Citations

Abstract Background: Induction therapy with daunorubicin (Dauno) & cytarabine (Ara-C) [DA] has been the standard of care for eligible older adults (age ≥ 60 years) with newly diagnosed acute myeloid leukemia (AML) for over 2 decades. Single agent Clofarabine (CLO) induction & consolidation (Consol.) therapy has demonstrated important clinical activity in this age group in large phase II studies. Lower induction mortality (IM) & similar reported complete remission rate (CR) & overall survival (OS), as well as notable activity in those with higher risk disease features [including unfavorable cytogenetics, therapy-related AML (t-AML) & prior antecedent hematologic disorder (AHD)] raises the possibility that a non-Ara-C-based regimen could achieve similar or superior OS with lower toxicity. Methods: We performed a randomized United States Intergroup Phase III trial of single agent CLO [30mg/m2 x 5 days induction; 20 mg/m2 re-induction (if indicated) & 2 cycles Consol.] vs. standard DA therapy [Dauno 60mg/m2 D1-3 & Ara-C 100mg/m2 D1-7 induction x 1-2 cycles; 2 cycles Consol. with Ara-C (1.5g/m2 Q12hrs D1-6 age 60-69; once daily if age 70+)] in patients (pts) age ≥ 60 yrs with newly diagnosed AML. Patients with serum creatinine >1.0 (or GFR <60 mL/min) and those with AML-M3 and ECOG performance status >3 (PS>2 if age 70+ yrs) were excluded. Randomization was stratified by age (60-69 vs. 70+), t-AML, & AHD. Pts with HLA-matched donor were eligible for allogeneic transplantation (AlloHCT) after induction, and those completing Consol. were eligible for randomization #2 (R#2) to maintenance decitabine [20mg/m2 x 3D, monthly x 1 year] versus observation. With a target accrual of 747, E2906 was powered to determine non-inferiority [and possible superiority] of CLO vs. standard DA, and primary endpoint was OS. A weighted statistical analysis was performed to account for confounding impact of R#2. AlloHCT patients were censored at transplant in this analysis. Responses & cytogenetics were confirmed centrally and OS & CR rates were monitored by an independent Data Safety Monitoring Committee (DSMC) at pre-specified time points. Results: As of Feb 23, 2015, 727 pts were randomized. Median age was 68 years (range 60-86); 57% were male, and 38% were age ≥70 yrs. Treatment arms are well balanced for all baselineclinical & AML characteristics, & 30% had unfavorable cytogenetics. Of 659 with complete treatment information reported, 30.4% on DA vs. 40.1% on CLO received 2 cycles of induction (p=0.006). Median follow-up of surviving patients is 7.6 months. Table 1. shows early treatment results (CR, toxicity) for the 686 pts randomized as of Dec 23, 2014 (2 months prior to study end, & excluding 90 with ongoing response evaluation). DA CLO p-value CR/CRi 43.8% 42.8% p=0.87 30-day mortality 8.5% 7.9% p=0.89 60-day mortality 14.9% 13.1% p=0.58 Gr 4-5 Non-Heme Tox.Induction 27% 19% p=0.02 Gr 4-5 Non-Heme Tox.Consol. 20% 7% p=0.001 374 pts have died (174, DA; 200, CLO) & significantly inferior OS was observed for CLO vs. DA [Hazard Ratio (HR) 1.41 (95% CI 1.12-1.78)] (Fig. 1). Planned subgroup analyses were performed (Table 2) demonstrating significant differences in OS after CLO for patients age 60-69 yrs, without AHD, & with intermediate risk cytogenetics; but not for those with Unfav. Cytogen. (Fig. 2) or t-AML. Based on the primary weighted analysis, DSMC recommended suspension of new accrual to E2906 on Feb 23, 2015 & all active patients on CLO were transitioned to DA Arm. Table 2.NHR CLO/Standard (95% CI)*Weighted OS7271.41 (1.12-1.78)Unweighted OS7271.23 (1.00-1.50)Age 60-694491.48 (1.10-1.99)Age 70+2781.34 (0.93-1.93)Intermed. Risk Cytogen.3781.77 (1.27-2.47)Unfav. Risk Cytogen.2160.96 (0.65-1.43)No AHD6041.46 (1.13-1.89)AHD1231.22 (0.74-2.00)De novo AML6271.52 (1.18-1.96)Therapy-related AML1000.94 (0.54-1.61) Conclusions: Despite similar CR & IM, OS after single agent CLO is inferior to standard DA therapy for pts age ≥60 years with newly diagnosed AML who are fit for intensive therapy, and DA remains the standard of care. However no difference in OS was observed after CLO in some pre-specified high risk AML subgroups. R#2 & AlloHCT arms continue in E2906 for pts already enrolled. Embedded prospective minimal residual disease study at CR is being performed to identify pts at higher risk after CLO & DA. Figure 1. Weighted Kaplan-Meier Curves for OS Figure 1. Weighted Kaplan-Meier Curves for OS Figure 2. Unfavorable Cytogenetics OS by Therapy Figure 2. Unfavorable Cytogenetics OS by Therapy Disclosures Off Label Use: Use of clofarabine in AML, and maintenance therapy with decitabine in AML. Claxton:Medimmune: Research Funding; BMS: Consultancy; Astellas: Research Funding; Cyclacel: Research Funding; Merck: Research Funding; Ambit: Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Altman:Seattle Genetics: Consultancy; BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Al-Kali:Novartis: Research Funding.

Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy observed in the pediatric population. Recent genomic studies have made considerable strides in improving our understanding of the molecular pathogenesis of pediatric B-cell ALL. This includes the discovery of recurrent somatic alterations targeting B-cell transcription factors, mutations in epigenetic regulators, and oncogenic mutations which activate signaling effectors, including in Ph-like B-ALL. However, the molecular pathogenesis of adult B-cell ALL has been less well studied, and there is a need to identify novel therapeutic targets in adult B-ALL. We therefore performed detailed genomic profiling in adults with B-cell ALL. We performed targeted DNA/RNA capture and sequencing of 189 patients with B-cell ALL enrolled on the ECOG E2993 clinical trial. All samples were taken at the time of diagnosis before patients were treated with multi-agent chemotherapy and followed for clinical outcomes including overall survival and remission/relapse duration and kinetics. We used the FoundationOne® Heme assay for our genomics study. This platform allows us to identify short events (point substitutions, short insertions/deletions) copy number and fusion events present in DNA and/or RNA. Of the 203 samples profiled, 189 had sufficient quality genomic data with a median coverage of 435 on DNA sequencing and 7.85 million on target distinct reads per case on RNA sequencing. In all, we identified cancer-related mutations in 108 genes, 55 of these genes being mutated in more than one sample. We identified a median of 2.98 genomic alterations per sample (standard deviation of 1.78) in the target gene set, which included all genes known to be altered in B-ALL and in other hematologic malignancies. The most common genomic events were the BCR-ABL1 fusion (69 samples, 36.5%), followed by CDKN2A loss (57 samples, 30%), CDKN2B loss (35 samples, 18%), NRAS and KRAS point mutations (32 samples, 16.9%), and MLL fusion genes with a spectrum of partners (25 samples, 13.2%). Notably, we found that BCR-ABL1 fusion are mutually exclusive with both RAS mutations (p<10^-7) and MLL mutations (p<5*10^-4). We next investigated the spectrum and frequency of alterations observed in different classes of oncogenes/tumor suppressors. We identified mutations which result in activation of oncogenic signaling pathways in 130 cases or 68.7% of our cohort. This included known mutations/fusions, such as BCR-ABL, RAS-MAPK pathway mutations, and JAK-STAT pathway alterations, and included missense alleles, insertion/deletion events, and fusion genes targeting a spectrum of genes including ABL, PDGFRB, and CRLF2. In aggregate, 33.8% of the cohort had mutations which activate signaling exclusive of BCR-ABL, demonstrating the high prevalence of the Ph-like B-ALL subtype in adult B-ALL. We identified mutations affecting key transcription factors, including PAX5 and IKZF1, in 31.2% of our cohort including missense, nonsense and deletion events. To confirm our ability to detect small deletions of PAX5 and IKZF1, we performed array CGH of 50 cases and compared copy number calls using high-throughput sequencing and CGH. Of note, all deletions targeting PAX5 and IKZF1 identified by NGS were confirmed by CGH. We also identified mutations in epigenetic regulators in 30.6% of cases, including MLL fusions, mutations in the DNA methylation/hydroxymethylation the pathway (DNMT3A, TET1, TET2), and mutations targeted chromatin modulators. Detailed analyses of the mutational spectra and their relationship to clinical outcome will be presented at the meeting. Taken together, these data show we can use a clinically validated sequencing assay to identify known and novel somatic mutations in adult B-ALL, including sequence alterations, rearrangements and copy number aberrations. These data demonstrate the feasibility of combined DNA and RNA study to identify a complex landscape of fusions and short mutations with prognostic and therapeutic relevance, and inform the use of genomic profiling in B-ALL in the clinical context. Figure 1. Figure 1. Disclosures He: Foundation Medicine, Inc.: Employment, Equity Ownership. Brennan:Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Balassubramanian:Foundation Medicine, Inc.: Employment, Equity Ownership. Otto:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. van den Brink:Boehringer Ingelheim: Consultancy, Other: Advisory board attendee; Merck: Honoraria; Regeneron: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tobira Therapeutics: Other: Advisory board attendee. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Retrospective analyses have demonstrated significantly improved survival for AYA ALL patients (pts) aged 16-21 years (yrs) when treated on pediatric versus adult U.S. NCI Cooperative group regimens where 2-yr event-free survivals (EFS) have been only 35-40%. The purpose of C10403, a large prospective US intergroup trial, was to evaluate the feasibility and effectiveness [with EFS as a primary endpoint), of treating AYA ALL pts (ages 16-39 yrs) using the standard arm of the successful Children's Oncology Group regimen (COG AALL0232) . Methods: Newly diagnosed AYA patients with B-precursor (B-ALL) or T-precursor (T-ALL) ALL were eligible to enroll on C10403. Burkitt type and Ph+ ALL were excluded. The regimen was identical to the Capizzi methotrexate arm of COG AALL0232 (Larsen E. JCO 2011; 29 suppl:3) and consisted of four intensive courses: remission induction, remission consolidation, interim maintenance, delayed intensification, and prolonged maintenance therapy. Pts with M2 marrow response (>5% but < 25% lymphoblasts) after remission induction received an extended remission induction course of therapy. Events were defined as induction failure (M3 [³25% blasts] day 29 of induction or M2 day 43 of extended induction), death, relapse, or second malignancy. Key correlative science studies in a subset of the total accrued population included assessment of Minimal Residual Disease (MRD) using quantitative real-time PCR of clonal IgH or TCR gene rearrangements as well as Low Density Microarray (LDA) assays designed to detect a previously validated gene expression profile (Harvey, R; ASH 2013, abstract 826) which can prospectively identify ALL pts with Ph-like (BCR-ABL1-like) ALL. Results: 318 pts were enrolled on C10403 from 11/2007 to 8/2012; 22 withdrew prior to therapy. Of 296 evaluable pts, the median age at diagnosis was 24 yrs (range: 17 to 39): 25% were 17-20 yrs, 53% were 21-29 yrs, and 22% were 30-39 yrs. The majority had B-ALL (76%) and were male ( 61%). Approximately 25% were non-Caucasian and 15% were Hispanic or Latino. 32% of pts were obese (BMI³30). There were 5 (2%) treatment-related deaths during protocol therapy: liver failure (n=2, both during induction), infection (1 in induction, 1 in consolidation), and ventricular arrhythmia (1 in induction). Overall, treatment toxicities were similar to those reported in the standard arm of COG AALL0232, with an increased thrombosis and early hyperbilirubinemia for C10403 pts, as reported previously (Advani A, ASH 2013, abstract 303). To date, 70 deaths have been reported and 87 pts remain on protocol therapy. With a median follow-up of 28 months for surviving pts, 105 events have been observed. The median EFS overall is 59.4 months (95% CI: 38.4 to NR) and the 2-yr EFS rate overall is 66% (95% CI: 60 – 72%) [Fig 1a] with similar 2-yr EFS rates for B and T- ALL pts (65%, and 68%). The 2-yr OS rate is 78% (95% CI: 72 – 83%)[Fig 1b], which is similar for B (78%, 95% CI: 72 – 84%) and T-ALL, (80%, 95% CI: 70 – 91%). These results allow rejection of the null hypothesis of this Phase II trial that the true median EFS is, at most, 32 months. In multivariable analysis of presenting clinical features, age > 20 years and initial WBC count ³ 30k/microliter were significantly associated with worse EFS and OS. Presence of MRD at day 28 following initiation of induction therapy and presence of a Ph-like gene expression signature were significantly associated with both worse EFS and OS. Notably, absence of detectable MRD noted in 22/58 [38%] evaluable pts at day 28 of induction was associated with 100% EFS (p=0.0006). The Ph-like like signature was detected in 28% of pts tested on C10403 and the 2 yr EFS for these patients was only 52%, compared to 81% for those without Ph-like disease (p = 0.04). Conclusions: This large prospective US adult intergroup trial (C10403) for pts 16-39 years old employing an intensive pediatric regimen demonstrates a significant improvement (compared to historical controls) in AYA EFS and OS and validates this approach for treatment of AYA with ALL by adult hematologists. The improved clinical outcomes and the predictive value of the correlative studies in this trial lay the foundation for the design of future trials, where incorporation of novel agents to eradicate MRD, and/or use of tyrosine kinase inhibitors to target the frequently detected Ph-like ALL in AYA pts may further improve survival for young adults with ALL. