Klisovic, Rebecca B.

Background: C10603/RATFIY was the first AML trial to show the benefit of adding a targeted agent to intensive chemotherapy for a specific genetically determined subset (Stone R et al, NEJM 2017). The addition of the multi-kinase inhibitor midostaurin (M) to chemotherapy in previously untreated adults with FLT3-mutant AML resulted in superior event-free (EFS) and overall survival (OS) compared to placebo (P) and led to the approval of this agent in combination therapy. Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval. Long-term follow-up after reporting of the primary endpoint, especially if met, is important in oncology. Objective: We report the EFS and OS data from C10603 using 10 years of follow up to determine the persistence of a midostaurin benefit and to assess the nature of late relapses or toxicity. Methods: C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5. M (50 mg bid) or P was given orally on days 8-22 of each chemotherapy cycle as well as daily during one year of single-agent maintenance. Allogeneic transplantation (alloHCT) was employed at investigator's discretion; study drug was not continued post-HCT. Pts stayed on their randomized arm and were not re-randomized prior to maintenance. Pts were followed for relapse and survival after the end of protocol therapy, regardless of subsequent therapy, for 10 years. Log-rank tests, Kaplan-Meier methods, and Cox proportional hazard models were used to evaluate the treatment effect in EFS and OS, as well as the alloHCT effect. All p values are two-sided. Results: We have completed the 10-year FU on this trial and data collection has concluded. The median EFS was 8.2 months (95% CI, 5.5-11.4) on the M arm compared with 3.0 months for P (95% CI, 1.9-6.0) with a HR of 0.79 (95% CI 0.67-0.94, p=0.0067). Among the 420 CR pts who achieved complete remission (CR) by the protocol specified time of 60 days, 253 have had an event (death in 69 and relapse in 184); these events were relatively equal on each arm. OS, the co-primary endpoint, remained marginally superior for those randomized to M compared to P; the 10-year OS estimate was 43.7% (95% CI, 38.7-49.3%) vs 38.6% (95% CI, 33.6-44.4%) (p= 0.0485). The hazard ratios for OS favored randomization to M in each key biological subgroup (FLT3-ITD low or high allelic ratio or FLT3-TKD), but smaller subsets precluded statistical significance. There was a 10-year OS benefit in favor of M in men (p=0.005), but not women (p=0.9). A total of 414 transplants were performed: only 5 in the latter half of the follow-up period. Transplantation in CR1 was highly beneficial overall (10-year OS, 56% vs 35.8% without transplantation, p=0.001). Among those transplanted in CR1, randomization to M was marginally better than P (61.5% vs 49%, p=.064). After censoring for alloHCT in CR1, there was an OS trend in favor of M (51.8% v 48.0%, p=0.102). In CR1 patients who were randomized to maintenance therapy, M reduced the cumulative incidence of relapse in ELN 2017 favorable and intermediate risk pts, but not in those with adverse risk disease (HR 0.71, 0.47, and 1.01, respectively); maintenance M had no effect on OS. Only 3 pts relapsed after 5 years (all randomized to M). 25 pts randomized to M vs 13 P pts died after 5 years of follow-up. 5 pts on each arm died of a new primary cancer whereas 17 M and 5 P pts were coded as having died from treatment-related causes. None of the 3 pts who relapsed after 4 years had spliceosome mutations at diagnosis; whereas 18% (21/117) patients pts who had relapsed earlier had spliceosome mutations at diagnosis (p=0.419). Conclusions: The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could suggest the use of alternative therapies during distinct therapeutic stages.

PURPOSE Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome–negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome–negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome–negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.

