Background: The multi-targeted tyrosine kinase inhibitor (TKI) Midostaurin has recently been approved by the FDA for the treatment of newly diagnosed acute myeloid leukemia (AML) with FLT3 -ITD mutation in combination with intensive standard chemotherapy (Stone et al. NEJM 2017). Monitoring of the efficacy of such a targeted therapy and correlation of the results with clinical outcome is of major importance. The plasma inhibitor activity (PIA) assay allows to determine the level of dephosphorylation of the target under TKI therapy, which is suggested to correlate, as a marker for activity, with clinical outcome.
Aim: To individually measure the level of FLT3 dephosphorylation by PIA analysis in a large cohort of FLT3 -ITD positive AML patients (pts) treated in our AMLSG16-10 trial (NCT: NCT01477606) and to correlate the results with clinical outcome.
Methods: Plasma samples from 118 pts (age 18-70 years) with newly diagnosed FLT3 -ITD positive AML were obtained at defined time points during and after therapy for PIA analysis. Pts were enrolled in the ongoing AMLSG16-10 trial (NCT01477606) applying intensive therapy in combination with Midostaurin (continuous dosing except days of chemotherapy). 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) with Midostaurin from day 6 onwards, followed by 12 28-day cycles of Midostaurin maintenance therapy. PIA analyses were performed at day 15 and at the end of each induction and consolidation cycle, monthly during maintenance therapy and every three months during follow-up.
Results: So far, 946 plasma samples from 118 pts have been analyzed during (n=116) and after (n=136) 1st and 2nd induction cycle, during (n=104) and after (n=122) consolidation therapy as well as during maintenance therapy (n=346) and the follow-up period (n=122). The strongest reduction of FLT3 phosphorylation (p-FLT3) was observed at the end of 1st induction to 41.3% p-FLT3 (median; range, 0.3-100%). During treatment p-FLT3 levels increased again up to 80.2% (median; range, 32.6-100%), while during maintenance therapy p-FLT3 levels subsequently decreased down to 48.5% (median; range, 15.7-100%). P-FLT3 levels stratified by the median (41.3%) obtained after the 1st induction cycle were not associated with clinical or genetic features and they had no impact on response to induction therapy. So far, pts with a p-FLT3 level below that median showed an in trend better overall survival (OS) (P= .09), while there was no effect on event-free survival (EFS) and the cumulative incidence of relapse (CIR) between pts with p-FLT3 below or above the median level (P= .11 and P= .80, respectively). In addition, we also evaluated if a lower value (20%) for p-FLT3 levels allows to better discriminate pts with regard to their clinical outcome. However, there was no difference for the clinical endpoints OS, EFS and CIR between pts with target inhibition of >80% and <80% (P= .21, P= .75 and P= .58, respectively).
Conclusions: In our study of FLT3 -ITD positive AML pts treated with Midostaurin in combination with intensive chemotherapy the strongest target inhibition was reached after the 1st induction cycle indicating the highest TKI activity against FLT3 at that time point. First correlations with clinical outcome suggest that p-FLT3 levels below the median after the 1st induction cycle may correlate with better overall survival. Interestingly, target-inhibition was not maintained during subsequent treatment cycles in most of the pts, while a more sufficient inhibition of p-FLT3 was again achieved during TKI maintenance therapy. It has to be determined if loss of stable target-inhibition during treatment might be triggered by the combination of the TKI and concomitant standard chemotherapy. In addition, effects of Midostaurin maintenance therapy have to be evaluated in larger patient cohorts.
Schroeder: Celgene: Consultancy, Honoraria, Other: travel support. Salwender: Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support; Takeda: Honoraria. Fiedler: Amgen, Pfizer: Research Funding; Amgen: Patents & Royalties; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Götze: Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Abbvie: Honoraria. Kindler: Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner: Novartis: Honoraria, Research Funding.
Asterisk with author names denotes non-ASH members.