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PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Abstract Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p<0.001 compared to historical rate of 40%). Twenty-five (37%) had a matched related donor, 31 (45%) had a matched unrelated donor, 3 (4%) had a mismatched related donor, 8 (12%) had a mismatched unrelated donor, and 1 (1%) received an umbilical cord blood transplant. Sixty-six high-risk patients transplanted in CR/CRi have detailed data. Median time to HCT from CR1 was 76 days (range, 20-365). Fifty-seven patients (86%) received a myeloablative regimen and 9 (14%) reduced-intensity conditioning. Reasons for 39 high-risk CR1 patients not receiving a transplant in CR1 were: co-morbidities (n=1), death (n=6), no insurance (n=1), no donor (n=1), physician decision (n=3), patient decision (n=3), relapse (n=6), other (n=10), or unknown (n=8). The 2-year RFS estimate in the entire high-risk cohort is 32%, significantly higher than the 22% historical rate (p=0.05). Median RFS in the high-risk CR1 cohort (n=107) was 10 months [range, 1-32* (censored) months]. RFS and OS were similar among HCT patients using matched related [1 year estimates: 40% (95% CI 27%, 74%) and 56% (37%, 74%), respectively] and matched unrelated [1 year estimates: 52% (37%, 75%) and 56% (37%, 74%), respectively] donors in CR1. The HR (reference = unrelated) for RFS was 0.67 (0.32, 1.37) and for OS was 0.88 (0.41, 1.90). Median overall survival (OS) among all patients in the high-risk cohort (n=159) was 12 months [range, 1-33* (censored) months] and was 18 months [range 3-33* (censored) months] for those transplanted in CR1 (Fig. 1). Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Figure 1 Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Figure 1. Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

Abstract The UKALLXII/ECOG2993 international study for adults with acute lymphoblastic leukeamia (ALL) included a separate, single-arm study (still open) to evaluate the role of etoposide/TBI conditioned allogeneic bone marrow transplantation (BMT) in patients with Philadelphia chromosome positive (Ph pos) disease. Patients received 2 phases of induction, intensification with high dose methotrexate and BMT using unrelated donor stem cells where a matched sibling was not available. 267 patients with Ph pos ALL were treated from 1993 onwards, in the pre-imatinib era. The study was amended in 2003 to add imatinib 600mg per day following induction and after BMT for 2 years or until relapse. A subsequent amendment at the end of 2005, added imatinib 600mg per day also to phase 2 of induction. 153 patients have now been treated on the imatinib-containing protocol − 89 received imatinib following induction and 64 started imatinib with phase 2 induction. Complete remission (CR) rate at the end of 2 phases of induction was 91% with imatinib started in induction, 81% with imatinib started in consolidation only & 83% in the pre imatinib era. 128 of the 153 patients treated with any imatinib were eligible for BMT. Of the 98 patients with over 6 months follow-up, 57 (58%) actually received BMT. This transplant rate does not differ from the 62% in the pre-imatinib era although the data pertain mostly to those whose imatinib started later during therapy. Overall survival of the imatinib-treated group as a whole is 23% at 3 years, which does not differ from the 26% pre-imatinib rate as shown in the figure. Hence, imatinib started post-induction does not appear to improve survival. Imatinib given with induction may improve the CR rate, but there is insufficient follow up to assess transplant or survival rates. Earlier imatinib may be optimal but overall, our study does not provide evidence yet that imatinib alters the outcome of this disease. Figure Figure Patient characteristics Pre-imatinib (N=267) Post-imatinib (N=153) Gender: Male 150 (56%) 96 (63%) WBC (x 10 ^9/l) (2 unknown): <30 141(53%) 86 (56%) ≥ 30 124 (47%) 67 (44%) Median (range) 26.8 (1.5–438) 21.0 (0.5–491) Age: median (range) 40 (15–60) 42 (16–64) CNS disease (82 unknown) 14 (8%) 4 (3%)

Background: Patients with HR-MDS have a dismal prognosis after failure of hypomethylating agents (HMAs) (Zeidan 2014), with median overall survival (OS) of less than 6 months (Prebet 2011) and currently no approved second-line therapy (Garcia-Manero 2016). Targeted therapies with novel mechanisms of action, combination strategies, as well as innovative study designs, are all needed to expedite and address the high unmet medical need in patients with HMA refractory HR-MDS. Rigosertib is a unique targeted therapy that inhibits PI3K and PLK signaling pathways by binding directly to the Ras-binding domain (Athuluri-Divakar 2016) and in vitro cytotoxicity studies have demonstrated synergy with azacitidine (Cosenza 2015). INSPIRE study is an example of a study with a novel compound and unique mechanism of action as well as an innovative study design. Methods: INSPIRE (NCT02562443) is a global randomized Phase 3 trial in patients with HR-MDS after HMA failure. Patients are randomized in a 2:1 fashion to rigosertib or physician's choice of treatment. Key inclusion criteria: age <82 years; MDS classified as RAEB-1, RAEB-2 or RAEB-t; ≥1 cytopenia; patient must demonstrate one of the following: progression any time after initiation of HMA treatment, intolerance to HMA, failure to achieve complete remission (CR), partial remission (PR), or hematologic improvement (HI) after six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC, or relapse after initial CR, PR or HI; duration of prior HMA ≤9 cycles within 12 months; last dose of HMA ≤6 months before enrollment; and ECOG score 0-2. The primary endpoint of overall survival (OS) will be tested in a sequential fashion in the intention to treat (ITT) population and the IPSS-R very high risk (VHR) subgroup. Secondary endpoints include OS in patients with monosomy 7 or trisomy 8, overall response, quality-of-life, and HI. The initial sample size was 225 patients with a pre-planned interim analysis (IA) after 88 deaths. INSPIRE featured an adaptive trial design with a pre-planned Sample Size Re-estimation (Cui 1999) to 360 patients and 288 OS events as one option that the Independent Data Monitoring Committee (IDMC) could implement at IA. The adaptive sample size modification of an on-going two-arm, group sequential clinical trial is used to categorize the results for each population into three zones of Unfavorable, Promising, and Favorable. This adaptive design is advantageous as it allows study sample size to be adjusted when there is high variance in estimating the true effect of the drug under investigation which could otherwise result in underpowering of the study. The IDMC had several options following the interim analysis, including continuation of the study as initially planned, discontinuation for futility or safety, trial expansion using pre-planned sample size re-estimation, and continuation for only the pre-defined VHR subgroup. The investigators remain blinded to the specific interim analysis results. Enrollment in the trial is ongoing with topline data expected in 2020. Conclusions: Based on the results of interim analysis, the IDMC recommended continuation of the trial based on ITT result in promising zone with one-time expansion in enrollment, using a pre-planned sample size re-estimation, the sample size for the study was increased from 225 to 360 with unchanged eligibility criteria. The Adaptive Design used real time data from the IA to modify sample size and mitigate the risk of underpowering without undermining its validity and integrity, while preserving type-1 error. The study design used in INSPIRE may be advantageous for other novel agents in rare hematological diseases during the transition from phase 2 to phase 3 studies. Clinical trial information: (NCT02562443). Disclosures Luger: Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Woodman:Onconova Therapeutics, Inc.: Employment. Adesanya:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Parris:Onconova Therapeutics, Inc.: Employment. Jedrzejczak:Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Novartis: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Díez-Campelo:Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