Abstract Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Abstract We conducted a two-stage Simon phase II, multi-center study in two groups: related and unrelated donor transplants. Based on the results of a previously conducted prospective study (MPD-RC 101, Rondelli et al, Blood, 2014) demonstrating relatively poor outcome in the unrelated donor arm due to high non-relapse mortality and graft failure (GF), we sought to improve this noted disparate outcome. The hypothesis driving this trial was that pre-transplant JAK1/2 inhibition would result in an increase in performance status, reduction in splenomegaly and inflammatory cytokine expression leading to improved HCT outcome. In the unrelated arm in the first 11 patients, the trial was to be terminated if 6 or more failures (GF or death due to any cause by 100 days post-transplant) were observed. In the related arm in the first 11 patients, the trial was to be terminated if 3 or more failures were observed. Key eligibility criteria included diagnosis of primary MF or post-PV MF or post-ET MF, age 18-70 years, and DIPSS int-2/high risk disease or int-1 risk disease with at least one additional risk factor. Patients could have received up to 6 months of ruxolitinib prior to enrollment provided that there was no evidence of loss of response to ruxolitinib during this period. Ruxolitinib was given for 56 days followed by a 4-day taper ending day -6. The conditioning regimen utilized was IV fludarabine 40 mg/m2 IV and IV busulfan 2.0 mg/KBW IV once daily for 4 days from days -5 to -2. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Patients undergoing unrelated donor HCT also received low dose thymoglobulin (0.5 mg/KBW on day -3/2.0 mg/KBW on day -2 & day -1). The study has enrolled 21 patients (related, 7; unrelated, 14) with a median age of 59 years (range 39-70). 17 (81%) patients had palpable splenomegaly with median spleen size of 11 cm, and 16 patients had int-2/high risk disease. Of the 21 patients, 19 patients received transplantation (related 5/7 [71%], unrelated 14/14 [100%] underwent transplant). Two patients in the related arm did not proceed with transplantation as one progressed to acute myeloid leukemia (baseline blast count 14%) and another experienced sudden death of unknown cause the day after starting ruxolitinib. In addition, there was one GF in the related arm. Due to these 3 failures in the related arm, further enrollment was stopped in this arm per protocol criteria. In the unrelated arm, there were 4 failures (Table 1), and the study met the protocol criteria for further enrollment. Mean percent reduction from baseline to day -9 in palpable spleen length below the left costal margin was 30% (p=0.04) in 12 patients with palpable spleen. 5/12 (42%) had any reduction, and 4/12 (33%) had ≥50% reduction. From baseline to best score on day -9 or day -5, 11/19 (58%) patients with data had any improvement in MPN-SAF Total Symptom Score, and 7/19 (37%) had ≥50% reduction. Of the 19 patients undergoing transplant, ruxolitinib was tapered off successfully in all patients with no significant withdrawal syndrome or delay in transplant noted. In the pre-transplant phase, most common Grade 3 or higher toxicity considered to be related to ruxolitinib was anemia (6/21, 29%), and one patient had legionella pneumonia deemed not related to ruxolitinib. Median time to neutrophil recovery (> 0.5 x 109/L) and platelet recovery (>20 x 109/L) was 19 and 19.5 days. By day 100, 7/19 (37%) experienced Grade 2-4 acute GVHD (G2 in 5, G3 in 2). In the first 30 days post HCT, most common Grade 3 or higher toxicity was febrile neutropenia seen in 5/19 (26%) patients. In all 21 patients from time of registration with median follow-up of 5.8 months, 6-mo overall survival was 75% (95% CI 44-90%). For the 19 transplant recipients, 6-mo OS was 83% (95% CI 55-94%) from date of transplant. Conclusions: Stage 1 trial results highlight important observations. First, ruxolitinib may not be suitable for all myelofibrosis patients pre-transplant, eg, alternative approaches might be more appropriate in the context of accelerating disease. Second, we demonstrated a safe approach for tapering ruxolitinib prior to transplant which allowed patients to commence conditioning with reduced spleen size and symptoms. Third, pre-transplant ruxolitinib does not appear to have any adverse impact on early post-HCT outcomes following unrelated donor transplant, although Stage 2 enrollment will be required to better assess the potential benefits of this approach. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Mascarenhas:Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, 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.

Abstract The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS). Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0. Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 103/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response. Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses. Disclosures Advani: Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Wieduwilt:Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Park:Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Erba:Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Jazz: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Agios: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; MacroGenics: Consultancy; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau.

