Abstract: Activating mutations in the receptor tyrosine kinase FLT3 occur in roughly 30% of acute myeloid leukemia (AML) patients (pts), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin (PKC412) shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Besides its mere presence, the allelic ratio as well as ITD insertion site within the FLT3 gene had been reported as prognostic factors in FLT3-ITD positive AML. Furthermore, pharmacokinetic analyses revealed clinically important interactions between potent CYP3A4 inhibitors, such as azoles, and midostaurin. Aims To evaluate the pharmacodynamic activity of midostaurin measured as inhibition of the degree of phosphorylated FLT3 (pFLT3) in correlation to co-medication and outcome data. Methods The study includes intensively treated adults (age 18-70 years) 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 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 twice daily is applied from day 8 onwards until 48h before start of the next treatment cycle. For consolidation therapy, pts proceed to allogeneic hematopoietic stem cell transplantation (HSCT) as first priority; if allogeneic HSCT is not possible pts receive three cycles of age-adapted high-dose cytarabine in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. A total sample size of n=142 is planned to show an improvement in event-free survival from 25% after 2 years to 37.5%. Plasma inhibitory activity assay (PIA) for pFLT3 is performed as previously described (Levis MJ, et al. Blood 2006; 108:3477-83). For PIA, measured time points include day 15 of induction therapy, the end of each treatment cycle and every three months during maintenance therapy. Results To date, 72 pts (median age, 54.5 years; range, 29-69 years) have been included and PIA was performed so far in 37 pts during induction therapy. Median pFLT3 inhibition after one week of midostaurin intake measured on day 15 of cycle 1 (C1D15) was 57.5% (range, 14.2-93.7%) with 2 of 31 pts showing inhibition 〉 85%. At the end of the first induction cycle (C1end), median inhibition was 60.3% (range, 0-99.8%); here, 6 of 37 pts had an inhibition 〉 85%. Co-medication with azoles was present in 7 of 23 pts at C1D15 and 13 of 28 pts at C1end. There was no significant difference in pFLT3 inhibition either on C1D15 (p=0.79) or at C1end (p=0.70) between pts on (median pFLT3 inhibition: 52.5%) or off (median pFLT3 inhibition 57.5%) azoles. Response data were available in 56 pts: complete remission (CR) was achieved in 78.5%; rates of early death and refractory disease (RD) were 9% and 12.5%, respectively. In first analyses, there was no difference in pFLT3 inhibition in pts achieving CR (n=30) as compared to those with RD (n=3; p=0.99). In contrast to our previously published data from three historical trials without a FLT3 inhibitor which showed that high allelic ratio was associated with low CR rates (Kayser S, et al. Blood 2009;114:2386-92), in the current trial CR rates remained high (81.5%) despite of a high allelic ratio above the median ( 〉 0.58). In addition, we did not see a negative prognostic impact of ITD insertion site within the tyrosine kinase domain of the FLT3 gene (p=0.99). Analyses are currently ongoing, measurement of FLT3 ligand levels and evaluation of pharmacokinetics of midostaurin are also intended. Conclusions The addition of 50 mg midostaurin twice daily to intensive induction therapy resulted in a moderate pFLT3 inhibition during induction therapy. Nonetheless, CR rates are promising, especially in pts with unfavorable FLT3-ITD characteristics. Concomitant azoles do not appear to significantly influence pFLT3 inhibitory activity of midostaurin. Disclosures: Levis: Ambit Biosciences: Consultancy. Schlenk:Ambit: Honoraria; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Abstract: Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI] , 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; P & lt; .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.

Abstract: To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P = .005), relapse-free survival (RFS, P 〈 .001), and overall survival (OS, P 〈 .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P 〈 .001) and RFS (P 〈 .001). High-risk patients with related donors had longer OS (P = .016) and RFS (P = .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P = .003) and RFS (P = .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833.

