Fernández, Hugo F.

SummaryThere are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi‐institutional treatment studies from March 1984 to November 2008. Kaplan–Meier estimates were used to estimate event‐time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two‐sided tests. Non‐APL female patients had a significantly better overall (OS) but not disease‐free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)‐positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that both affect the epigenetic regulation of DNA methylation. Although the proteins antagonistically regulate the epigenetic mark of 5-methylcytosine (5-mC), where DNMT3A catalyzes addition of 5-mC while TET2 oxidizes 5-mC as a first step in DNA demethylation, mutations in both genes appear in a similar spectrum of human hematopoietic malignancies. Mutations in both genes often co-occur with activating mutations in oncogenic tyrosine kinases (OTKs) such as FLT3ITD, BCR-ABL1, JAK2V617F, MPLW515L or mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Moreover, while the mutations exert divergent effect on primitive hematopoietic progenitor cells, they lead to similar disease phenotypes, suggesting the roles of these mutations in hematopoietic malignancies may relate to mechanisms outside of DNA methylation. OTK-positive malignant cells accumulate high numbers of spontaneous and drug-induced DNA double-strand breaks (DSBs) in comparison to normal cells, but they manage to survive because of their enhanced/altered ability to repair these breaks. DSBs, the most lethal DNA lesions, are repaired by two major mechanisms, BRCA1/2-dependent homologous recombination (HR) and DNA-PK -mediated non-homologous end-joining (D-NHEJ). Both HR and D-NHEJ repair DSBs in proliferating cells, while D-NHEJ plays a major role in quiescent cells. PARP1 -dependent alternative NHEJ (Alt-NHEJ) serves as back-up in both proliferating and quiescent cells. The existence of these redundant pathways creates the opportunity to employ a phenomenon called "synthetic lethality", which was originally applied to eliminate cancer cells with mutations in BRCA1 and BRCA2 by PARP inhibitor (PARPi). Our previous report [M. Nieborowska-Skorska et al., Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127, 2392-2406 (2017)] suggested that certain leukemias are sensitive to PARPi-triggered synthetic lethality. Here we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing OTKs. Malignant TET2-deficient cells display downregulation of BRCA1 and LIG4 resulting in reduced activity of HR and D-NHEJ, respectively, and rely on Alt-NHEJ to protect them from the toxic effects of replication stress and drug-induced DSBs. Conversely, DNMT3A-deficient cells favor HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells are sensitive to PARPi treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity and/or TET2 - Wilms tumor 1 (WT1) binding ability were responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Our findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. Disclosures Valent: Allcyte GmbH: Research Funding; Pfizer: Honoraria; Cellgene: Honoraria, Research Funding. Tallman:Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Martinelli:Roche: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Daichii Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy, Research Funding. Vassiliou:Kymab Ltd - Monoclonal antibody company. Currently not working in myeloid cancers or clonal haematopoiesis.: Consultancy.

7003 Background: In younger adults with newly diagnosed acute myeloid leukemia (AML), anthracycline dose intensification during induction may improve complete remission (CR) rates; however, an improvement in overall survival (OS) in a randomized trial has not been demonstrated. This unresolved issue led the ECOG to compare standard dose (SDD) to high-dose daunorubicin (HDD) in induction. Methods: Adult patients with previously untreated AML were randomized to receive either SDD (45 mg/m2/d) or HDD (90 mg/m2/d) each for 3days combined with standard-dose cytarabine (100 mg/m2/d) for 7 days by continuous intravenous infusion. Those achieving a CR were allocated to allogeneic hematopoietic stem cell transplantation (HSCT) or high-dose cytarabine (with or without a single dose of gemtuzumab ozogamicin) prior to autologous HSCT. Intravenous busulfan and cyclophosphamide was the preparative regimen for both allogeneic and autologous HSCT. The primary end point of this study was OS from the time of induction randomization. Results: 633 patients, age 18 to 60 (median 48) years, were entered in this study. There were no differences in patient demographics or disease characteristics between the two groups at presentation. In an intention-to-treat analysis, HDD resulted in a significantly higher CR rate (63.3% vs. 47.7%, p = 0.0003) than SDD. Induction deaths were similar between the two groups (5.4 vs. 5.0%, p = ns). 334 (52.8%) patients entered the consolidation phase. 57.4% of HDD and 48.1% of the SDD patients, received consolidation therapy on study, and 28.7% and 23.1% proceeded to HSCT respectively. Median OS was superior for the HDD (23.7 months) over the SDD (15.1 months) group (p = 0.005). In subgroup analysis, patients with favorable or intermediate-risk cytogenetics or age <55 years benefited from the HDD. Conclusions: We demonstrate for the first time in a prospective randomized trial that intensifying induction therapy through a higher daily anthracycline dose, in the setting of identical intensive consolidation therapy, results in a higher CR rate as well as prolonged OS. In younger AML patients a higher dose of anthracycline in induction should be considered the new standard of care. No significant financial relationships to disclose.

