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      Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

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          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.

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          Most cited references 59

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          Venoocclusive disease of the liver following bone marrow transplantation.

          Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.
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            Regimen-related toxicity in patients undergoing bone marrow transplantation.

            Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.
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              Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan.

              Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.

                Author and article information

                Bone Marrow Transplant
                Bone Marrow Transplant
                Bone Marrow Transplantation
                Nature Publishing Group UK (London )
                20 March 2020
                20 March 2020
                : 55
                : 10
                : 1996-2007
                [1 ]GRID grid.4495.c, ISNI 0000 0001 1090 049X, Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, , Wroclaw Medical University, ; Wroclaw, Poland
                [2 ]GRID grid.413991.7, ISNI 0000 0004 0641 6082, Sheffield Children’s Hospital, ; Sheffield, UK
                [3 ]Department of Pediatric Hematology and Oncology, Collegium Medicum UMK Torun, Bydgoszcz, Poland
                [4 ]GRID grid.7839.5, ISNI 0000 0004 1936 9721, Department for Children and Adolescents, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, , Goethe University, ; Frankfurt, Germany
                [5 ]GRID grid.411941.8, ISNI 0000 0000 9194 7179, University Hospital of Regensburg, ; Regensburg, Germany
                [6 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Pediatric Hematology, Oncology and BMT, , University Hospital Muenster, ; Muenster, Germany
                [7 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Pediatrics, , Hannover Medical School, ; Hannover, Germany
                [8 ]GRID grid.411484.c, ISNI 0000 0001 1033 7158, Department of Pediatric Hematology, Oncology and Transplantology, , Medical University of Lublin, ; Lublin, Poland
                [9 ]GRID grid.415112.2, Medical College, , University Children’s Hospital in Cracow Jagiellonian University, ; Cracow, Poland
                [10 ]GRID grid.7605.4, ISNI 0000 0001 2336 6580, Children’s Hospital Regina Margherita, , University of Turin, ; Turin, Italy
                [11 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, University Children’s Hospital Heidelberg, ; Heidelberg, Germany
                [12 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Department of Pediatrics, , Jena University Hospital, ; Jena, Germany
                [13 ]GRID grid.410718.b, ISNI 0000 0001 0262 7331, Depertment of Pediatrics III, , University Hospital of Essen, ; Essen, Germany
                [14 ]GRID grid.7841.a, IRCCS Bambino Gesú Children’s Hospital, , Sapienza University of Rome, ; Rome, Italy
                [15 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [16 ]GRID grid.488568.f, ISNI 0000 0004 0490 6520, University Children’s Hospital of Wuerzburg, ; Wuerzburg, Germany
                [17 ]GRID grid.412826.b, ISNI 0000 0004 0611 0905, Department of Pediatric Hematology and Oncology, , University Hospital Motol, ; Prague, Czech Republic
                [18 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Children’s Hospital, , University of Erlangen, ; Erlangen, Germany
                [19 ]GRID grid.476484.d, ISNI 0000 0004 0554 5851, medac GmbH, ; Wedel, Germany
                [20 ]GRID grid.420468.c, Great Ormond Street Hospital, ; London, UK
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

                Funded by: medac GmbH, MC-FludT.17/M, EudraCT No. 2013-003604-39
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                haematopoietic stem cells, leukaemia


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