von Bernd Metzner ; Thomas H. Müller ; Jochen Casper ; Christoph Kimmich ; Claus-Henning Köhne ; Eduard Petershofen ; Andrea Renzelmann ; Ruth Thole ; Andreas Voß ; Martin Dreyling
von Emin Abbasov ; Bernd Metzner ; Thomas H. Müller ; Jochen Casper ; Christoph Kimmich ; Eduard K. Petershofen ; Andrea Renzelmann ; Bernd Rosien ; Ruth Thole ; Andreas Voß ; Claus-Henning Köhne
von Veronika Brixner ; Gesine Bug ; Petra Pohler ; Doris Krämer ; Bernd Metzner ; Andreas Voß ; Jochen Casper ; Ulrich Ritter ; Stefan Klein ; Nael Alakel ; Rudolf Peceny ; Hans G. Derigs ; Frank Stegelmann ; Martin Wolf ; Hubert Schrezenmeier ; Thomas Thiele ; Erhard Seifried ; Hans-Hermann Kapels ; Andrea Döscher ; Eduard K. Petershofen ; Thomas H. Müller ; Axel Seltsam
von Bernd Metzner ; Christiane Pott ; Thomas H. Müller ; Jochen Casper ; Christoph Kimmich ; Andrea Renzelmann ; Ruth Thole ; Andreas Voß ; Claus-Henning Köhne
Treosulfan und Fludarabin (Treo/Flu) ist ein etabliertes Behandlungsschema für Patienten mit myeloischen Neoplasien vor allogenen Stammzelltransplantationen (SZT). Das Rezidivrisiko bleibt ein Problem. Es wurde über die Ergebnisse eines individuellen Behandlungsansatzes mit Treo/Flu und Cytarabin (Treo/Flu/AraC) vor SZT bei Patienten mit akuter myeloischer Leukämie (AML), myelodysplastischem Syndrom (MDS) oder myeloproliferativen Neoplasien (MPN) berichtet. 77 Patienten mit Hochrisikoerkrankungen wurden betrachtet. Der mediane Nachbeobachtungszeitraum umfasste 3,2 Jahre. Ein-, zwei- und dreijährige RFS betrugen 47,5%, 40,7% und 37,3% und die OS 59,3%, 49,3% bzw. 45,4%. Die kumulative Inzidenz (CI) der NRM betrug 10% an Tag +100, 18,8% nach einem Jahr und 20,1% nach zwei Jahren. Die CI des Rückfalls stieg von 34% nach einem Jahr auf 41% nach drei Jahren. Die Toxizität des Schemas war vergleichbar mit den Treo/Flu Studien. Treo/Flu/AraC bietet eine tolerierbare und praktikable Konditionierung für Patienten mit AML, MDS oder MPN mit hohem Rezidivrisiko. Eine prospektive Studie zum Vergleich mit dem Treo/Flu Regimen ist erforderlich.
Treosulfan and fludarabine (Treo/Flu) were successfully introduced into toxicity-reduced conditioning for stem cell transplantations (SCT). The risk of relapse remains a concern. We report the results of an individual treatment approach with Treo/Flu and cytarabine (Treo/Flu/AraC) prior to allogeneic SCT in patients with acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm (MPN). 77 patients (median age 54 years) with high-risk disease were included. Median follow-up was 3.2 years. One-, two- and three-year RFS were 47.5%, 40.7% and 37.3% and OS were 59.3%, 49.3% and 45.4%, respectively. Cumulative incidence (CI) of NRM was 10% at 100 days, 18.8% at one year and 20.1% at two years. The CI of relapse increased from 34% at one year to 41% after three years. The CIs of engraftment, chimerism, GvHD and toxicities were acceptable and comparable with similar patients conditioned with Treo/Flu or FLAMSA-RIC. Treo/Flu/AraC provides tolerable and feasible conditioning for patients with AML, MDS or MPN at high risk of relapse. A prospective controlled trial is needed to make conclusions as to the effectiveness of this regimen.
Published Online October 9, 2019 ; Gesehen am 15.04.2020
Background - Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. - Methods - We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). - Findings - Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. - Interpretation - Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. - Funding - medac GmbH.
The lancet. Haematology London [u.a.] : Elsevier, 2014 7(2020), 1, Seite e28-e39 Online-Ressource
