Niederweiser, Dietger

Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%]). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt], one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: The CD19 antigen is an attractive therapeutic target as it is highly expressed in chronic lymphocytic leukemia (CLL). CD19 is not down-regulated in patients (pts) pretreated with CD20-targeting agents and has a signaling function that promotes the malignant phenotype. In preclinical studies, the Fc-enhanced, humanized, CD19 antibody MOR208 showed synergistic potential in combination with venetoclax (VEN, a small molecule selective inhibitor of the apoptosis regulator BCL-2). Pts with relapsed or refractory (R/R) CLL who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have poor prognosis. A previous phase I study showed that MOR208 was well tolerated, with encouraging single-agent activity in pts with R/R CLL. This ongoing phase II study was designed to assess the safety and preliminary efficacy of MOR208 in combination with idelalisib (Cohort A) or VEN (Cohort B) in pts with R/R CLL previously treated with a BTKi. Results of Cohort A were previously published at EHA 2018 (Poster PF350). Here we report the initial safety and efficacy results for Cohort B. Methods: Adult pts with R/R CLL without transformation or Richter's syndrome, who progressed on BTKi therapy or were intolerant to a BTKi during their last prior therapy, were eligible if they had ECOG performance status 0-2 and adequate organ function. In Cohort B, pts were treated until progression or for up to 24 cycles (C; 28 days (D)/C). MOR208 was administered intravenously at 12 mg/kg body weight, starting from C1D1, weekly during C1-3 (with an equivalent loading dose on D4 of C1), every other week in C4-6, and monthly in C7-24. Oral VEN was administered daily starting from C1D8 on a weekly ramp up dosing schedule, starting at 20 mg on C1D8, increasing to 50 mg on C1D15, 100 mg C1D22, 200 mg C2D1 and reaching the full daily dose of 400 mg from C2D8 onwards. Primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to IWCLL 2008 guidelines. Results: We report preliminary results of Cohort B with a data cutoff date of June 18, 2018 and a median observation time of 4.6 months. Recruitment in Cohort B was completed with 13 pts who received at least one dose of MOR208. Eleven pts started combination treatment with VEN; 10 pts completed at least 5 weeks of combination treatment, reaching the full daily dose of VEN. Baseline characteristics are shown in Table 1. All pts had received ibrutinib therapy and 1 pt had subsequent acalabrutinib treatment. The median number of prior treatment lines, including BTKi therapy in all 13 pts, was 3 (range 1-4). Table 2 summarizes treatment-emergent (TE)AEs. The most common hematological TEAE was neutropenia (38%). Eleven TE serious (S)AEs were reported in 9 pts (69%); all resolved. One grade 3 SAE, tumor lysis syndrome, occurred at ramp up to 50 mg VEN. The pt recovered after treatment and continued VEN 50 mg the day after event onset. Three serious adverse reactions (2 pts with infusion-related reactions, 1 pt with bone pain with pyrexia) were reported in total. Two pts (15%) permanently discontinued study treatment due to an infusion-related reaction arising during MOR208 monotherapy (i.e. before C1D8). One pt (8%) discontinued study participation due to withdrawal of informed consent, when on a dose of 50 mg VEN. The 3 discontinued pts did not undergo a response assessment. Treatment of 10 pts is ongoing and seven pts had at least 1 post-baseline assessment of tumor response on C4D1; all (7/7) had a partial response (PR) based on local investigator assessment. Conclusions: The novel combination treatment of MOR208 with VEN showed generally acceptable safety and tolerability as well as encouraging antitumor activity in pts with R/R CLL who discontinued prior treatment with a BTK inhibitor. Disclosures Staber: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munir:Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Schetelig:Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Middeke:Janssen: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Weirather:MorphoSys: Employment. Parikh:MorphoSys: Research Funding; Gilead: Honoraria; Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding. Stilgenbauer:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding. Wendtner:Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding.

