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: Background:Despite recent advances in identifying novel molecular targets in AML patients, intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) still remains a cornerstone of AML therapy. However, outcome of HSCT depends on the availability of a donor and the donor type. Prior studies comparing HSCT from HLA-matched related donors (MRD) with matched unrelated donors (MUD), demonstrated conflicting results with regards to outcome. These conflicting results might be attributed to the genetic heterogeneity of AML. Aims:To analyze outcome with respect to donor type of 952 AML patients who received HSCT in first complete remission (CR) and were treated within prospective AMLSG trials. Methods:Within the AMLSG trials conducted between 1993 and 2013, of a total of 4991 patients (excluding acute promyelocytic leukemia), 3408 (2744 younger ( 〈 61 years old), 664 older (≥61 years old)) patients achieved a first CR after intensive double induction therapy. Of these, 867 (31%) younger and 85 (13%) older patients received HSCT in first CR. Distributions of donor types were 511 matched related donors (MRD), 435 matched unrelated donors (MUD) and 6 haplo-identical donors. The latter were grouped together with MUD. Results:Distributions of donor type over time are illustrated in table 1 indicating two clear trends with increasing numbers of MUD transplants and increasing median age in MUD- and MRD-transplants in recent years. There was no significant difference in overall survival, cumulative incidence of relapse (CIR) and death (CID) all estimated at 4 years according to the three time periods for MRD (p=0.56, p=0.15, p=0.10, respectively) and MUD (p=0.27, p=0.20, p=0.88, respectively). Table 1 Time period 1993-2002 2003-2007 2008-2013 Total no. 1036 1102 1270 MRD  No. 186 (18%) 182 (17%) 143 (11%)  Median age 42.7yrs 46.0yrs 51yrs  4-yr-OS (95%-CI) 59% (53-67) 66% (59-73) 61% (53-72)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%) MUD  No. 42 (4%) 131 (12%) 268 (21%)  Median age 41.1yrs 47.9yrs 50.6yrs  4-yr-OS (95%-CI) 52% (39-70) 46% (38-58) 54% (47-61)  4-yr-CIR (SE) 21% (3%) 25% (3%) 29% (4%)  4-yr-CID (SE) 25% (3%) 15% (3%) 18% (3%) Table 2 ELN risk category low inter-1 inter-2 high Total no. 867 711 433 318 MRD  No. 78 (9%) 122 (17%) 66 (15%) 57 (18%)  4-yr-OS (95%-CI) 84% (76-93) 50% (51-69) 53% (41-67) 57% (44-72)  4-yr-CIR (SE) 7% (3%) 24% (4%) 35% (6%) 49% (7%)  4-yr-CID (SE) 13% (4%) 23% (4%) 23% (6%) 12% (4%) MUD  No. 21 (2%) 139 (20%) 76 (18%) 109 (36%) 4-yr-OS (95%-CI) 69% (52-93) 58 (49-68) 52% (41 67) 35% (26-46)  4-yr-CIR (SE) 0% 28% (4%) 32% (6%) 44% (5%)  4-yr-CID (SE) 31% (11%) 20% (4%) 17% (5%) 28% (4%) There were no differences in stratified survival analyses for time period between MRD and MUD-transplants in the low, intermediate-1 and intermediate-2 risk groups with respect to OS (p=0.12, p=0.86, p=0.98), CIR (p=0.28, p=0.54, p=0.94) and CID (p=0.09, p=0.57, p=0.39). In the high risk group, OS was significantly superior after MRD-transplant compared to MUD-transplant (p=0.02), but without significant differences in CIR (p=0.74) and CID (p=0.08). Equivalent efficacy could also be shown in a subgroup analyses focusing on all FLT3-ITD positive patients (MRD, n=103, MRD, n=147) for OS (p=0.71), CIR (p=0.53) and CID (p=0.69). Conclusions: Our results based on prospective interventional studies support the perception that MUD-transplants are equal to MRD-transplants in patients with AML in first CR. Only within the ELN high risk group, patients with MRD-transplants showed superior OS but without differences in CIR and CID as compared to MUD-transplants. Disclosures Kobbe: Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Petzer:Celgene: Honoraria, unrestricted grant Other. Lübbert:Cephalon / TEVA: Travel support Other. Greil:Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Roche: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding. Döhner:Novartis: Research Funding. Döhner:TEVA: Research Funding.

