=84) were compared. The following transplant outcomes were analyzed: overall survival (OS), event-free survival (EFS), relapse incidence (RI), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS). RESULTS All analyzed long-term transplant outcomes were significantly better for patients conditioned with TBI at 2 years after transplant. OS at 2 years was 84% after TBI and 60.5% after chemotherapy-conditioning (p=0.005). Risk factor analysis showed that two factors, TBI-based conditioning and transplant in first remission of ALL, significantly improved OS, EFS, GRFS, and decreased RI. CONCLUSION TBI-based conditioning before allogeneic HCT in children with acute lymphoblastic leukemia provides significantly better transplant outcomes, when compared to chemotherapy-based conditioning.
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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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Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies
Kalwak, K., Mielcarek, M., Patrick, K., Styczynski, J., Bader, P., Corbacioglu, S., Burkhardt, B., Sykora, K. W., Drabko, K., Gozdzik, J., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m(2)/day (7.7%), 12 g/m(2)/day (35.4%), or 14 g/m(2)/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.
PICO Summary
Population
Children with haematological malignancies (n=65)
Intervention
Conditioning with treosulfan, dosed according to body surface area, in combination with fludarabine and thiotepa
Comparison
None
Outcome
The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported.