Roellig, Christoph and Serve, Hubert and Huettmann, Andreas and Noppeney, Richard and Mueller-Tidow, Carsten and Krug, Utz and Baldus, Claudia D. and Brandts, Christian H. and Kunzmann, Volker and Einsele, Hermann and Kraemer, Alwin and Schaefer-Eckart, Kerstin and Neubauer, Andreas and Burchert, Andreas and Giagounidis, Aristoteles and Krause, Stefan W. and Mackensen, Andreas and Aulitzky, Walter and Herbst, Regina and Haenel, Mathias and Kiani, Alexander and Frickhofen, Norbert and Kullmer, Johannes and Kaiser, Ufrich and Link, Hartmut and Geer, Thomas and Reiche, Albert and Junghanss, Christian and Repp, Roland and Heits, Frank and Duerk, Heinz and Hase, Jana and Klut, Ina-Maria and Illmer, Thomas and Bornhaeuser, Martin and Schaich, Markus and Parmentier, Stefani and Goerner, Martin and Thiede, Christian and von Bonin, Malte and Schetelig, Johannes and Kramer, Michael and Berdel, Welfgang E. and Ehninger, Gerhard (2015) Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. LANCET ONCOLOGY, 16 (16). pp. 1691-1699. ISSN 1470-2045, 1474-5488
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Background Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1: 1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials. gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40). Findings Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35.5-38.1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0.64, 95% CI; 0.45-0.91; p=0.013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1.54, 95% CI 1.04-2.28), diarrhoea (RR 7.89, 2.94-25.2), bleeding (RR 3.75, 1.5-10.0), cardiac events (RR 3.46, 1.15-11.8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4.06, 1.25-15.7). Interpretation In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACUTE MYELOGENOUS LEUKEMIA; STEM-CELL TRANSPLANTATION; ELDERLY-PATIENTS; FLT3 MUTATIONS; BONE-MARROW; COMBINATION; CHEMOTHERAPY; CYTARABINE; AML; CLASSIFICATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 May 2019 08:14 |
| Last Modified: | 07 May 2019 08:14 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4406 |
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