Citations

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.

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.

Abstract Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials. Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times. Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively. Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001). Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. Disclosures Ustun: novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Background Activating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients (pts) age ≥60 yrs (n=727) were randomized to 'Standard' therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. 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 FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)]. Results In the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41). Conclusions FLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.

Abstract Background: Overall survival (OS) remains the definitive primary efficacy endpoint to evaluate previously untreated acute myeloid leukemia (AML) therapies, but it requires prolonged follow-up. An earlier endpoint assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate event-free survival (EFS) as a surrogate endpoint for OS in untreated AML. Methods: Individual patient data were analyzed from 2,475 patients (pts) from 4 multicenter, randomized controlled phase III trials of active treatment in previously untreated AML using anthracycline and cytarabine induction chemotherapy as the concurrent control (CALGB 10201, n=506, enrollment period 2003-2006, age 60-88 years (y); CALGB 10603, n=717, enrollment period 2008-2015, age 18-60 y, FLT3-mutated pts only; SWOG 0106, n=595, enrollment period 2004-2009, age 18-60 y; ECOG-ACRIN 1900, n=657, enrollment period 2002-2008, age 17-60 y). Individual patient-level surrogacy examines the association between the individual patients' EFS and OS time after adjusting for treatment effect, and was assessed using the copula bivariate survival model (Kendall's tau). Trial-level surrogacy measures how precisely the treatment effect on OS can be predicted on the basis of observed treatment effect on EFS, and was evaluated using both linear regression (R2WLS) weighted by trial size and Copula bivariate (R2Copula) models. Pre-specified criteria for surrogacy required either R2WLS or R2Copula ≥0.80, neither below 0.7, with either lower bound 95% Confidence Interval (CI) >0.60. Sensitivity analyses were conducted using different EFS definitions (Table 1). Results: With a median follow-up of 50.2 months for the 896 patients still alive, the median OS and EFS across all four trials were 20.9 months (95% CI: 19.0-22.7) and 5.6 months (95% CI: 4.5-6.4), respectively. Trial-level surrogacy for EFS was strong (R2WLS=0.79; R2Copula=0.89), indicating a high correlation of treatment effect between EFS and OS. At the individual patient-level, however, EFS showed weak association with OS (tau= 0.52), compared to the strength of trial-level surrogacy. The discrepancy between patient-level EFS and OS was greatest among patients who did not achieve a CR, followed by those who achieved a CR but relapsed (Figure 1). Sensitivity analysis on alternative EFS definitions showed that the trial-level surrogacy was similar, but individual patient-level surrogacy varied across different EFS definitions (Table 1). This is consistent with what we previously reported (ASH 2016): EFS estimates differed considerably based on the definition of induction failure (IF) in a single arm setting, but this had minimal impact on the estimation of the treatment effect using EFS in randomized trials. In addition, when considering only relapse and death as events (definition 4), both individual patient- and trial-level correlations were high. Conclusions: Correlation between EFS and OS was impacted by patients not achieving CR during induction. Despite the lack of patient-level correlation, a strong correlation between hazard ratios for treatment effects was observed between EFS and OS on the trial level. Hence, it remains debatable whether EFS represents a clinical benefit in itself for patient with untreated AML considering the strong correlation in treatment effects. Further validation is needed due to the small number of trials included and the heterogeneity across trials. Acknowledgment: We gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf, SWOG S0106 Study Chair. Support: U10CA180821, U10CA180882, U10CA180794, U10CA180820, U10CA180888; Clinicaltrials.gov Identifiers: NCT00085124 (10201), NCT00651261 (10603), NCT01253070 (11001), NCT00085709 (SWOG S0106), and NCT00049517 (ECOG-ACRIN E1900) Disclosures Uy: Curis: Consultancy; GlycoMimetics: Consultancy. Larson:Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding.

Abstract Abstract 2568 Background: Obesity is associated with an increased risk of development of adult AML (Relative Risk approx. 2-fold) (Ross J, Cancer Epidemiol Biomarkers Prev 2004;13:1810) and significantly higher mortality in pediatric AML (Lange B, JAMA 2005;293:203). We therefore examined the association of obesity with presenting characteristics in 2 recent large ECOG phase III adult AML trials to determine whether there was a unique clinical and genetic phenotype, and also the impact of obesity on clinical outcomes (complete remission - CR; early death - ED; overall survival - OS) in association with other known risk factors. The impact of obesity on receiving full-dose daunorubicin (D) was also evaluated in these studies. We included patients (pts) from E1900 receiving standard infusional cytarabine with intensified D (45 vs. 90mg/m2) in adults age ≤60 yrs (NEJM 2009;361:1249), and from E3999 receiving conventional intensive chemotherapy +/− the MDR-inhibitor zosuquidar in adults age >60 yrs (Blood 2010;116:4077). Obesity was defined as Body Mass Index (BMI) >30kg/m2. Methods: Pt baseline characteristics were compared using Fisher's exact (categories variables) or Wilcoxon rank sum tests (continuous variables). Logistic regression models were used to examine the association between obesity and CR or ED; Cox models stratified on induction treatment arms were used to examine the association between obesity and OS. Multivariate models to examine the effect of Obesity controlled for known prognostic factors (including cytogenetics & secondary AML - sAML). Results: A total of 1089 pts (E1900, n=651; E3999, n=438) with available BMI data were included, the median follow-up of living pts is 4.7 yrs. Obesity was prevalent, with n=359 (33%) of pts with a BMI>30 at presentation. For all patients, median BMI was 27.1 (range 16.7–93.0); for non-obese patients median BMI was 25.0 (range 16.7–29.96) while for obese patients the median BMI was 34.0 (range 30.0–93.0). Obese pts were older (p=0.06), and significantly more likely female gender (p=0.05), ECOG PS>0 (p=0.01), & Intermediate Risk cytogenetics (p=0.006) but not sAML (14% overall, p=ns). Genotyping for FLT3 & MLL was performed in E1900 pts (age ≤60yrs): there was no difference in incidence of FLT3-ITD, but lower incidence of MLL-PTD was observed (p=0.08) in obese pts (not performed in E3999) (See Table). Overall, only 3.7% of pts received <90% of intended D dose. However obesity was significantly associated with receiving <90% intended D dose: in E1900, 11% of obese pts received <90% intended D (45mg/m2 cohort, p<0.001; 90mg/m2 cohort p=0.002), while in E3999 4% obese pts received <90% intended D (45mg/m2, p=0.07). There was no clear difference in toxicity/adverse events during initial induction therapy reported in obese vs. non-obese pts. On multivariate analysis obesity was not significantly associated with achieving CR (p=0.09), and had no direct independent association with ED (p=0.38). Kaplan-Meier plots of OS are shown in Figure. On multivariate analysis, age (p<0.001); ECOG PS (p<0.001); cytogenetic risk group (p<0.001); sAML (p=0.03); gender (p=0.05); and peripheral blasts (p=0.003) but not obesity were significantly associated with OS. Receiving <90% intended D dose was marginally associated with increased hazard ratio for OS (HR 1.50, 95%CI 0.98–2.28, p=0.06). Conclusion: Obesity is associated with specific presenting clinical characteristics in adult AML (female, older, PS>0, Int. risk cytogenetics, less frequent MLL-PTD), but has no direct impact on CR, ED or OS in the setting of a controlled therapeutic trial. Obese pts are at risk of receiving <90% intended D dose, which may impact OS. This analysis suggests that factors that predispose to adult AML may present with a unique clinical phenotype. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups. Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis. Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04). Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group. Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group. Conclusion: With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy. Table HR for death by AML cohort. Subgroup N Univariate Model DNR 45 DNR 90 HR (DNR 90/DNR 45) & 95% CI Wald P All patients (n=657) Overall 330 327 0.74 (0.61, 0.89) 0.001 Age < 50 yrs³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.12 Cytogenetic Favorable Intermediate Unfavorable 38 232 59 51 212 63 0.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16) 0.03 0.02 0.22 FLT3-ITD WT MUT 215 83 241 64 0.74 (0.59, 0.92) 0.61 (0.42, 0.89) 0.008 0.009 MLL-PTD WT MUT 290 16 296 15 0.70 (0.58, 0.86) 0.46 (0.21, 1.04) 0.0004 0.06 NPM1* WT MUT 180 65 192 65 0.70 (0.55, 0.89) 0.50 (0.32, 0.78) 0.003 0.002 DNMT3A WT MUT 177 61 194 58 0.66 (0.52, 0.85) 0.62 (0.41, 0.94) 0.001 0.02 * Statistically significant test of interaction (p<0.2) Figure 1A: Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1A:. Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1B: Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Figure 1B:. Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 851 Clinical studies have demonstrated that acute myeloid leukemia (AML) is heterogeneous with respect to presentation and to clinical outcome, and many studies have shown that cytogenetics can be used to improve prognostication. More recently, it has been shown that FLT3, NPM1, and CEBPA mutations can be used to further risk stratify AML patients. Although recent studies have identified novel, recurrent somatic mutations in AML in genes including TET2, ASXL1, IDH1, IDH2, and PHF6, their prognostic value has not yet been evaluated among patients treated on a large phase III clinical trial. Here we report full-length DNA resequencing of FLT3, NPM1, CEBPA, H/K/NRAS, KIT, WT1, TET2, ASXL1, IDH1/2, TP53, RUNX1, PTEN, and PHF6 in pre-treatment genomic DNA from 398 patients with de novo AML younger than 60 years of age enrolled in the ECOG E1900 protocol. We could identify a clonal alteration, defined as a somatic mutation or cytogenetic abnormality, in 91.2% of all patients; 42% had 1 somatic alteration, 36.4% had 2 alterations, 11.3% had 3 alterations and 1.5% had 4 or more somatic alterations. Mutational Analysis: We identified somatic mutations in FLT3 (37% total; 30% ITD, 7% TKD), NPM1 (14%), CEBPA (10%), TET2 (10%), NRAS (10%), WT1 (10%), KIT (9%), IDH2 (8%), IDH1 (6%), RUNX1 (6%), ASXL1 (4%), PHF6 (3%), KRAS (2.5%), TP53 (2%), and PTEN (1.5%) (Figure 1A). We then performed correlation analysis to determine the frequency of different mutational combinations in AML patients. In addition to previously identified mutational correlations (FLT3 and NPM1, KIT and core binding factor leukemia), we found that FLT3 and ASXL1 mutations were mutually exclusive in this large cohort (p =0.0008). In addition, we found that IDH1/IDH2 mutations were mutually exclusive of both TET2 (p=0.02), and WT1 (p=0.01) mutations consistent with overlapping roles in AML pathogenesis (Figure 1B). Integration of mutational data with response data and outcome: Mutations in ASXL1 (CR rate 33.3% versus 66.5% for ASXL1-WT patients; p= 0.009) were enriched in patients who did not respond to induction chemotherapy. We found that mutations in FLT3 (p=0.0005), ASXL1 (p=0.005; Figure 1C), and PHF6 (p=0.02) were associated with reduced OS. Notably, the adverse effects of ASXL1 and PHF6 mutations on outcome were restricted to patients treated with standard dose daunorubicin (p<0.01 for each mutational cohort); ASXL1 and PHF6 mutational status did not affect outcome in patients treated with high-dose daunorubicin, demonstrating that increased intensity induction chemotherapy can improve outcomes in genetically defined poor risk AML subsets. We also found that mutations in CEBPA (p= 0.04) and in IDH2 (p=0.003) were associated with improved OS; the favorable impact of IDH2 mutations on outcome was exclusive to patients with IDH2 R140Q mutations (Figure 1D). Within the subset of patients with cytogenetically defined intermediate risk AML, we found, as expected, that FLT3-ITD mutations were associated with reduced OS and CEBPA mutations were associated with improved OS. Importantly, we found that IDH2 R140Q mutations were associated with improved OS (p=0.003) in patients with intermediate risk AML regardless of FLT3 mutational status. In contrast, TET2 mutations (P=0.0002) and PHF6 (p<0.0001) were associated with reduced OS in intermediate risk, FLT3-WT, AML. Summary: These data provide important clinical implications of genetic alterations in AML and provides insight into the multistep pathogenesis of adult AML. We identified novel mutations that impact response to induction chemotherapy and predict overall outcome, including ASXL1, PHF6, TET2 and IDH2, suggesting these mutations can be used