Abstract: Background: Target inhibition of FLT3 by therapy with the recently FDA- and EMA-approved multi-targeted tyrosine kinase inhibitor (TKI) midostaurin can be monitored by plasma inhibitor activity (PIA) analysis by visualizing the level of target-dephosphorylation as previously described. When combining intensive chemotherapy with midostaurin, we have recently shown that the TKI achieves the lowest level of FLT3 phosphorylation (p-FLT3) at the end of the 1st induction cycle, indicating a deep target inhibition. However, sufficient inhibition could not be maintained during subsequent cycles by midostaurin in combination with chemotherapy, but it was reestablished during maintenance therapy with the TKI alone. Recent data indicate that this might be due to an increase in FLT3 ligand (FL) plasma levels induced by concomitant intensive chemotherapy. Aim: To individually measure the plasma levels of FL and to correlate the results with those from PIA analysis at defined time points during treatment in a large cohort of FLT3-ITD AML patients (pts) treated within our AMLSG 16-10 trial (NCT01477606). Methods: FL levels were measured in plasma samples from pts (age 18-70 years) with newly diagnosed FLT3-ITD positive AML obtained at defined time points during therapy in which PIA analyses were also previously performed. All pts were enrolled in the AMLSG 16-10 trial applying intensive standard chemotherapy in combination with midostaurin. For consolidation therapy allogeneic hematopoietic cell transplantation (allo HCT) was intended whereas pts not eligible for allo HCT received 3 cycles of age-adapted high-dose cytarabine (HiDAC) in combination with midostaurin starting on day 6, followed by one year of midostaurin maintenance therapy for both groups. FL levels were measured at diagnosis, at day 15 and at the end of each treatment cycle, after allo HCT and monthly during maintenance therapy using a Quantikine® ELISA kit obtained from R & D Systems®. Results: So far, we have analyzed 709 plasma samples from 68 pts at the time of diagnosis (n=62), during (day 15, n=73) and after (n=83) 1st and 2nd induction cycle, during (day 15, n=69) and after (n=82) consolidation therapy, after allo HCT (n=36) as well as during maintenance therapy (n=304). The median level of FL at diagnosis was 5.2pg/ml (0 - 66.2pg/ml). At day 15 of the 1st induction cycle FL levels showed a drastic increase (median 1057.3pg/ml; 23.6 - 2287.8pg/ml) which maintained high at day 15 of each following consolidation cycle, up to a maximum of 1696.6pg/ml (133.4 - 2461pg/ml) in median at day 15 of the 3rd consolidation cycle. Interestingly, at this time point p-FLT3 levels in median (80.2%; 32.6 - 100%) reached highest values indicating a loss of target inhibition. Of note, FL levels decreased at the end of each treatment cycle with a median level between 116.6pg/ml (19.7 - 1676.7pg/ml) and 184.5pg/ml (10.4 - 2398.3pg/ml) supporting the hypothesis of an induction of FL secretion during each treatment cycle due to concomitant chemotherapy. Consistent with this hypothesis, median FL levels decreased and stayed low during the 12 months of TKI maintenance therapy without concomitant chemotherapy with the lowest level after month 5 (median 186.7pg/ml; 125.2 - 468.6pg/ml) congruent with our previous results of a decrease in p-FLT3 levels and reestablished target inhibition during maintenance therapy. Interestingly, pts who received allo HCT showed significantly higher median FL levels after 6 months of maintenance therapy than pts who received consolidation chemotherapy (230.3pg/ml; (58.8 - 441pg/ml) vs 169.8pg/ml; (60.6-218.5pg/ml); P=.03). However this has no impact on the median p-FLT3 level at this time point. Conclusions: In our study of FLT3-ITD positive AML pts treated with midostaurin in combination with intensive chemotherapy or allo HCT we could observe a drastic increase of FL plasma levels promptly after start of chemotherapy followed by loss of stable target inhibition. In contrast, during maintenance therapy with the TKI alone FL plasma levels decreased and remained low. This correlated with a decrease of p-FLT3 levels as well indicating target inhibition. Further studies are needed to evaluate if different scheduling of the TKI in combination with chemotherapy might overcome the loss of target inhibition and if this might improve clinical outcome. These pharmacodynamic data may provide support for single-agent TKI maintenance therapy. Disclosures Paschka: Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Agios: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Janssen: Other: Travel support; Takeda: Other: Travel support. Fiedler:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Patents & Royalties; Amgen: Research Funding; Pfizer: Research Funding; Amgen: Other: support for meetíng attendance; Gilead: Other: support for meeting attendance; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Lübbert:Janssen: Honoraria, Research Funding; Celgene: Other: Travel Grant; Teva: Other: Study drug. Salih:Several patent applications: Patents & Royalties: e.g. EP3064507A1. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel aid ASH 2017; Novartis: Honoraria. Salwender:Amgen: Honoraria, Other: travel suppport, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Bullinger:Amgen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Bayer Oncology: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Janssen: Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Pfizer: Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR] , 0.55; P & lt; .001); both in younger (HR, 0.59; P & lt; .001) and older patients (HR, 0.42; P & lt; .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P & lt; .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

Abstract: Background: Mutations of the NPM1 gene are one of the most frequent genetic aberrations in adult AML. AML with mutated NPM1 is categorized as a disease entity according the WHO-2016 classification and clinically associated with female sex, high white blood cells at diagnosis, normal karyotype and high CD33 antigen expression. We recently showed that patients with NPM1-mutated AML benefit from all-trans retinoic acid (ATRA) as adjunct to intensive induction therapy (Ann Hematol. 2016; 95:1931-1942; Haematologica. 2009;94:54-60). Based on the regular high CD33 expression in AML with mutated NPM1 we hypothesized that gemtuzumab ozogamicin (GO) added to intensive therapy with ATRA may further improve clinical outcome in AML with mutated NPM1. Aim: To evaluate GO in combination with intensive induction and consolidation therapy and ATRA in NPM1 mutated AML within the randomized AMLSG 09-09 trial (NCT00893399) Methods: Between May 2010 and September 2017, patients ≥18 years of age and considered eligible for intensive therapy were randomized up-front for open-label treatment with GO. Induction therapy consisted of two cycles of A-ICE (idarubicin 12mg/m² iv, day 1,3,5 [in induction II and for patients 〉 60 years reduced to d 1, 3]; cytarabine 100mg/m² continuous iv, day 1 to 7; etoposide 100mg/m² iv, day 1-3 [in induction II and for patients 〉 60 years reduced to d 1, 3]; ATRA 45 mg/m²/day po on days 6-8 and 15mg/m² days 9-21, +/- GO 3mg/m² iv day 1). Consolidation therapy consisted of 3 cycles of high-dose cytarabine (HiDAC; 3g/m² [reduced to 1g/m² in patients 〉 60 years] bid, days 1-3; Pegfilgrastim 6mg sc, day 10; ATRA 15 mg/m²/day po, days 4-21; +/- GO 3mg/m² on day 1 [first consolidation only] ). The primary endpoints of the study were event-free survival (EFS) as early endpoint tested 6 months and overall survival (OS) tested 4 years after study completion with sequential testing according the fallback procedure described by Wiens (Statistics 2003;2:211-215). This report focusses on the early EFS endpoint. Further secondary endpoints were response to induction therapy, cumulative incidence of relapse (CIR) and cumulative incidence of death (CID). Results: In total 588 patients were evaluable for analysis (n=296, standard-arm; n=292 GO-arm). Median age was 58.7 years (range, 18.4-82.3 years), ECOG performance status was 0 in 34.1% and 1 in 55.1%, and FLT3-ITD was present in 16.8% of the patients, with baseline characteristics well balanced between the two arms. After first induction therapy death rates were significantly higher in the GO-arm (7.5%) (p=0.02) compared to the standard-arm (3.4%); in both study-arms causes of death were mainly infections. Following induction therapy complete remission (CR) and CR with incomplete count recovery (CRi) were 88.5% and 85.3% (p=0.28), refractory disease (RD) 6.1% and 5.1% (p=0.72), death 5.4% and 9.6% (p=0.06) in the