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Stock: Sigma-Tau: Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Sigma Tau: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Liedtke:Onyx: Membership on an entity's Board of Directors or advisory committees. Larson:Novartis: Consultancy, Research Funding.

Abstract Background: A majority of younger pts with AML receive initial therapy with a 7+3 scheme. Escalated doses of daunorubicin (dauno) in combination with standard doses of ara-C may lead to improved outcomes (Fernandez; NEJM 2009). A phase II trial of idarubicin and high-dose ara-C (IA) in combination with the histone deacetylase inhibitor vorinostat (IA+V) resulted in historically high response rates compared to IA or 7+3 (Garcia-Manero; JCO 2011). SWOG 1203 tested whether a high-dose ara-C induction with or without vorinostat could result in improved outcomes for younger AML pts compared to 7+3. Methods: The primary endpoints were comparison of event-free survival (EFS) of 7+3 vs IA vs IA+V and evaluating the frequency of allogeneic hematopoietic cell transplantation. Secondary endpoints included toxicity, remission rate, relapse-free survival (RFS), and overall survival (OS) according to treatment arm, and by cytogenetic and molecular subgroups. Because of the historical trend of cured pts in S0106, EFS was modeled with an exponential cure model, and it was assumed IA or IA+vorinostat increased the proportion of pts cured from 35% to 45% and increased median EFS among those not cured from 4.7 months to 7.1 months. Main inclusion criteria included a diagnosis of previously untreated non-APL AML by WHO criteria, age 15 to 60 years, and preserved cardiac function but no severe comorbidities. Pts with known CBF rearranged or FLT3 mutant leukemias were eligible if no other alternative clinical trials existed. Treatment was as follows: Induction: 7+3 arm: dauno 90 mg/m2 IV QD x 3 on days 1-3 with ara-C CI 100 mg/m2 QD x 7 days on days 1 to 7. IA arm: ida 12 mg/m2 QD x 3 on days 1 to 3 with 24 hours CI ara-C 1.5 gm/m2 QD for 4 days on days 1 to 4. IA+vorinostat was as IA but with vorinostat 500 mg orally TID for 3 days on days 1 to 3. Consolidation: 7+3 arm: standard high-dose ara-c at 3 gm/m2 over 3 hrs q12 hours x 6 doses for 1 to 4 cycles depending on transplant availability. IA arm: idarubicin 8 mg/m2 IV QD x 2 days on days 1 to 2 with ara-C 0.75 gm/m2 CI for 3 days on days 1 to 3 for 4 cycles. The number of consolidation cycles depended on transplant indication; a secondary aim of the study was to transplant all cytogenetically-determined high risk pts (presented in a different abstract). Results: Of 754 pts randomized, 738 were eligible (261 to 7+3, 261 to IA, and 216 to IA+V). Baseline characteristics were well balanced among all three groups. Most (75%) pts were between 40 and 60 years, 51% were male, median (range) WBC and platelets were 10.8 (0.3-800) and 49 (3-3900), respectively; marrow blast percentage was 60% (0%-100%); cytogenetics were favorable in 13% of pts, intermediate in 63%, and high-risk in 22%; FLT-3 was mutated in 21% and unknown in 31%; NPM1 was mutated in 20% and was unknown in 37%. Complete remission (CR) rates were 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). Significantly more pts received reinduction with 7+3 (24%) versus 11% with IA and 9% with IA+V (p=0.001). 48% of intermediate and unfavorable risk pts received transplant in CR1, with no significant differences among arms (p=0.44). There were no significant differences in EFS, RFS or OS among all three arms (Figure 1, all p>0.5). By cytogenetic or molecular group, there were no differences in outcome for any standard risk subset (FLT-3, NPM1, or CEBPα or cytogenetic subset), although pts with favorable cytogenetics had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (Figure 2, all p≤0.015). 