Abstract Background: Cytogenetic risk categories based on conventional chromosome studies are widely used in clinical practice to make treatment decisions for AML. We evaluated the efficacy of interphase FISH to detect chromosome anomalies in the workup of young (&lt;60 years) patients with AML. Methods: Study subjects were enrolled in E1900, a front-line Eastern Cooperative Oncology Group (ECOG) clinical trial for AML. This is an on-going Phase III clinical trial with Daunorubicin dose-intensification ± Gemtuzumab-Ozogamicin consolidation therapy prior to stem cell transplant. This trial opened December 2002; as of February 2005, 223 patients were enrolled. The protocol was designed to collect bone marrow for both cytogenetic and FISH studies at study entry (diagnosis). Cytogenetic studies were done by local laboratories with results reviewed centrally by the ECOG Cytogenetics Committee. Each case was classified as acceptable or unacceptable based on predefined ECOG cytogenetic criteria. FISH for each patient was performed in the ECOG FISH laboratory at Mayo Clinic and utilized eight probe sets to detect t(8;21), t(9;22), t(11;var), t(15;17), inv(16), +8, −5/5q, and −7/7q (Vysis, Downer Grove, IL). Results: 64 (29%) of 223 specimens had incomplete cytogenetic and/or FISH results. We analyzed the remaining 159 (71%) specimens with complete cytogenetic and FISH results. Results for each specimen were classified by probe set into one of the following categories: Normal cytogenetics and normal FISH; Abnormal cytogenetics and abnormal FISH for the anomaly the probe was designed to detect; Abnormal cytogenetics and abnormal FISH for an anomaly the probe was not primarily designed to detect; Normal cytogenetics and abnormal FISH; Abnormal cytogenetics and normal FISH; or Abnormal cytogenetics and abnormal FISH that further defined the karyotype. Figure 1: Results for 159 patients by category and FISH probe set: *t(8;21); t(9;22); t(11;var); t(15;17); inv(16); cen(8); del(5/5q); de(7/7q). Figure 1:. Results for 159 patients by category and FISH probe set: *t(8;21); t(9;22); t(11;var); t(15;17); inv(16); cen(8); del(5/5q); de(7/7q). The concordance rate between cytogenetic and FISH results ranged from 97 to 100% for all probe sets and kappa analysis for concordance had a p value of &lt;0.0001. Of the total 159 cases, discrepancies between FISH and cytogenetic results occurred in only 4 cases; two with normal cytogenetics and abnormal FISH and two with abnormal cytogenetics and normal FISH results. Conclusions: The high level of agreement between cytogenetics and FISH demonstrates the accuracy of a panel of 8 FISH probe sets for the detection of significant abnormalities in AML. The data from this investigation support the use of FISH as an adjunct in cases of failed cytogenetic analyses to increase the yield of useful cytogenetic results in large cooperative trials. Furthermore, because of the strong correlation between cytogenetics and FISH, our results demonstrate the potential of FISH as a follow-up study of minimal residual disease in ECOG trials.