to improve AML risk stratification and therapeutic decisions in AML patients 18–60 years of age. Most importantly, we identify TET2, IDH1/2, and WT1 mutations as mutually exclusive somatic alterations that form a novel mutational complementation group that contributes to AML pathogenesis. Figure 1. A) Circos diagram depicting relative frequency and pairwise co-occurrence of mutations in de novo AML patients enrolled in the ECOG protocol E1900. B) Circos diagram showing mutational events in IDH1/2, TET2, and WT1 mutant AML patient. C) Overall survival in AML patients with and without ASXL1 mutations (p=0.005). D) Overall survival in AML patients with and without IDH2 R172 and R140 mutations (p=0.003). Figure 1. A) Circos diagram depicting relative frequency and pairwise co-occurrence of mutations in de novo AML patients enrolled in the ECOG protocol E1900. B) Circos diagram showing mutational events in IDH1/2, TET2, and WT1 mutant AML patient. C) Overall survival in AML patients with and without ASXL1 mutations (p=0.005). D) Overall survival in AML patients with and without IDH2 R172 and R140 mutations (p=0.003). Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3619 Extramedullary (EM) acute myeloid leukemia (AML) is generally associated with a poor prognosis. We evaluated the baseline characteristics, response and survival characteristics in a subset of patients age ≤ 60 years with de novo AML and EM manifestations at presentation, treated on the Eastern Cooperative Oncology Group E1900 protocol: daunorubicin 45 or 90 mg /m2 x3 days in conjunction with cytarabine 100 mg/m2 × 7 days followed by risk-stratified consolidation. (Fernandez et al New Engl J Med 2009) Methods: Patient baseline characteristics were compared using Fisher's exact test if they were categories and Wilcoxon rank sum tests if they were continuous. Logistic regression models were used for complete remission (CR) rates and Cox regression models were used for overall survival (OS) and disease-free survival (DFS). The univariate models included indication of whether patient had extramedullary disease involvement, adjusted by induction treatment. The multivariate models were further adjusted for age, gender, cytogenetic risk, ECOG PS, WBC, platelets, marrow blast, hemoglobin, peripheral blasts, and secondary AML. All P values were based on 2-sided tests. Results: 58 (8.9%) of 651 patients in the study presented with evidence of EM at diagnosis. Patients with EM disease were younger and presented with higher peripheral WBC counts and circulating blasts than those without. Immunophenotyping did not demonstrate a difference in baseline CD56 expression (p=0.77). Sites of EM involvement included gingival hypertrophy (n= 33), skin (n= 7), central nervous system (n= 6), lymphadenopathy (n=6), mediastinum (n=2) and other (n=6). 3 patients had multiple sites. Cytogenetic risk in the EM subgroup was favorable (8.6%), indeterminate (inadequate/missing) (34.5%), intermediate (37.9%) and unfavorable (19%) and did not differ statistically from those without EM disease. The complete remission (CR) rates were similar for patients with EM disease compared to those patient's without, regardless of the anthracycline dose (univariate model p= 0.93; multivariate model p=0.88. DFS (patients in CR) and OS of patients with EM disease was not significantly different in the univariate (p= 0.99, p=0.49) or multivariate models (p= 0.92, p=0.37), respectively. On multivariate modeling patients with EM AML who received the standard-dose of daunorubicin had a shorter OS (HR 1.86, 95% CI 1.20 to 2.91, p=0.006). OS was not improved in EM patients treated with high-dose daunorubicin (HR 0.62, 95% CI 0.34 to 1.14, p=0.12) (Table). There was a significant difference in OS for patients with EM treated with the 90 mg/m2 dose of daunorubicin compared to patients with EM treated with the 45 mg/m2 dose (multivariate model: HR 0.30, 95% CI 0.12 to 0.76, p=0.01). Conclusion: Younger patients with de novo EM AML are sensitive to higher doses of anthracycline in induction therapy and should be treated in a similar fashion as patients without EM involvement. For both groups the higher doses of anthracycline are recommended as CR rates, DFS and OS are improved. Further evaluation of immunophenotypic and molecular/ genetic characteristics should be undertaken in this subset of patients. Disclosures: No relevant conflicts of interest to declare.