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 Cyto- and molecular-genetic abnormalities evaluated at initial diagnosis are the most powerful prognostic and in part also predictive markers in acute myeloid leukemia (AML) with regard to achievement of complete remission (CR) and survival. Nonetheless, after relapse the prognostic impact of clinical characteristics and genetic abnormalities assessed at initial diagnosis with respect to achievement of subsequent CR and survival are less clear. Aims To evaluate the probability of CR achievement and survival in relapsed AML patients in correlation to clinical characteristics and genetic abnormalities assessed at initial diagnosis as well as treatment strategy. Methods The study includes intensively treated adults with newly diagnosed AML enrolled in 5 prospective AMLSG treatment trials between 1993 and 2009. Patients with acute promyelocytic leukemia were excluded. All patients received intensive therapy, including allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) during first line therapy. Results A total of 3218 patients (median age, 54 years; range, 16-85 years) were enrolled in 5 AMLSG treatment trials. Of these, 1307 (41%) patients (16-60 years, n=958; ≥61 years, n=349) experienced relapse, n=194 after alloHSCT, n=75 after autoHSCT and 1038 after chemotherapy. Salvage strategies were as follows: (i) n=907, intensive chemotherapy (INT) followed in n=450 by HSCT (matched related donor [MRD], n=114; matched unrelated donor [MUD] , n=303; cord blood graft [CB], n=3; haplo-identical family donor [HID] , n=18; autoHSCT, n=12); (ii) n=100, direct alloHSCT (MRD, n=31; MUD, n=63; HID, n=4) or n=2 autoHSCT (TPL); (iii) n=29, donor lymphocyte infusions (DLI) in patients after alloHSCT in CR1; (iv) n=60, demethylating agents/low-dose cytarabine (NON-INT); (v) n=24, experimental treatment within phase I/II studies (EXP); (vi) all other patients (n=187) received best supportive care (BSC). After salvage therapy CR rate was 38% and after the different treatment approaches as follows: INT, 37%; TPL, 73%; DLI, 38%; NON-INT, 8%; EXP, 29%. After failure to respond to INT, n=159 additional patients achieved a CR2 after HSCT resulting in an overall CR2 rate of 50%. A logistic regression model revealed CEBPA double-mutant (dm) (OR, 6.42; p=0.0001), core-binding factor (CBF) AML (OR, 2.87; p=0.0002), a direct HSCT strategy (OR, 3.32; p=0.0002), and mutated NPM1 (OR, 1.59; p=0.02) as favorable (only if response after HSCT was included) and FLT3-ITD (OR, 0.66; p=0.04), age (difference of 10 years; OR, 0.82; p=0.003), NON-INT (OR, 0.08; p=0.0001) and in trend a previous alloHSCT in CR1 (OR, 0.65; p=0.08) as unfavorable independent parameters for achievement of CR2. Median follow-up for survival after relapse was 4.3 years and survival after 4 years was 22% (95%-CI, 19-25%). Patients proceeding to alloHSCT after first relapse (n=536; MRD, n=145; MUD, n=366; HID, n=22; CB, n=3) had a 4-year survival of 36% (95%-CI, 32-41%) and those not proceeding to alloHSCT of 8% (95%-CI, 6-11%). In univariable analyses the combined genotype mutated NPM1 in the absence of FLT3-ITD (p=0.66) was not associated with a favorable outcome. A multivariable regression model including alloHSCT as a time-dependent co-variable revealed alloHSCT performed after relapse (HR, 0.34; p 〈 0.0001), CEBPAdm (HR, 0.48; p=0.002), CBF- AML (HR, 0.50; p 〈 0.0003) and DLI in relapsed patients with a previous alloHSCT performed in CR1 (HR, 0.40; p=0.002) as significant favorable factors, whereas FLT3-ITD (HR, 1.35; p=0.005) and in trend NON-INT (OR, 1.40; p=0.06) were unfavorable factors. Due to collinearity of FLT3-ITD with duration of first remission (cut point at 1 yr), the latter was not included into the multivariable models. Of 561 patients achieving CR2, 252 experienced 2nd relapse (REL2) and 114 died in CR2. Most REL2 patients (n=117) received INT whereas n=54 received BSC only. Allo- and autoHSCT were performed in 55 and 3 REL2 patients, respectively. CR3 rate in patients who received treatment was overall 40% including response to HSCT of 58%. Conclusions Patients with relapsed AML have an overall probability of less than 50% to achieve a CR2 and CR3 after intensive salvage chemotherapy; the only exceptions are AML with CEBPAdm and CBF-AML. AlloHSCT either as direct treatment of relapse or as salvage therapy after failure of intensive chemotherapy may overcome chemo-resistance. Disclosures: Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Kindler:Novartis: Membership on an entity’s Board of Directors or advisory committees.