Abstract Introduction: Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3-TKD), representing point mutations in codon D835/I836 and rarely deletions of codon I836, induce constitutive tyrosine phosphorylation and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3-TKD in AML, particularly in the presence of NPM1 mutations, is not well established. The phase 3 RATIFY trial [NCT00651261; Stone et al. N Engl J Med. 2017] showed that in combination with standard chemotherapy, midostaurin (PKC412) improved survival outcomes across all 3 FLT3 stratification subgroups (ITD high allelic ratio [≥ 0.7], ITD low allelic ratio [< 0.7], and TKD) vs placebo in patients with newly diagnosed FLT3-mutated AML. Here, we evaluated the prognostic impact of FLT3-TKD and NPM1 mutations in a post hoc analysis from the RATIFY trial. Methods: In RATIFY, newly diagnosed patients with AML 18-60 years old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by 12 28-day cycles of maintenance therapy with midostaurin or placebo. FLT3-TKD mutation was detected by PCR and capillary electrophoresis at 9 reference laboratories. Patients were categorized as NPM1 mutated (mut) or NPM1 wild-type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event-free survival (EFS) and disease-free survival (DFS). EFS and DFS analyses were performed considering CR within a 60-day window. P values presented have not been adjusted for multiplicity. Results: Of the total randomized 162 FLT3-TKD patients, 134 with available NPM1 data had consented for exploratory analysis and thus were included in this study (see Table for subgroup distribution). Overall, 47.8% of patients were male, and the median age was 49 years (95% CI, 45.5-51.1 years). The median white blood cell (WBC) count was higher in patients with NPM1-mut than in patients with NPM1-WT (34.1 vs 15.5 × 109/L, P = .0011). CR rates (during the first 60 days) were higher in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT (66% vs 53%); however, this was driven by the higher rate of CR in the midostaurin arm (76% NPM1-mut vs 44% NPM1-WT) rather than the placebo arm (53% NPM1-mut vs 60% NPM1-WT). The overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3-TKD patients. The prognostic effect of the NPM1 mutation concurrent with FLT3-TKD was seen for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower (Figures 1 and 2 and Table). Overall (regardless of treatment) OS, EFS, and DFS estimates at 3 years were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT. Whereas the HRs for midostaurin vs placebo were 0.73 for both OS and EFS, the impact of treatment on outcomes varied between the individual NPM1/TKD subgroups and was not consistently observed when endpoints were censored at stem cell transplant (SCT) (Table). It should be noted that the number of patients in each subgroup was small and therefore the HRs with 95% CIs should be interpreted with caution. Multivariate analyses in these FLT3-TKD patients revealed that NPM1 genotype was an independent prognostic factor for OS, EFS and DFS (2-sided P < .05), whereas study drug, age, sex, WBC at baseline and SCT (no/yes) did not reach this level of significance in the Cox model. Conclusions: This post hoc analysis of the FLT3-TKD patient subset in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Whereas midostaurin showed an overall benefit in the FLT3-TKD patients for OS, EFS, CR and DFS, the impact of treatment on outcome varied between the individual NPM1 subgroups within these FLT3-TKD patients and was not consistently observed.Further analyses using additional endpoints and additional multivariate analyses are planned. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180791, U10CA180888, U10CA180863, (CCSRI) #704970, U24CA196171; ClinicalTrials.gov Identifier: NCT00651261 Disclosures Voso: Celgene: Research Funding, Speakers Bureau. Larson:Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Heuser:Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; StemLine Therapeutics: Consultancy; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; Tetralogic: Research Funding; Sunesis: Research Funding; Daiichi Sankyo: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Amgen: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Brandwein:Lundbeck: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding. de Witte:Novartis: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Research Funding. Medeiros:Celgene: Consultancy, Research Funding; Genentech: Employment. Tallman:Cellerant: Research Funding; Orsenix: Other: Advisory board; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Cheng:Novartis: Employment. Gathmann:Novartis: Employment. Tiecke:Novartis: Employment. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Stone:Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; Agios: Consultancy, Research Funding; Orsenix: Consultancy; Ono: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Arog: Consultancy, Research Funding; Merck: Consultancy; Cornerstone: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Pfizer: Consultancy; Sumitomo: Consultancy; AbbVie: Consultancy.

Background:Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3‐TKD), induce constitutive tyrosine phosphorylation, and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3‐TKD in AML is not well established. In the phase 3 RATIFY trial [CALGB 10603/Alliance; NCT00651261; Stone et al. N Engl J Med. 2017] midostaurin, in combination with standard chemotherapy, improved survival outcomes across all three FLT3 stratification subgroups (ITD high allelic ratio (AR) [≥ 0.7], ITD low AR [< 0.7] and TKD) vs placebo.Aims:Here, a post hoc analysis was used to establish the efficacy of midostaurin in patients (pts) in the RATIFY trial stratified by FLT3‐TKD AR and NPM1 mutational status.Methods:In RATIFY, newly diagnosed pts with AML 18–60 years (y) old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by twelve 28‐day cycles of maintenance therapy with midostaurin or placebo. FLT3‐TKD mutation was detected by PCR and capillary electrophoresis at nine reference laboratories. The FLT3‐TKD AR was calculated as the ratio between the areas under the curve of mutant to wild‐type allele. Pts were categorized as NPM1 mutated (mut) or NPM1 wild‐type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event‐free survival (EFS) and disease‐free survival (DFS). EFS and DFS analyses were performed considering CR within a 60‐day window. P values presented were not adjusted for multiplicity.Results:Of 163 FLT3‐TKD pts, 134 with available NPM1 data had consented for exploratory analysis and were included in this study. Overall, 58.9% of pts had NPM1‐mut, 47.8% were male and the median age was 49 y (range: 19.3–59.9 y). The median white blood cell (WBC) count was higher in pts with NPM1‐mut than in pts with NPM1‐WT (34.1 vs 15.5 × 109 /L). The median FLT3‐TKD AR was 0.4 (range: 0–2.7). Overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3‐TKD pts. Pts with FLT3‐TKD AR ≥ 0.4 treated with midostaurin showed a trend towards improved OS and reduced cumulative incidence of relapse (CIR) (Figure). In FLT3‐TKD AR ≥ 0.4 pts, the presence of a NPM1 mutation had a significant prognostic effect for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower. Regardless of treatment OS, EFS, and DFS estimates at 3 y were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, for the 45 pts with FLT3‐TKD/NPM1‐mut vs the 25 pts with FLT3‐TKD/NPM1‐WT. It should be noted that the number of pts in each subgroup was small. Multivariate analyses in these FLT3‐TKD pts revealed that NPM1 genotype was an independent prognostic factor for OS and EFS (2‐sided P < 0.05), whereas study drug, age, sex, TKD AR, WBC at baseline and stem cell transplantation (SCT) (no/yes) did not reach this level of significance in the Cox model.Summary/Conclusion:This post hoc analysis of the subset of FLT3‐TKD pts in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Midostaurin showed an overall benefit in the FLT3‐TKD pts for OS, EFS, CR and DFS, with the impact of treatment on outcome for NPM1‐mut pts being greatest in those with higher FLT3‐TKD allelic burden. U10CA180821, U10CA180882, U24CA196171, U10CA180861; Novartis; htt∗∗∗ps://acknowledgments.alliancefound.orgimage