Sorafenib In Combination with Standard Induction and Consolidation Therapy In Elderly AML Patients: Results From a Randomized, Placebo-Controlled Phase II Trial

Standard chemotherapy for elderly AML patients results in a median overall survival of only about one year. Case reports and early phase I/II data have shown that the kinase inhibitor Sorafenib might show clinical benefit for Flt3-ITD-positive AML patients (Metzelder S Blood 2009; 113:6567) and that its addition to standard chemotherapy is feasible (Ravandi F JCO 2010; 28:1856). Sorafenib is a potent Raf, c-Kit and FLT3 inhibitor that may also affect AML blasts and bone marrow (BM) stroma cells via VEGFR and PDGFR-β inhibition. Therefore, we performed a multicenter, randomized, placebo-controlled, double-blind phase II trial in elderly (>60 y) AML patients analyzing the effect of Sorafenib in addition to standard chemotherapy and as a maintenance therapy for up to one year.

197 AML patients in 16 centers received up to two cycles of standard 7+3 induction chemotherapy plus two cycles of consolidation therapy with intermediate dose (6 × 1g/sqm) AraC. Before start of treatment, they were randomly assigned to receive either placebo or Sorafenib (400 mg bid between the cycles and after chemotherapy for up to one year after start of induction). The primary aim was to compare the event-free survival (EFS) of the two treatment groups. Secondary end points were to compare EFS and overall survival (OS) of predefined subgroups according to NPM and FLT3 mutation status and toxicity of treatment.

Among the 197 evaluable patients, 102 pts received Sorafenib and 95 pts placebo. EFS and OS were not significantly different between the two treatment groups (placebo vs. Sorafenib: EFS: Median: 7 vs. 5 months, hazard Ratio (HR): 1.261(p=0.13); OS: Median: 15 vs. 13 months, HR 1.025 (p=0.89)). CR or blast clearance without complete blood count recovery was observed in 49 (48%) and 9 (8.8%) Sorafenib patients and 57 (60%) and 4 (4.2%) placebo pts, respectively. Exploratory subgroup analyses did not reveal any significant difference between the treatment groups but showed a tendency towards decreased EFS in the Sorafenib arm for NPM1-wild type AML cases. Flt3-ITD mutations were found in 28 out of 197 patients (14.2%), in line with the reported incidence in the target population. No differences in EFS or OS were to be noted in this small patient population. Also, CR rate was not improved by the study drug in this subgroup of patients. Sorafenib was relatively well tolerated. The most frequent adverse events (AE) ≥grade 3 were febrile neutropenia, pneumonia in neutropenia, sepsis, diarrhea, skin rash, mucositis, hypertension (77 vs 74, 54 vs 35, 15 vs 15, 17 vs 6, 14 vs 7, 9 vs 6, 8 vs 5 events in the Sorafenib vs the placebo group). A hand-foot-skin reaction (≥grade 3) was noted in 5 vs 0 events in Sorafenib vs control pts. There was a trend of slower regeneration of leukocytes and thrombocytes within the Sorafenib arm compared to the control arm after the first and second induction course but not after consolidation cycles.

Although the combination regimen appeared to be feasible and tolerable in elderly AML pts, Sorafenib treatment did not improve EFS or OS in this unselected elderly AML patient population. Further studies should focus on selected AML target populations for Sorafenib, especially FLT3-ITD+ AML patients.

Off Label Use: Sorafenib (multikinase inhibitor) is given in combination with standard chemotherapy in elderly AML patients. (See title of the abstract!).