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

Krzysztof Kalwak, Monika Mielcarek, Katharine Patrick, Jan Styczynski, Peter Bader, Selim Corbacioglu, Birgit Burkhardt, Karl Walter Sykora, Katarzyna Drabko, Jolanta Gozdzik, Franca Fagioli, Johann Greil, Bernd Gruhn, Rita Beier, Franco Locatelli, Ingo Müller, Paul Gerhardt Schlegel, Petr Sedlacek, Klaus Daniel Stachel, Claudia Hemmelmann, Ann-Kristin Möller, Joachim Baumgart, Ajay Vora, Krzysztof Kalwak, Monika Mielcarek, Katharine Patrick, Jan Styczynski, Peter Bader, Selim Corbacioglu, Birgit Burkhardt, Karl Walter Sykora, Katarzyna Drabko, Jolanta Gozdzik, Franca Fagioli, Johann Greil, Bernd Gruhn, Rita Beier, Franco Locatelli, Ingo Müller, Paul Gerhardt Schlegel, Petr Sedlacek, Klaus Daniel Stachel, Claudia Hemmelmann, Ann-Kristin Möller, Joachim Baumgart, Ajay Vora

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/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/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.

Trial registration: ClinicalTrials.gov NCT02333058.

Conflict of interest statement

KK has received research funding from medac GmbH, Sanofi, and other travel grants. PB has received research funding and patents and royalties from medac GmbH, research funding from Riemser and Neovii. He also received compensation from Cellgene and Novartis for his consultations. In addition, he received compensation from Novartis for Speakers Bureau. BG received honoraria from Jazz Pharmaceuticals. KP received funding from medac GmbH and other funding for EBMT conference fees and accommodation. Prof. KW S received research funding and travel grants from medac GmbH and Aventis-Behring. SC received honoraria for his consultations from Gentium and Jazz Pharmaceuticals. RB received travel grants from medac GmbH and Neovii and is on Bluebird Bio’s advisory board. FL received funding for EBMT/ASH conference fees and accommodation as well as speakers bureau from medac GmbH. AV is on the advisory board for Pfizer, medac GmbH, Novartis, Amgen, and Jazz Pharmaceuticals and also received other funding from them. CH, AKM, and JB are employees of medac GmbH. JB has licensed an employee’s invention (PCT/EP00/10871) to medac GmbH.

Figures

Fig. 1
Fig. 1
Treosulfan dose-dependent cumulative incidence of non-relapse mortality (a), relapse/progression (b), Kaplan–Meier estimate of relapse/progression-free survival (c) and of overall survival (d).
Fig. 2
Fig. 2
Forest plot for relapse/progression-free survival displaying 36 months rates by subgroups.
Fig. 3
Fig. 3
Kaplan–Meier estimates of (a) GvHD-free and relapse/progression-free survival and (b) chronic GvHD-free and relapse/progression-free survival.
Fig. 4
Fig. 4
Kaplan–Meier estimate of overall survival.

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