Background: More than 45 mutations have been identified in association with HR-MDS. In the majority of patients with MDS (80%) co-mutations are present and the prognostic contribution of each individual mutation remains elusive, especially after adjusting for clinical variables such as IPSS-R score. N-RAS and K-RAS mutations as well as regulators of the Ras pathway (e.g. PTPN11, NF1) are frequently observed (15-20%) in HR-MDS, however their clinical impact is unclear, especially in de novo MDS. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways (Athuluri-Divakar 2016). Rigosertib has the potential to also inhibit wildtype upregulation of RAS. We report here genomic profiling at the time of study entry in the ongoing phase 3 randomized global study (known as INSPIRE) in patients with HR-MDS after failure of HMA therapy. Methods: INSPIRE (NCT02562443) is a global randomized Ph3 trial in pts with HR-MDS after HMA failure with an overall target enrollment of 360 pts with currently 298 pts randomized. Pts are randomized 2:1 to rigosertib or physician's choice of treatment. The primary endpoint is overall survival (OS). All pts failed to respond or progressed on HMA therapy. Key inclusion criteria includes: age < 82 years, RAEB-1, RAEB-2 or RAEB-t; intermediate risk (IR), high risk (HR) and very high risk (VHR) per IPSS-R; ≥ 1 cytopenia; duration of prior HMA ≤ 9 cycles within 12 months; last dose of HMA ≤ 6 months before enrollment; baseline blast counts between 5-29% and one of the following: progression any time after initiation of HMA treatment, intolerance to HMA, failure to achieve complete remission (CR), partial remission (PR), or hematologic improvement (HI) after six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC, or relapse after initial CR, PR or HI. Bone marrow samples were collected at study baseline and throughout the study for mutational analysis as an exploratory endpoint. Baseline blast counts are described as % reported in bone marrow aspirate at screening. Genomic DNA was extracted from diagnostic bone marrow or peripheral blood samples and targeted capture deep sequencing of 295 genes were performed (median sequencing depth 500x) using Agilent's SureSelect custom panel. Modified Mutect and Pindel were used to identify high-confidence somatic mutations. Results: All data is presented as blinded aggregate results for both arms of the study. Baseline mutations are presented for 114 pts; 92 pts were randomized and 22 pts were screen failures. Median age is 72 years (59-81). The IPSS-R scores for the pts randomized were: Intermediate 5(5%), High 30 (32%) and VHR 56 (60%). In total 48 different mutations were identified at baseline prior to pts receiving study treatment. The most common mutations identified in pts were ASXL1 40%, STAG2 26%, TP53 24%, RUNX1 22%, SRSF2 and TET2 each 18%. Average number of mutations per pt was 3.06. At baseline, 4 pts (4%) had no mutations, 17 pts (18%) had only 1 mutation while 17 pts (18%) had between 6-8 mutations. N-RAS and K-RAS mutations occurred in 4 pts each (7% of pts) and all in the presence of other mutations. Mutations involving regulators of the Ras pathway (N-RAS, K-RAS, PTPN11, NF1) occurred in 12 (13%) of patients. Of note, 23 pts (25%) had IDH1 (6 pts) or IDH2 (17 pts) and the majority of these pts (68%) were High/VHR with an average blast count of 15% (range 5-27%) at study entry. The high proportion of IDH1/2 mutations observed is most likely due to inclusion of patients with RAEB-t. These results will be updated at the meeting with blinded baseline mutational analyses for all pts randomized into the study. Conclusion: The baseline mutational analyses from the INSPIRE study provides important initial insights into the genomic profile of pts with HMA failure, especially for the subset with VHR. Following analysis of the primary endpoint, it is anticipated that correlation of overall survival and clinical response with mutational status will be possible, including changes in mutations following therapy. Given the number of mutations involving the Ras pathway the efficacy of rigosertib in patients with this group of mutations will also be examined. Figure Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Luger:Agios: Honoraria; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Cyslacel: Research Funding; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Jedrzejczak:Amgen: Consultancy, Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Celgene: Other: travel support for hematology meetings (ASH, EBMT, EHA) ; Takeda: Consultancy; Novartis: Research Funding; Roche: Other: travel support for hematology meetings (ASH, EBMT, EHA) . Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Cavanaugh:Onconova Therapeutics, Inc.: Employment. Woodman:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Takahashi:Symbio Pharmaceuticals: Consultancy.