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), 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 & gt;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 & lt;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 ( & lt;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.

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: Background Overall survival (OS) in acute myeloid leukemia (AML) treated with intensive chemotherapy has improved over the last 20 year especially in younger adults (18-60 years) but still remains poor in older patients ( 〉 60 years) (Döhner et al. Blood 2010). The German-Austrian AMLSG performed controlled prospective treatment trials since 1993 starting with a risk-adapted approach (phase I, 1993-1997), followed by randomized and risk-adapted treatment strategies based on cytogenetic risk groups (phase II, 1997-2002); since 2003 addition of differentiating agents and HiDAC inhibitors to intensive induction therapy was evaluated (phase III, 2003-2007). Of note, until 2007 younger and older patients ( 〉 60 years) were treated in separate protocols with significantly lower dosages of chemotherapy in older patients. Starting from 2008, risk-adapted therapies were replaced successively by a genotype-adapted approach and the artificial age cut-off at 60 years was abandoned (phase IV, 2008-2012). Aims To evaluate the outcome of adult AML patients within the different time periods. Methods The study included 4705 intensively treated adults (younger, n=3546; older, n=1159) with newly diagnosed AML enrolled on 11 AMLSG treatment trials between 1993 and 2012. Patients with acute promyelocytic leukemia were excluded. All patients received intensive induction and consolidation therapy. Analyzed outcome variables were first complete remission rates (CR1), relapse-free survival (RFS), survival after relapse (SAR) and OS. Analyses were performed according to age groups (18-60 vs. 〉 60 yrs). In younger patients comparisons were performed for the 4 treatment phases (I-IV), whereas for older patients analyses were restricted to phase II-IV. Results In younger patients CR rates did not improve over time (1993-2013) and varied between 72% and 77% (p=0.12), whereas early and hypoplastic (ED/HD) death rates significantly declined from 10% to 5% (p=0.0001). In older patients CR rates significantly improved over time from 44% to 50% between 1998 and 2007 to 67% after 2008 (p 〈 0.0001); ED/HD rates gradually declined from 12% to 8%, but the difference was not statistically significant (p=0.17). The proportion of younger patients receiving an allogeneic hematopoietic stem cell transplantation (alloHSCT) increased from 30% (15% in CR1) in phase I to 58% (29% in CR1) in phase III and remained there in phase IV with 53% (26% CR1), whereas the proportion of patients receiving an autologous HSCT constantly decreased from maximally 16% (15% in CR1) in phase II to 0.4% (0.2% in CR1) in phase IV; the proportion of older patients receiving an alloHSCT steadily increased from 4% (2% CR1) in phase II to 21% (12% CR1) in phase IV; autoHSCT was rarely performed. OS at 4 years in both age groups significantly improved (p 〈 0.0001, each) from 41% to 56% and from 10% to 23% in younger and older patients, respectively. This beneficial effect on OS over time in younger patients was due to a better RFS (p=0.01) and SAR (p 〈 0.0001), whereas in older patients no improvement in RFS (p=0.20) and only in trend for SAR (p=0.07) was noted. In cytogenetically high-risk patients, OS in younger (p=0.001) and in older (p=0.007) patients got better; in older patients mainly driven by increase in CR rates (p=0.001) and in younger patients by an improvement in RFS (p=0.02) and SAR (p=0.05). Nearly the same pattern was identified for cytogenetically intermediate risk patients with a better OS in younger (p 〈 0.0001) and older patients (p=0.01) due to higher CR rates in older patients (p 〈 0.0001), no improvement in RFS in both age groups and a significantly better SAR in younger patients (p=0.0002). In contrast, in low risk patients improvement in OS was only present in older patients (p=0.02), due to a better RFS in older patients (p=0.02) but without any progress in younger patients. Furthermore we performed two subgroup analyses in intermediate risk patients. In the subgroup of patients characterized by the genotype NPM1-mut/FLT3-ITDneg a significant better OS was present only in younger patients (p=0.03); in FLT3-ITD positive AML a better OS was seen in younger patients (p 〈 0.0001) due to a better RFS (p=0.05) and SAR (p=0.01). Conclusions Based on the German-Austrian AMLSG experience the prognosis in younger and older AML patients has improved over time. In older patients this is mainly a result of higher CR rates and in younger patients of better RFS and SAR. Disclosures: Schlenk: Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Ambit: Honoraria. Off Label Use: Pomalidomide in Myelofibrosis. Greil:Novartis: Honoraria, Research Funding.