ALBERT

Description: Background: Activating mutations in receptor tyrosine kinases like FLT3 (FLT3mut) lead to an aberrant signal transduction thereby causing an increased proliferation of hematopoietic cells. Internal tandem duplications (FLT3-ITD) or mutations in the tyrosine kinase domain (FLT3-TKD) occur in about 25% of younger adult patients (pts) with acute myeloid leukemia (AML), with FLT3 -ITD being associated with an unfavourable outcome. FLT3mut present an excellent target for small molecule tyrosine kinase inhibitors (TKI). The multi-targeted kinase inhibitor midostaurin (PKC412) is currently under investigation as a FLT3-inhibitor in combination with intensive chemotherapy. Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome will be of major importance. The plasma inhibitor activity (PIA) assay allows the visualization of the level of dephosphorylation of the target under TKI therapy. Preliminary data suggest a correlation between the grade of dephosphorylation, as a marker for the activity of the TKI, and clinical outcome. Aims: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3-ITD AML pts treated within our AMLSG16-10 trial (NCT: NCT01477606) which combines midostaurin with intensive chemotherapy, and to correlate the results with clinical outcome. Methods: Plasma samples from pts (age 18-70 years) with newly diagnosed FLT3-ITD AML were obtained at different time points for PIA analysis. All pts were enrolled on the ongoing AMLSG 16-10 trial applying intensive therapy in combination with midostaurin (50mg twice a day). For consolidation therapy, pts proceeded to allogeneic hematopoietic stem cell transplantation (alloHSCT) as first priority; pts not eligible for alloHSCT were intended to receive 3 cycles of age-adapted high-dose cytarabine (HiDAC) in combination with midostaurin from day 6 onwards. In all pts one year of maintenance therapy with midostaurin was intended. PIA analyses were performed at defined time points (day 15 of induction, each consolidation cycle, at the end of each treatment cycle, every 3 months during maintenance therapy) as previously described (Levis MJ, et al. Blood 2006; 108:3477-83). Results: So far, PIA analyses were performed in 63 pts (median age, 51.6 years; range, 20-70 years) during (n=63) and after (n=73) first and second induction cycle, during (n=40) and after (n=53) consolidation therapy with HiDAC as well as during maintenance therapy (n=82). During and after induction therapy median levels of phosphorylated FLT3 (p-FLT3) were 46.6% (4.5-100%,