Background: The use of midostaurin in combination with standard induction chemotherapy has been shown to improve the outcomes in patients with newly diagnosed FLT3 mutated (FLT3m) AML (Stone et al) and allogeneic transplant is often recommended in first remission. While likely to achieve remission with standard induction, the majority of these patients will relapse and die of their disease. Gilteritinib, a potent FLT3 inhibitor, has been approved for use in patients with relapsed or refractory FLT3 mutated AML. In Phase I/II studies, when used as part of induction therapy, gilteritinib has shown promising CR rates. We have designed a trial comparing the outcomes of induction therapy with gilteritinib to those with midostaurin. The hypothesis is that gilteritinib, when added to induction chemotherapy, will produce more FLT3m negative composite complete remission (CRc). The Ratify trial combined midostaurin with daunorubicin 60 mg/m2/d X 3 days and cytarabine X 7 days Daunorubicin 90 mg/m2/d has however been shown to be superior during induction in patients with newly diagnosed FLT3 ITD mutated AML (Luskin et al, Burnett et al) While improved survival is the ultimate goal of any leukemia regimen, it is known that AML patients who proceed to allogeneic transplant with measurable residual disease (MRD) positive disease fare worse than those with MRD negative disease. As such, our goal is to increase the likelihood of an MRD negative state after induction. Study Design This is a randomized, open-label, multicenter phase II study comparing gilteritinib to midostaurin in combination with cytarabine 100 mg/m2 and daunorubicin 90 mg/m2 in newly diagnosed FLT3 mutated AML patients ages 18-65. Central confirmation of FLT3 mutation and other pretreatment studies are required. In order to identify patients without delay, all patients with suspected AML will be able to be prescreened without enrollment to the randomized treatment trial. Patients will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation will undergo further stratification with NPM1 mutation status (positive vs. negative) and FLT3 ITD to FLT3 wild type signal ratio (high [≥ 0.5] vs. low [<0.5]). Patients will be randomized to receive standard induction treatment (cytarabine and daunorubicin) with either gilteritinib or midostaurin. Mandatory bone marrow samples are required after Induction and Consolidation. Patients who achieve CR or complete remission with incomplete hematologic recovery (CRi) will be assessed for MRD and be eligible at count recovery to go on to receive standard consolidation treatment of high-dose cytarabine with the study drug received during induction (gilteritinib or midostaurin). Patients may proceed to allogeneic transplant after induction or after 0-4 cycles of chemotherapy consolidation and may participate in BMT CTN 1506. Key Eligibility: Newly diagnosed FLT3m AML Primary Objective To evaluate the FLT3m negative (evaluated by polymerase chain reaction [PCR] and capillary electrophoresis) composite complete response (CRc) (includes CR or CRi)rate of patients with FLT3 mutated AML who receive gilteritinib compared to those who receive midostaurin in addition to standard therapy with cytarabine and daunorubicin during induction. Sample Size and Statistical design The accrual goal of this study will be 179 patients. Patients who achieve remission will be followed for survival and relapse. With an allocation ratio of 1:1 to the two arms, the study will have 80% power to detect an improvement of 20% in the FLT3 mutation negative CRc rate in the gilteritinib arm (i.e. from 40% to 60%) at the one-sided significance level of 0.05 based on Fisher's exact test. This study is conducted through PrECOG and is funded by Astellas Pharma. The study is slated to open in the summer of 2019 at 30 US sites. References: Stone R.M., Mandrekar S.J., Sanford B.L., et al. N Engl J Med 2017; 377:454-464 Luskin MR, Lee JW, Fernandez HF et al. Blood 2016 :blood-2015-07-657403; doi: https://doi.org/10.1182/blood-2015-07-657403 Burnett AK, Russell NH, Hills RK et al. Blood 2016; Blood 2016 128:449-452; doi: https://doi.org/10.1182/blood-2016-04-712091 Figure Disclosures Luger: Genetech: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Lazarus:Genentech: Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, 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, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; CSL Behring: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau. Rowe:BioSight: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Pratz:Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy. OffLabel Disclosure: In this study gilteritinib is being studies in newly diagnosed AML.

AbstractBackgroundPatients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low‐dose anthracycline‐based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy.MethodsThirty two patients enrolled in the ECOG‐ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two‐dimensional transthoracic echocardiography (TTE) imaging with Doppler and two‐dimensional speckle‐tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy.ResultsEighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (−19.1 ± 2.8 to −17.2 ± 3.0, P = .01) and circumferential strain (−29.4 ± 6.3 to −23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF).ConclusionsIn older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline‐based induction chemotherapy and may help us better identify those patients at risk for adverse long‐term cardiovascular outcomes.