standard- and GO-arm, respectively. Due to prolonged thrombocytopenia after second induction therapy in the GO-arm, the protocol was amended in that GO was omitted in second induction and first consolidation cycles, if prolonged cytopenias were observed during first induction therapy. The study treatment was completed in 197 and 171 patients (p=0.11), allogeneic hematopoietic cell transplantation in first CR was performed in 18 and 21 patients (p=0.51) in the standard- and GO-arm, respectively. Median follow-up was 2.6 years (95%-CI, 2.4-3.1 years). Two- and 4-year EFS were 53% (95%-CI, 48-60%) and 58% (95%-CI, 52%-64%), and 44% (95%-CI, 38-52%) and 52% (95%-CI, 46%-59%) in the standard- and GO-arm, respectively. According to the pre-specified significance level of 0.025, EFS in the GO-arm was not different to that in the standard-arm (p=0.21). In patients achieving CR/CRi after induction therapy, CIR was significantly reduced in the GO-arm compared to the standard-arm (p=0.018), whereas no difference in CID was noted between both arms (p=0.89). Conclusion: The addition of GO to intensive induction therapy with ICE plus ATRA was associated with a higher death rate. In patients achieving a CR/CRi after induction therapy significantly less relapses occurred in the GO- compared to the standard-arm. Disclosures Schlenk: Pfizer: Research Funding, Speakers Bureau. Paschka:Astex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Otsuka: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Amgen: Other: Travel support; Janssen: Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Travel support. Fiedler:Amgen: Other: support for meetíng attendance; Gilead: Other: support for meeting attendance; Pfizer: Research Funding; Amgen: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; Daiichi Sankyo: Other: support for meeting attendance. Lübbert:Cheplapharm: Other: Study drug; Celgene: Other: Travel Support; Janssen: Honoraria, Research Funding; TEVA: Other: Study drug. Götze:Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; JAZZ Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Agios: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Jazz: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract: 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). The multi-targeted kinase inhibitor midostaurin combined with intensive chemotherapy has shown activity against AML with FLT3 mutations. However, toxicity and potential drug-drug interactions with strong CYP3A4 inhibitors such as posaconazole may necessitate dose reduction. Aims: To evaluate the impact of age and midostaurin dose-adaptation after intensive induction chemotherapy on response and outcome in AML with FLT3-ITD within the AMLSG 16-10 trial (NCT01477606). Methods: The study included 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. Pts with acute promyelocytic leukemia were not eligible. The presence of FLT3-ITD was analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based DNA fragment-length analysis. Induction therapy consisted of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid was applied from day 8 until 48h before start of the next treatment cycle. A second cycle was allowed in case of partial remission (PR). For consolidation therapy, pts proceeded to allogeneic hematopoietic-cell transplantation (HCT) as first priority; if alloHCT was not feasible, pts received three cycles of age-adapted high-dose cytarabine (HDAC) in combination with midostaurin starting on day 6. In all pts one-year maintenance therapy with midostaurin was intended. The first patient entered the study in June 2012 and in April 2014, after recruitment of n=147 pts, the study was amended including a sample size increase to 284 pts and a dose reduction to 12.5% of the initial dose of midostaurin in case of co-medication with strong CYP3A4 inhibitors (e.g. posaconazole). This report focuses on age and the comparison between the first (n=147) and the second cohort (n=137) of the study in terms midostaurin dose-adaptation. Results: Patient characteristics were as follows: median age 54 yrs (range, 18-70; younger, 68% 〈 60 yrs; older, 32% ≥ 60 yrs); median white cell count 44.7G/l (range 1.1-1543 G/l); karyotype, n=161 normal, n=16 high-risk according to ELN recommendations; mutated NPM1 n=174 (59%). Data on response to first induction therapy were available in 277 pts; complete remission (CR) including CR with incomplete hematological recovery (CRi) 60%, PR 20%, refractory disease (RD) 15%, and death 5%. A second induction cycle was given in 54 pts. Overall response (CR/CRi) after induction therapy was 76% (76%, younger; 76%, older) and death 6% (4%, younger; 10% older). The dose of midostaurin during first induction therapy was reduced in 53% and 71% of patients in cohort-1 and cohort-2, respectively. Reasons for dose reduction were in 58% and 49% toxicity, and in 9% and 23% co-medication in cohort-1 and cohort-2, respectively. No difference in response to induction therapy was noted between cohorts (p=0.81). Median follow-up was 18 months. Overall 146 pts received an alloHCT, 128 in first CR (n=94 younger, n=34 older; n=92 from a matched unrelated and n=36 from a matched related donor). In pts receiving an alloHCT within the protocol in median two chemotherapy cycles were applied before transplant (range 1-4). The cumulative incidence of relapse (CIR) and death after transplant were 13% (SE 3.2%) and 16% (SE 3.5%) without differences (p=0.97, p=0.41, respectively) between younger and older patients. So far maintenance therapy was started in 86 pts, 61 pts after alloHCT and 25 pts after HDAC. Fifty-five adverse events 3°/4° were reported being attributed to midostaurin; cytopenias after alloHCT were the most frequent (29%). CIR in patients starting maintenance therapy was 20% one year after start of maintenance without difference between alloHCT and HiDAC (p=0.99). In addition, no difference in CIR was identified in patients after consolidation with alloHCT or HDAC according to dose reduction of midostaurin during first induction therapy (p=0.43, p=0.98, respectively). Median overall survival was 25 months (younger, 26 months; older 23 months; p=0.15). Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHCT or HDAC is feasible and effective without an impact of age and dose adaptation on outcome. Disclosures Schlenk: Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Gilead: Other: Travel; Ariad/Incyte: Consultancy; Novartis: Consultancy; Teva: Other: Travel. Lübbert:Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Greil:Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Eisai: Honoraria; Amgen: Honoraria, Research Funding. Greiner:BMS: Research Funding. Paschka:ASTEX Pharmaceuticals: Consultancy; Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria. Heuser:Bayer Pharma AG: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; BerGenBio: Research Funding; Tetralogic: Research Funding.

Abstract: Background: Measurable residual disease (MRD), as determined by quantitation of Nucleophosmin 1-mutated (NPM1mut) transcript levels (TL), provides significant prognostic information independent of other risk factors in patients (pts) with acute myeloid leukemia (AML). This is also addressed by the 2017 European LeukemiaNet (ELN) risk stratification system, which recommends taking into account results from MRD monitoring when selecting the appropriate post-remission therapy. Furthermore, MRD monitoring provides a powerful tool to evaluate treatment effects within clinical trials investigating novel therapies. Aims: To determine the impact of the anti-CD33 immunotoxin Gemtuzumab-Ozogamicin (GO) on kinetics of NPM1mut TL in pts with newly diagnosed NPM1mut AML [18 to 82 years (yrs), median age 58 yrs] enrolled in our randomized Phase III AMLSG 09-09 study (NCT00893399). In this study GO was randomized (1:1) to standard chemotherapy plus ATRA. Patients and Methods: In total, 588 evaluable pts were enrolled in the clinical AMLSG 09-09 study. Standard treatment comprised two cycles of induction therapy with A-ICE (ATRA, idarubicin, cytarabine, etoposide; arm A) followed by three consolidation cycles of high-dose cytarabine (n=371, 63%) or allogeneic hematopoietic cell transplantation (n=42, 8%). In the investigational arm (arm B), GO (3 mg/m²) was given at d1 of each induction and in the first consolidation cycle. 296 pts were randomized to arm A and 292 pts to arm B. For this correlative study, outcome analysis was restricted to the clinical endpoint cumulative incidence of relapse (CIR) due to study protocol requirements allowing overall survival analysis to be performed only two years after the last pt had been enrolled. MRD monitoring was performed in a total 503 pts for whom at least one bone marrow (BM) sample was available using RQ-PCR technique; the median follow-up (FU) of the 503 pts was 2.8 yrs. NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR (sensitivity 10-5 to 10-6). Results: In total, 3711 BM samples were analyzed (at diagnosis, n=415; during treatment, n=1765; during FU, n=1531). Both study arms were well balanced with regard to pts characteristics and pretreatment NPM1mut TL. First, we evaluated the impact of GO on kinetics of NPM1mut TL during treatment. After the first induction cycle, median NPM1mut TL were significantly lower in the investigational arm (p=.001) and this was true for all subsequent treatment cycles [after induction II (p=.008), consolidation I (p 〈 .001), consolidation II (p=.006), consolidation III (p=.009)]. Next, we evaluated treatment effects on NPM1mut TL after two cycles of induction therapy in pts in complete remission (CR, n=378). At this time point, there was no difference in the proportion of pts achieving RQ-PCR negativity (RQ-PCRneg) [arm A 15% (28/192), vs arm B 17% (32/186); p=.57] between the two treatment arms. However, treatment according to investigational arm B with GO was associated with a significantly lower CIR rate (CIR at 4 yrs: arm B 29% vs arm A 45%, p=.02). In multivariate analysis randomization to arm B revealed as an independent prognostic factor for remission duration (HR 0.63, p=.018). At the end of treatment (EOT, n=288 pts in CR) the proportion of pts achieving RQ-PCRneg was significantly higher (55% vs 41%; p=.02) in the investigational arm; pts treated in arm B had a significantly lower CIR rate compared to arm A (CIR at 4 yrs: arm B 29% vs arm A 45%, p=.04). Conclusion: In our randomized Phase III AMLSG 09-09 study, the addition of GO to intensive chemotherapy plus ATRA was associated with a significantly better reduction of NPM1mut TL after each treatment cycle. This better clearance translated into a significantly lower CIR in the investigational arm with GO. Disclosures Paschka: Otsuka: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Janssen: Other: Travel support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Takeda: Other: Travel support. Krönke:Celgene: Honoraria. Fiedler:Amgen: Other: support for meetíng attendance; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Other: support for meeting attendance. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Lübbert:Janssen: Honoraria, Research Funding; TEVA: Other: Study drug; Cheplapharm: Other: Study drug; Celgene: Other: Travel Support. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Abstract: BACKGROUND: Midostaurin is a first-generation, type I multi-targeted kinase inhibitor with inhibitory activity against FLT3-ITD and -TKD mutations. Midostaurin is approved by FDA and EMA in combination with intensive induction and consolidation chemotherapy for adult patients with AML exhibiting an activating FLT3 mutation; the EMA label also includes single-agent maintenance therapy following consolidation chemotherapy. We conducted a phase-II trial (AMLSG 16-10) to evaluate midostaurin with induction chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in younger and older patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (ITD). METHODS: Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS); results were compared to those of a historical control cohort of 415 patients with FLT3-ITD AML. Statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Major differences in trial design compared to the pivotal CALGB 10603/RATIFY trial were: i) only AML with FLT3-ITD were eligible; ii) AML with FLT3 tyrosine kinase domain mutations (only) and core-binding factor AML were not eligible; iii) older patients 60-70 years of age were eligible; iv) all patients were assigned to allogeneic HCT; v) a one-year maintenance treatment with midostaurin was included also after allogeneic HCT; vi) a continuous dosing schedule of midostaurin was applied with the aim to achieve a better target inhibition. Results: The trial accrued 440 patients, including 312 younger (18-60 yrs) and 128 older (61-70 yrs) patients. Complete remission (CR)/CR with incomplete hematologic recovery rate, median EFS and OS of the 440 patients were 74.9%, 13.6 and 36.2 months, respectively. Multivariate analysis of EFS