Abstract Background: Midostaurin (M) is a multi-targeted small molecule FLT3 inhibitor which has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant FLT3 AML. The objective of this global rand phase III trial was to determine if the addition of M to ind and consol therapy followed by one year of maint would improve overall survival (OS) compared to standard chemotherapy in younger adults with activating FLT3 muts. Methods: Between May 2008 and October 2011, 3279 previously untreated AML pts age 18-60 (exclusive of acute promyelocytic leukemia) in 225 sites/17 countries were screened for FLT3 muts at one of 7 academic labs (subject to extensive assay cross-validation). Hydroxyurea was allowed for up to 5 d prior to beginning ind therapy while awaiting results of mut testing. Pts were rand for the duration of therapy to M or P stratified by FLT3 mut subtype (TKD v ITD high allelic mut fraction (>0.7) vs low mut fraction (0.05-0.7). Ind therapy consisted of D 60 mg/m2 IV d1-3 and C 200 mg/m2 d1-7 CIV plus M or P (50 mg po bid, d 8-22). Re-treatment with a second blinded course was allowed if residual AML was noted on a d 21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of C 3g/m2 over 3h q 12h on days 1, 3, and 5 plus M or P (50 mg po bid, d 8-22) followed by a year of maint therapy with M or P (50 mg po bid). Transplantation (SCT) was allowed. With a sample size of 717 pts, the trial was powered to detect an improvement from 16.3 (P) to 20.9 (M) months in median OS (HR = 0.78) using a one-sided alpha of 0.025 and power of 84%. The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis, and promote event free survival (EFS, defined as the earliest of death, relapse, or no CR within 61 d of the start of ind) as a key secondary endpoint. The critical value for this primary analysis is set at 0.02286 (1-sided) accounting for the alpha spent at the interim analysis (0.5%). Support: U10CA180821, U10CA180882, CA31946, Novartis Results: 717 pts (341 FLT3 ITD-Low, 214 FLT3 ITD-High; 162 FLT3 TKD) were rand to either M (n=360) or P (n=357). There were no significant differences between the arms in age (median, 48y), race, FLT3 subtype, or baseline CBC except for gender (M, 48.2% male; P, 40.6% male; p=.04). All pts are off active treatment, with a median follow-up of 57 months for surviving pts. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events (AEs) between M and P (regardless of attribution). A total of 37 grade 5 AEs were reported (M, 5.3%; P, 5.0%; p=1.0). No differences in treatment-related grade 5 AEs were observed (M, 3.1%; P, 2.5%; p=0.82). CR rate is 59% (M) and 54% (P) (p=0.18). The HRs comparing M to P for OS is 0.77 (one-sided p = 0.007; Figure 1), and for EFS is 0.80 (one-sided p = 0.004; Figure 2). 402/717 (57%) pts received an allogeneic SCT (M, 58%; P, 54%) at any time; 177/717 (25%) in CR1 (M, 27%; P, 22%). Median time to allogeneic SCT was similar on each arm (M, 5.0 months; P, 4.6; p=0.23). Secondary analyses for OS and EFS censoring at the time of SCT provided similar results (Table). The benefit of M was consistent across all FLT3 subgroups for both EFS and OS (Figure 3). Conclusions: The C10603 trial demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of AML pts was feasible and that the addition of the multi-kinase inhibitor M to standard chemotherapy and for one year of maint therapy significantly improved EFS and OS (in both uncensored and censored for transplant analyses) in pts whose blasts had a TKD or ITD (low or high FLT3 mut burden). These findings may lead to improved outcomes through the use of M as a component of therapy in younger adults with mutant FLT3 AML. Table.ArmMedian, mos (95% CI)p-value 15-year Event rate% (95% CI)HR2(95% CI)OSM74.7 (31.5, * )0.00750.8 (45.4-55.9)0.77 (0.63, 0.95)P26.0 (18.5, 46.5)43.1 (37.6-48.4)OS, SCT censoredM* (*,*)0.04762.6 (54.6-69.7)0.77 (0.56,1.05)P* (36.9, *)54.9 (46.2-62.8)EFSM8.0 (5.3, 10.6)0.004426.7 (22.2-31.5)0.80 (0.67, 0.95)P3.0 (1.9, 5.8)19.1 (15.1-23.6)EFS, SCT censoredM8.2 (5.5, 10.7)0.02524.2 (18.9-29.8)0.84 (0.70, 1.0020)P3.0 (1.9, 5.8)21.8 (16.8-27.3)1Stratified on FLT3 subtype; one-sided, log-rank p-value.2Cox model stratified on FLT3 subtype.*= not attained Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Stone: Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Celator: Consultancy; Juno: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy. Off Label Use: midostaurin- FLT 3 inhibitor. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Larson:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: 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