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Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC). Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio >0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014. Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age<60 yrs, n=20 age ≥60 yrs) and 9 pts after salvage outside the protocol or after relapse (n=70 from a matched unrelated and n=24 from a matched related donor). In pts receiving an alloHSCT within the protocol in median 2 chemotherapy cycles were applied before transplant (range 1-4) and the cumulative incidence of relapse and death at 12 months were 9.2% (SE 3.3%) and 19.5% (SE 4.8%). Maintenance therapy was started in 52 pts, 40 pts after alloHSCT and 12 pts after HIDAC. Only 4 adverse events 3°/4° were attributed to midostaurin. First analyses revealed a low cumulative incidence of relapse irrespective of the FLT3-ITD mutant to wildtype ratio (<0.5 versus ≥0.5) in patients proceeding to alloHSCT with 12% and 5% as well as for those after HIDAC consolidation with 28% and 29%, respectively. Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHSCT or HIDAC is feasible and compared to historical data may be most effective in those patients with a high FLT3-ITD mutant to wildtype ratio. Disclosures Schlenk: Novartis: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18–82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

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%, <20% in 7.9%) and 39.4% (0.3-100%, <20% in 20.5%), respectively. Co-medication with azoles had no impact on p-FLT3 levels. In pts with a FLT3-ITD mutant to wildtype ratio above our recently defined cut-off value of 0.5, levels of p-FLT3 <20% were associated with a complete remission (CR)-rate of 100%, whereas in those pts with p-FLT3 levels ≥20%, 4 out of 22 pts (18%) had resistant disease. In contrast, response in pts with a mutant to wildtype ratio below 0.5 was independent of the p-FLT3 level. During and at the end of consolidation cycles as well as during maintenance therapy p-FLT3 levels in pts treated with midostaurin were 52% (14.8-100%, <20% in 5%), 63% (7.6-100%, <20% in 7.4%) and 60.2% (11.5-100%, <20% in 3.7%), respectively. In pts concomitantly treated with azoles levels of p-FLT3 were lower without reaching significance. 39 of 63 pts received alloHSCT in first CR; those pts with p-FLT3 levels <20% after induction therapy had an in trend better survival, whereas no impact of phosphorylation levels was evident in pts receiving chemotherapy alone. Conclusion: In our study of FLT3-ITD AML pts treated with midostaurin in combination with intensive chemotherapy we could show that the lowest levels of p-FLT3 were reached during and after induction therapy. In pts with a FLT3-ITD mutant to wildtype ratio >0.5, levels of p-FLT3 <20% during and after induction therapy were associated with a high CR-rate. When receiving alloHSCT these pts had an in trend better survival compared to those with p-FLT3 levels >20%. An update of the data will be presented at the meeting. Disclosures Salwender: Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Horst:Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Ingleheim: Research Funding; Boehringer: Research Funding; MSD: Research Funding; Gilead: Honoraria, Research Funding. Schlenk:Novartis: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Arog: Honoraria, Research Funding.

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