Medizinische Klinik und Poliklinik I
Contributions
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 09:00 to 14.06.2015 09:15
Location: Room C1
Background
Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of acute myeloid leukemia (AML). We present updated results from the randomized placebo-controlled SORAML trial (NCT00893373) testing sorafenib versus placebo as add-on to standard treatment in AML patients ≤60 years.
Aims
The data focus on treatment adherence, efficacy in cytogenetic subgroups and relapse pattern.
Methods
The trial enrolled 276 patients with newly diagnosed AML from 18 to 60 years and suitable for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7) or HAM (cytarabine 3 g/m2 b.i.d. days 1-3 plus mitoxantrone 10 mg/m2 days 3-5), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk patients in first complete remission (CR) with a sibling donor and for all high-risk patients with a matched related or unrelated donor. Patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation.
Results
Out of 276 enrolled patients, 267 received study treatment, 134 in the sorafenib arm and 133 in the placebo arm. Demographic and disease characteristics were equally distributed between the two arms; the incidence of FLT3-ITD was 17%. Toxicity-related drop-outs were slightly more frequent in the sorafenib arm with 32% vs 25% of patients commencing maintenance. After a median observation time of 36 months, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm (p=0.013). Induction mortality was 4% in both arms, but cumulative incidence of relapse was significantly higher in the placebo arm. Subgroup analyses on EFS suggest a beneficial effect of sorafenib already after induction treatment. In multivariate analysis, sorafenib exposure, favorable cytogenetics and NPM1 mutation were associated with superior EFS whereas FLT3-ITD remained a negative prognostic factor. Median RFS after standard treatment plus placebo was 23 months and not yet reached after sorafenib treatment (p=0.017). The median OS had not been reached in either arm; the 3-year OS was 56% with placebo versus 63% with sorafenib (p=0.382). More placebo patients (N=66; 50%) than sorafenib patients (N=39; 29%) received a SCT in relapse due to more and earlier relapses with placebo, whereas relative SCT rates among relapses were similar (sorafenib: 75%; placebo: 82%). Detailed subgroup analyses will be presented. The risk for fever, diarrhea, bleeding events, liver toxicity, hand-foot syndrome and rash was significantly higher in the sorafenib arm.
Summary
In younger AML patients, the addition of sorafenib to standard therapy is associated with significant EFS and RFS prolongation independent of FLT3-ITD status. After the current follow up, the RFS benefit does not translate into an OS benefit, most likely due to potent salvage strategies mainly based on SCT. Ongoing data collection on salvage treatments, second CR and molecular profiling plus additional follow up will contribute to further explain the mechanism of action of sorafenib in younger AML patients.
Keyword(s): AML, Randomized, Tyrosine kinase inhibitor
Session topic: AML: Molecular profile and targeting
Type: Oral Presentation
Presentation during EHA20: From 14.06.2015 09:00 to 14.06.2015 09:15
Location: Room C1
Background
Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of acute myeloid leukemia (AML). We present updated results from the randomized placebo-controlled SORAML trial (NCT00893373) testing sorafenib versus placebo as add-on to standard treatment in AML patients ≤60 years.
Aims
The data focus on treatment adherence, efficacy in cytogenetic subgroups and relapse pattern.
Methods
The trial enrolled 276 patients with newly diagnosed AML from 18 to 60 years and suitable for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7) or HAM (cytarabine 3 g/m2 b.i.d. days 1-3 plus mitoxantrone 10 mg/m2 days 3-5), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk patients in first complete remission (CR) with a sibling donor and for all high-risk patients with a matched related or unrelated donor. Patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation.
Results
Out of 276 enrolled patients, 267 received study treatment, 134 in the sorafenib arm and 133 in the placebo arm. Demographic and disease characteristics were equally distributed between the two arms; the incidence of FLT3-ITD was 17%. Toxicity-related drop-outs were slightly more frequent in the sorafenib arm with 32% vs 25% of patients commencing maintenance. After a median observation time of 36 months, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm (p=0.013). Induction mortality was 4% in both arms, but cumulative incidence of relapse was significantly higher in the placebo arm. Subgroup analyses on EFS suggest a beneficial effect of sorafenib already after induction treatment. In multivariate analysis, sorafenib exposure, favorable cytogenetics and NPM1 mutation were associated with superior EFS whereas FLT3-ITD remained a negative prognostic factor. Median RFS after standard treatment plus placebo was 23 months and not yet reached after sorafenib treatment (p=0.017). The median OS had not been reached in either arm; the 3-year OS was 56% with placebo versus 63% with sorafenib (p=0.382). More placebo patients (N=66; 50%) than sorafenib patients (N=39; 29%) received a SCT in relapse due to more and earlier relapses with placebo, whereas relative SCT rates among relapses were similar (sorafenib: 75%; placebo: 82%). Detailed subgroup analyses will be presented. The risk for fever, diarrhea, bleeding events, liver toxicity, hand-foot syndrome and rash was significantly higher in the sorafenib arm.
Summary
In younger AML patients, the addition of sorafenib to standard therapy is associated with significant EFS and RFS prolongation independent of FLT3-ITD status. After the current follow up, the RFS benefit does not translate into an OS benefit, most likely due to potent salvage strategies mainly based on SCT. Ongoing data collection on salvage treatments, second CR and molecular profiling plus additional follow up will contribute to further explain the mechanism of action of sorafenib in younger AML patients.
Keyword(s): AML, Randomized, Tyrosine kinase inhibitor
Session topic: AML: Molecular profile and targeting