Combination Therapy Improves Survival in a Subtype of AML
Addition of a multi-targeted kinase inhibitor to standard chemotherapy improves outcomes in patients with acute myeloid leukemia (AML) and a specific mutation, according to research published in The New England Journal of Medicine (online August 3, 2017; doi:10.1056/NEJMoa1614359).
Previous research has shown that patients with AML have poor survival outcomes – especially those with mutations in the fms-related tyrosine kinase 3 gene (FLT3). The effect of this mutation on prognosis is in need of further study.
Richard M Stone, MD, Dana-Farber Cancer Institute (Boston, MA), and colleagues conducted a phase II trial to determine whether the addition of midostaurin, a multi-targeted kinase inhibitor that is active in patients with a FLT3 mutation, to conventional chemotherapy would help prolong overall and event-free survival in patients with AML. A total of 117 patients (aged 18 to 59 years) with newly diagnosed AML and FLT3 mutations were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo. Patients who demonstrated remission entered maintenance therapy, in which they received either midostaurin or placebo.
Randomization was stratified according to FLT3 mutation subtype: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication mutation with either a high or low ratio (ITD [high] and ITD [low], respectively). The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients.
Researchers observed overall survival to be significantly longer in the midostaurin cohort compared with the placebo cohort (HR for death, 0.78; one-sided P = .04). Event-free survival also favored patients in the midostaurin cohort (HR for event or death, 0.78; one-sided P = .002).
The primary analysis and secondary analysis in which data for patients who underwent allogeneic transplantation were censored featured a consistent benefit across all FLT3 subtypes after treatment with midostaurin.
Further research is needed to explore more specific FLT3 inhibitors, researchers concluded. “It remains unclear whether agents with different target profiles, including more specific FLT3 inhibitors, would also improve outcomes if they were added to usual therapy for younger adults with AML and a FLT3 mutation and whether chemotherapy plus midostaurin might be beneficial for older adults or for those with wild-type FLT3,” they wrote.—Zachary Bessette