Abstract Over the past decade several prospective studies of post-remission therapy in AML have compared allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT and chemotherapy. The data are appropriately presented by intention-to-treat analyses. However, such analyses do not provide information to the clinician or patient as to outcome from the initiation of post-remission therapy, be it HSCT or chemotherapy. Furthermore, such analyses are impossible to interpret when a significant percentage of patients do not receive their intended therapies (for example, only 54% of patients randomized to autologous HSCT; Cassileth, NEJM, 1998). Finally, such studies present survival data that may not be relevant to current practice where the mortality from autologous HSCT has decreased sharply (for example, 14% non-relapse mortality from autologous HSCT; Cassileth, NEJM, 1998). In the current analysis, results from 4 consecutive ECOG studies that included autologous HSCT were analyzed and the data collated. In PC486 patients received standard induction followed by allogeneic HSCT if they had a compatible sibling; otherwise they were to undergo an autologous HSCT without any prior consolidation (Cassileth, JCO, 1993). E4995 studied standard induction with added high-dose cytarabine (HiDAC) intensification on D 8–10, followed by 2 courses of HiDAC consolidation. All patients were to undergo an autologous HSCT after induction and consolidation (Cassileth, Leuk Lymph, 2005). E3489 was a US Intergroup study in which patients received standard induction (3 + 7). If in CR, all patients received an attenuated course of induction (2 + 5). Patients who had a histocompatible sibling were assigned to allogeneic HSCT; those without a donor were randomized to an autologous HSCT or chemotherapy (Cassileth, NEJM, 1998). E1900 is an ongoing phase III study in which patients receive standard induction followed by allogeneic HSCT or two courses of HiDAC followed by autologous HSCT. The latter study is ongoing; therefore, only data describing transplant-related mortality (TRM) are presented. The relapse rate from start of each post-remission regimen in these studies, based on therapy actually received and not on intention-to-treat analysis, is presented in table 1 and the TRM is presented in table 2. Table 1. Relapse Rate from Start of Post-Remission Therapy Cytogenetics Allogeneic HSCT (n=85) Autologous HSCT (n=113) Chemotherapy (n=109) Favorable 11.8% (2/17) 10.5% (2/19) 60% (12/20) Intermediate 20.5% (8/39) 32.3% (10/31) 53.7% (22/41) Unfavorable 16.7% (2/12) 41.7% (5/12) 83.3% (15/18) Unknown 23.5% (4/17) 33.3% (17/51) 56.7% (17/30) Table 2. Treatment-Related Mortality after Post-Remission Therapy Allogeneic HSCT Autologous HSCT – Marrow Autologous HSCT – Blood Chemotherapy Study E3489, E4995, E1900 E3489, PC 486 E4995, E1900 E3489 Treatment-related mortality 15.3% (18/117) 11% (16/85) 1.5% (2/135) 2.7% (3/109) In conclusion: The TRM after autologous HSCT using mobilized peripheral blood has decreased substantially in recent years. As shown in table 2, in PC486 and E3489 where bone marrow was harvested and treated with perfosfamide (4-HC) prior to cryo-preservation, the TRM was significantly greater than in the later studies, E4995 and E1900, where peripheral blood was harvested after priming with chemotherapy and/or cytokines. The lower relapse rate post autologous transplant, together with the lower procedural mortality with current practice, may confer a survival advantage in future prospective studies of autologous HSCT versus chemotherapy. While absolute comparisons cannot be made, as the timing of each therapy may not be identical, these data provide crucial information for informed and patient/physician discussions prior to initiation of postremission therapy.

Key Points c-KIT activating mutations cause resistance to PARP inhibitor in AML1-ETO–positive leukemias. c-KIT inhibitor avapritinib downregulates BRCA1/2 and DNA-PK catalytic subunit to restore the sensitivity to PARP inhibitor.