Abstract Background: The persistence of detectable MRD in complete remission (CR/CRi - CR with incomplete CBC recovery) has been reported to contribute to inferior outcome in younger AML patients (pts) in retrospective studies, however MRD has not been studied prospectively in older adults (age ≥60 yrs) receiving intensive therapy with curative intent. We performed a planned prospective study of MRD status after AML induction therapy in older adults, integrated into the large multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients age ≥60 yrs with AML were randomized 1:1 to receive either 'Standard' 7&3 (Dauno 60mg/m2) induction, with 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior overall survival (OS) with standard therapy despite similar CR/CRi rates using stringent criteria, and similar 30-day induction mortality rates. Submission of diagnostic & remission bone marrow or peripheral blood samples was protocol mandated for prospective MRD assessment, and analysis was performed in the central E-A Leukemia Translational Research Lab (LTL) using 6-color multiparameter flow cytometry. MRD-positive (MRD+) was defined as ≥0.1%. LTL flow cytometric analysis was done blinded to treatment arm and outcome of patients. Only pt samples collected within +/-6 days of CR/CRi confirmation were included in this analysis. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine the MRD effect on OS and disease-free survival (DFS, relapse or death). Results The median follow-up is 47.8 months, and 297 of 685 evaluable patients (43.4%) achieved CR/CRi (Standard 44.6%; CLO 42.0%, p=ns). Remission MRD samples were only available for 147 CR/CRi patients (49.5%), owing to variability in sample viability and AML involvement, collection practices and timing of sample collection at individual sites, and patient/physician decision. 58/147 evaluable CR/CRi patients achieved MRD-negative (MRD-) status (Standard 40.7%, CLO 47.9%, p=0.74). Women (56.9% vs. men 43.1%, p=0.003) were more likely to be MRD-, but there was no other significant difference in MRD status stratified by clinical or disease features. MRD+ status at CR/CRi was associated with significantly inferior OS (p=0.031, Figure 1) and also inferior overall DFS (p=0.02); this was most pronounced for DFS after CLO (Arm B, Figure 2) (p=0.005), but not Standard (Arm A) therapy (p=0.41). The impact of MRD+ was confirmed on multivariate analysis using Cox Model Fitting, for OS: OS for All MRD+ pts, HR 1.64 (95% CI 1.00-2.68) (p=0.05); OS for Standard (Arm A) MRD+ pts, HR 1.06 (95% CI 0.51-2.21) (p=0.87); and OS for CLO (Arm B) MRD+ pts, HR 2.30 (95% CI 1.05-5.06) (p=0.04). There was a similar impact for DFS on multivariate analysis using Cox Model Fitting: DFS for All MRD+ pts, HR 1.86 (95% CI 1.16-2.98) (p=0.01); DFS for Standard (Arm A) MRD+ pts, HR 1.15 (95% CI 0.60-2.19) (p=0.67); and DFS for CLO (Arm B) MRD+ pts, HR 3.45 (95% CI 1.47-8.09) (p=0.004). Post-remission therapy was not stratified by MRD in E2906, and 33% of MRD-evaluable pts underwent allogeneic transplantation (no difference in transplant rate for MRD+ vs. MRD-). Conclusions MRD+ ≥0.1% is common (60.5%) after induction therapy in older adults & is significantly associated with inferior OS and DFS in 1st CR/CRi. However we observed excellent outcomes for MRD- pts in first CR/CRi regardless of induction regimen or post-remission therapy used. MRD+ pts in CR/CRi who went on to receive CLO consolidation had significantly poorer outcomes than those who went on to receive intermediate dose Ara-C consolidation. This observation differs strikingly from younger AML, and suggests that intensified Ara-C may abrogate the adverse impact of MRD in older pts in CR. These results strongly support incorporation of centralized MRD at the time of remission into future studies to guide optimal post-remission strategies in older pts with AML. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Altman:Bayer: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work. Al-Kali:Novartis: Research Funding. Pratz:Millenium/Takeda: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding.