Sorafenib in Combination With Standard Induction and Consolidation Therapy in Elderly AML Patients: Results From a Randomized, Placebo-Controlled Phase 2 Trial

ORLANDO, Fla. Elderly patients with acute myeloid leukemia (AML) have a median overall survival of about 1 year when treated with currently available standard chemotherapy. Recently, phase 1/2 data and case reports have shown that the kinase inhibitor sorafenib may have clinical benefit in FLT3-ITD-positive AML patients when combined with standard chemotherapy. 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.

Hubert Serve of the Goethe University of Frankfurt in Frankfurt, Germany, and colleagues conducted a multicenter, randomized, placebo-controlled, double-blind, phase 2 trial in elderly (>60 years) AML patients to evaluate the effect of sorafenib in combination with standard chemotherapy and as a maintenance therapy for up to 1 year. The findings from this study were presented at the 52nd American Society of Hematology Meeting and Exposition.

The study enrolled 197 AML patients who received up to 2 cycles of standard 7 + 3 induction chemotherapy plus 2 cycles of consolidation therapy with intermediate dose (6 x 1 g/m2) AraC. Patients were randomized to receive either placebo or sorafenib (400 mg twice daily [bid] between the cycles and after chemotherapy for up to 1 year after the start of induction). The primary end point was to compare the event-free survival (EFS) of the 2 treatment groups. Secondary end points included a comparison of EFS and overall survival (OS) to predefined subgroups according to NPM and FLT3 mutation status and toxicity of treatment.

A total of 102 patients were randomized to receive sorafenib, and 95 patients to placebo. There was no difference between the 2 treatment groups in EFS and OS. The median EFS was 7 months, and 5 months for placebo and sorafenib, respectively (P=0.13). Median OS was 15 months and 13 months for placebo and sorafenib, respectively (P=0.89). A complete response (CR) was observed in 49 (48%) sorafenib patients and 57 (60%) placebo patients. A blast clearance without complete blood count recovery was observed in 9 (8.8%) sorafenib patients and 4 (4.2%) placebo patients.

A subgroup analysis did not result in any significant difference between the treatment groups but showed a tendency toward decreased EFS in the sorafenib arm for NPM1-wild type AML cases. Twenty-eight (14.2%) of the 197 patients were found to have FLT3-ITD mutations, but no differences in EFS or OS were observed in this small patient population. CR was also not found to improve in this subgroup of patients.

Overall, sorafenib was relatively well tolerated. The most frequent adverse events (AEs) ≥ grade 3 were febrile neutropenia, pneumonia in neutropenia, sepsis, diarrhea, skin rash, mucositis, and hypertension. Hand-foot-skin reaction was noted in 5 sorafenib patients. A trend towards slower regeneration of leukocytes and thrombocytes was observed in the sorafenib arm after the first and second induction course but not after consolidation cycles.

Despite the feasibility and tolerability of sorafenib treatment in combination with standard chemotherapy in elderly AML patients, it did not improve EFS and OS in this unselected elderly AML patient population. It may be feasible to conduct further studies on selected AML target populations, especially FLT3-ITD+ AML patients.

Off Label Use: Sorafenib is given in combination with standard chemotherapy in elderly AML patients.