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 Introduction: Midostaurin, a multitargeted tyrosine kinase inhibitor (TKI), plus induction and consolidation chemotherapy followed by single-agent midostaurin maintenance therapy resulted in significant benefits in event-free and overall survival (OS) in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) compared with placebo (RATIFY study; Stone et al, N Engl J Med, 2017). In RATIFY, patients who received allogeneic hematopoietic stem cell transplant (alloSCT) did not receive midostaurin maintenance. Despite alloSCT providing the highest likelihood of sustained remission, relapse rates remain high (30%-59%; Schiller et al, Biol Blood Marrow Transplant, 2016), especially in patients with FLT3-internal tandem duplication-positive (ITD+) AML. Posttransplant maintenance therapy may improve this outcome. Here, we report the primary results from RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) that investigated whether the addition of midostaurin to standard of care (SOC) after alloSCT could reduce the risk of relapse in patients with FLT3-ITD+ AML. Methods: Adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (CR1), had achieved hematologic recovery, and were transfusion independent were eligible. Patients enrolled postengraftment and were randomized to receive SOC with or without midostaurin 50 mg twice daily continuously (4-week cycles) for up to 12 cycles. Study treatment started 28 to 60 days post-alloSCT and patients were followed for ≥24 months post-alloSCT. The primary endpoint was relapse-free survival (RFS) at 18 months post-alloSCT. Secondary endpoints included safety and disease-free survival (DFS), OS, and RFS at 24 months post-alloSCT. The study was not adequately powered to detect a statistical difference between the 2 arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse. Results: 60 patients were randomized (30 per arm). Baseline characteristics were generally balanced between the 2 arms. Overall, 30 patients completed 12 cycles of study treatment (14 with SOC; 16 with midostaurin). The median exposure to midostaurin was 10.5 months (range, 0.2 to 12.0 months) and the median dose intensity was 93 mg/day (range, 15-100 mg/day). Early treatment discontinuations were similar between arms (15 in the SOC arm; 13 in the midostaurin arm), frequently due to adverse events (AEs; 3% vs 23%) and consent withdrawal (20% vs 7%). Among 6 patients who withdrew consent in the SOC arm, 2 did so to pursue other TKI therapies. Midostaurin dose modifications occurred in 19 patients (63%), mostly due to AEs (84%); 1 instance was due to receiving a concomitant CYP3A4 inhibitor. With an estimated 18-month RFS (95% CI) of 76% (54%-88%) in the SOC arm and 89% (69%-96%) in the midostaurin arm, estimated relapse rates were 24% and 11%, respectively, which is a 46% relative reduction in the risk of relapse with the addition of midostaurin (Figure 1). At 18 months, the median RFS was not reached in either arm. Longer follow-up at 24 months (data not yet matured) will be presented, including RFS, OS, and DFS. In the SOC and midostaurin arms, AEs were reported in 87% and 100% of patients, respectively (the most common any-grade AE was vomiting: 23% vs 73%; Figure 2); serious AEs were reported in 57% and 30% of patients, respectively, with diarrhea (7% vs 13%), nausea (10% vs 3%), vomiting (10% vs 3%), and pyrexia (7% vs 7%) being the most common. Overall, 8 patients discontinued midostaurin therapy due to AEs (mostly gastrointestinal related) and 12 died on study (all during the follow-up phase; 8 in the SOC arm and 4 in the midostaurin arm [n=4 vs n=2 due to AML disease progression]). Rates of graft-vs-host disease (GVHD) were generally similar between the SOC and midostaurin arms (overall, 70% vs 73%; acute GVHD, 53% vs 57% [grade 2/3 events: 37% vs 30%; no grade 4 events]; chronic GVHD, 47% vs 37% [most events were mild or moderate; severe events: 1 with SOC and 2 with midostaurin]). Conclusions: Adding midostaurin to SOC reduced the risk of relapse at 18 months post-alloSCT by 46% (vs SOC). The safety profile of single-agent midostaurin was consistent with previous reports; no major safety concerns were identified when adding midostaurin to SOC following alloSCT. These data suggest that midostaurin monotherapy can be safely administered for ≤1 year and may improve outcomes in patients who undergo alloSCT in CR1. Disclosures Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kim:Novartis: Consultancy, Honoraria, Research Funding; Briston-Meyers Squibb: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

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.