showed a highly significant hazard reduction for an event for patients treated within AMLSG 16-10 trial compared to the historical controls (HR 0.55; 95%-confidence interval [CI], 0.47, 0.65; P & lt;0.001); this effect was significant in the younger (HR 0.59; 95%-CI, 0.49, 0.71; P & lt;0.001) and the older patient cohort (HR 0.42; 95%-CI, 0.30, 0.60; P & lt;0.001). Multivariate analysis also showed a highly significant beneficial effect on OS (HR 0.57; 95%-CI, 0.47, 0.68; P & lt;0.001), again for both age subgroups. Allogeneic HCT in first CR/CRi was performed according to protocol in 199 of 440 (45%) patients (48% and 38% in younger and older patients, respectively), and an additional 60 patients received allogeneic HCT in firstline therapy (n=33 pts. in CR/CRi after salvage therapy and 27 pts. with active disease); the treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT (n=259) as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. Conclusions: In comparison to a historical control cohort, the addition of midostaurin to intensive therapy led to a significant improvement in EFS and OS in both younger and older adult patients with AML and FLT3-ITD. Figure: Survival distribution for the primary endpoint event-free survival (EFS) and key secondary endpoint overall survival (OS) according to study population and age group. A EFS by cohort and age group (≤60 versus & gt;60 years) B OS by cohort and age group (≤60 versus & gt;60 years) Figure 1 Figure 1. Disclosures Döhner: Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ulm University Hospital: Current Employment. Fiedler: Servier: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; MorphoSys: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Celgene: Consultancy, Honoraria; Ariad/Incyte: Honoraria; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material. Wulf: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Salih: BMS: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Synimmune GmbH: Honoraria; Novartis: Honoraria. Lübbert: Imago BioSciences: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Syros: Honoraria; Aristopharm: Research Funding; Cheplapharm: Research Funding; Janssen: Research Funding; Teva: Research Funding; Hexal: Honoraria; Astex: Honoraria; Abbvie: Honoraria. Kühn: Abbvie: Honoraria; Kura Oncology: Honoraria, Research Funding; Pfizer: Honoraria. Schroeder: Abbvie: Honoraria; Astellas: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pfizer: Honoraria. Götze: Abbvie: Honoraria; Celgene/BMS: Honoraria, Research Funding. Westermann: Amgen: Consultancy, Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Astellas: Honoraria. Fransecky: Abbvie: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Medac: Honoraria. Mayer: Novartis: Other: Travel support; Celgene: Other: Travel support; Roche: Other: Travel support; Amgen: Other: Travel support; BMS: Other: Travel support; Pfizer: Other: Travel support; Jazz: Other: Travel support; Astellas: Other: Travel support. Hertenstein: Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria; BMS: Honoraria. Tischler: AstraZeneca: Other: Travel support; Novartis: Other: Travel support; Janssen: Honoraria; GSK: Other: Travel support; Sanofi-Aventis: Other: Travel support; Abbvie: Other: Travel support. Paschka: Abbvie: Honoraria, Other: Travel support; Agios: Honoraria, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Astex: Honoraria; Celgene: Honoraria, Other: Travel support; Jazz: Honoraria; Novartis: Honoraria, Other: Travel support; Otsuka: Honoraria; Pfizer: Honoraria; Sunesis: Honoraria; BMS: Other, Speakers Bureau; Celgene: Honoraria; Janssen: Other; Takeda: Other. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlenk: Astellas: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Hexal: Honoraria; Neovio Biotech: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Honoraria; Agios: Honoraria. Bullinger: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Astellas: Honoraria; Bristol-Myers Squibb / Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Roche: Honoraria; Daiichi Sankyo: Honoraria; Agios: Research Funding; Astex: Research Funding; Astellas: Research Funding. Ganser: Novartis: Honoraria; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Midostaurin as single-agent maintenance therapy following allogeneic hematopoietic cell transplantation