Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial

Abstract

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

New Drugs Bringing New Challenges to AML: A Brief Review

“…The SORAML trial examined the role of combining sorafenib with intensive chemotherapy in patients with AML, not limited to those with the FLT3 mutation. This study demonstrated improved EFS outcomes across a diverse AML cohort, supporting the potential for a biologically relevant off-target activity associated with multikinase inhibitors in combination with chemotherapy in the first line treatment of AML [12].…”

Improved outcomes among newly diagnosed patients with FMS‐like tyrosine kinase 3 internal tandem duplication mutated acute myeloid leukemia treated with contemporary therapy: Revisiting the European LeukemiaNet adverse risk classification

“…The addition of sorafenib to intensive induction in the frontline setting demonstrated improved event and relapse-free survival in the SORAML study. 16 Midostaurin demonstrated an OS benefit when combined with 7 + 3 in newly diagnosed patients with FLT3 mutated AML in the RATIFY trial. 18 In addition, the use of quizartinib with intensive induction was recently reported to improve OS.…”

“…[12][13][14][15] Development of small molecule FLT3 inhibitors (FLT3i) that inhibit the aberrantly active FLT3 signaling have been shown to improve leukemia-specific clinical outcomes. [16][17][18][19] In the treatment of newly diagnosed patients with AML, both midostaurin and sorafenib have shown improvements in clinical outcomes in the frontline setting. In the phase 3 trial RATIFY study, midostaurin combined with cytarabine and daunorubicin (7 + 3) improved overall survival (OS) compared with placebo in patients < 60 years of age, regardless of AR or type of mutation (ITD vs. TKD).…”

“…18 Similarly, sorafenib combined with 7 + 3 in the SORAML study improved both event-free and relapse-free survival. 16 There is also evidence that use of fludarabine, cladribine, high-dose cytarabine, and idarubicin induction may overcome the negative impact of FLT3-ITD mutations. 20,21 In addition, the use of allogeneic stem cell transplant (SCT) in first remission for FLT3-ITD mutated patients also appears to improve both relapse-free and OS.…”

The cure of leukemia through the optimist's prism

“…They reported a composite CR (CR + CRi) rate of 82% and an estimated 2‐year survival rate of 70% in the FLT3 ‐mutated cohort. Rollig and colleagues 158 treated younger/fit patients with newly diagnosed AML ( FLT3 ‐ITD in 17%) with standard chemotherapy and the first‐generation FLT3 inhibitor sorafenib (n = 134) or a placebo (n = 133). The addition of sorafenib improved the 5‐year event‐free survival rate (41% vs 27%; hazard ratio, 0.68; P = .011) and the 5‐year relapse‐free survival rate (53% vs 36%; hazard ratio, 0.64; P = .035).…”