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High-dose treosulfan and melphalan as consolidation therapy versus standard therapy for high-risk (metastatic) ewing sarcoma

PURPOSE - - Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). - - MET...

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Main Authors: Koch, Raphael (Author) , Gelderblom, Hans (Author) , Haveman, Lianne (Author) , Brichard, Benedicte (Author) , Jürgens, Heribert (Author) , Cyprova, Sona (Author) , van den Berg, Henk (Author) , Hassenpflug, Wolf (Author) , Raciborska, Anna (Author) , Ek, Torben (Author) , Baumhoer, Daniel (Author) , Egerer, Gerlinde (Author) , Eich, Hans Theodor (Author) , Renard, Marleen (Author) , Hauser, Peter (Author) , Burdach, Stefan (Author) , Bovee, Judith (Author) , Bonar, Fiona (Author) , Reichardt, Peter (Author) , Kruseova, Jarmila (Author) , Hardes, Jendrik (Author) , Kühne, Thomas (Author) , Kessler, Torsten (Author) , Collaud, Stephane (Author) , Bernkopf, Marie (Author) , Butterfaß-Bahloul, Trude (Author) , Dhooge, Catharina (Author) , Bauer, Sebastian (Author) , Kiss, János (Author) , Paulussen, Michael (Author) , Hong, Angela (Author) , Ranft, Andreas (Author) , Timmermann, Beate (Author) , Rascon, Jelena (Author) , Vieth, Volker (Author) , Kanerva, Jukka (Author) , Faldum, Andreas (Author) , Metzler, Markus (Author) , Hartmann, Wolfgang (Author) , Hjorth, Lars (Author) , Bhadri, Vivek (Author) , Dirksen, Uta (Author)
Format: Article (Journal)
Language:English
Published: April 15, 2022
In: Journal of clinical oncology
Year: 2022, Volume: 40, Issue: 21, Pages: 2307-2320
ISSN:1527-7755
DOI:10.1200/JCO.21.01942
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1200/JCO.21.01942
Verlag, lizenzpflichtig, Volltext: https://ascopubs.org/doi/10.1200/JCO.21.01942
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Author Notes:Raphael Koch, PhD; Hans Gelderblom, MD; Lianne Haveman, MD; Benedicte Brichard, MD; Heribert Jürgens, MD; Sona Cyprova, MD; Henk van den Berg, MD, MMED, PhD; Wolf Hassenpflug, MD; Anna Raciborska, MD; Torben Ek, MD, PhD; Daniel Baumhoer, MD; Gerlinde Egerer, MD; Hans Theodor Eich, MD; Marleen Renard, MD; Peter Hauser, MD; Stefan Burdach, MD; Judith Bovee, MD; Fiona Bonar, MD; Peter Reichardt, MD; Jarmila Kruseova, MD, PhD; Jendrik Hardes, MD; Thomas Kühne, MD; Torsten Kessler, MD; Stephane Collaud, MD; Marie Bernkopf, PhD; Trude Butterfaß-Bahloul, MD; Catharina Dhooge, MD, PhD; Sebastian Bauer, MD; János Kiss, MD; Michael Paulussen, MD; Angela Hong, MBBS, MMed, PhD; Andreas Ranft, Dr rer nat; Beate Timmermann, MD; Jelena Rascon, MD, PhD; Volker Vieth, MD; Jukka Kanerva, MD; Andreas Faldum, PhD; Markus Metzler, MD; Wolfgang Hartmann, MD; Lars Hjorth, MD, PhD; Vivek Bhadri, MA, MD, PhD; and Uta Dirksen, MD
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Summary:PURPOSE - - Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). - - METHODS - - Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. - - RESULTS - - Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. - - CONCLUSION - - In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.
Item Description:Gesehen am 29.08.2022
Physical Description:Online Resource
ISSN:1527-7755
DOI:10.1200/JCO.21.01942

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