30% of pts received 1 consolidation cycle, 18% 2, 16% 3, and 37% 4 cycles. Grade 5 induction toxicity rates were 4% (7+3), 8% (IA), and 9% (IA+V) by arm (p=0.07), and for toxicities related to therapy, 2%, 7%, 8%, respectively (p=0.01). Grade 4 induction toxicity rates were similar across arms (p=0.38). Conclusion: Treatment with IA is not more effective than 7+3 in younger pts with AML. Outcomes with IA or IA plus vorinostat are similar. In pts with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation. Clinical Trials Registry: NCT #0180233 Support: NIH/NCI grants CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI grant #021039 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy; BMS: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; Baxalta: Consultancy; Cyclacel: Research Funding; Celator: Research Funding; Abbvie: Research Funding; Ambit: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Lundbeck: 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; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Ariad: Consultancy; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Agios: Research Funding; Jannsen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Agios: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Ariad: Consultancy; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB.

Abstract On behalf of the ECOG-ACRIN Cancer Research Group Background: Venous thromboembolism (VTE) occurs in 2-12% of patients with acute leukemia (AL) despite disease and therapy-associated thrombocytopenia, and can be associated with significant morbidity and mortality. Due to limited high-quality studies, there are no evidence-based guidelines for VTE prophylaxis in this patient population. Based on our experience and the lack of consensus guidelines, we hypothesized that there would be a wide range in provider practice regarding methods of VTE prevention in patients with AL. To determine the current individual practices in North America, we devised a web-based survey of VTE prophylaxis practice among clinicians caring for patients with AL. Methods: An anonymous 19 question web-based survey, approved by the Johns Hopkins Institutional Review Board, was distributed by email to members of the ECOG-ACRIN Cancer Research Group on 10/22/14. Four reminders were sent at two-week intervals with the survey closing on 12/8/14. Results: Of the total 215 respondents, 64 were excluded for the following reasons: 52 did not directly manage medical care of AL patients, 3 referred AL patients to other centers, 5 left blank responses to all questions regarding VTE prophylaxis, 1 was a duplicate entry, and 3 described their position as support or office staff. One hundred fifty-one responses were eligible for analysis, with a response rate of 20.9% among physicians who treated leukemias. One hundred forty-seven were from the United States and 4 from Canada, representing 88 different institutions and 37 states or provinces. Overall, 47% and 45% of providers reported using pharmacologic VTE prophylaxis during induction and consolidation phases, respectively. Among the providers using pharmacologic prophylaxis, 60% designated 50,000/μL as the platelet count threshold below which they would hold prophylaxis and 26% used a platelet count of 30,000/μL. Fewer providers chose a platelet count of 20,000/μL (4%), 75,000/μL (4%), and 100,000/μL (2%). Lastly, 2% held prophylactic anticoagulation only in the setting of an active bleed and 2% reported variable thresholds. Approximately 15% of providers did not utilize any VTE prophylaxis while 36% used mechanical methods and ambulation. Among providers who did not recommend pharmacologic prophylaxis, the most commonly cited reasons were the perceived high risk of bleeding (51%), absence of data supporting use (38%), and perceived low risk of VTE (11%). Conclusions: These results demonstrate wide variation in clinician practice regarding VTE prevention in hospitalized AL patients during induction and consolidation therapy. Our findings emphasize the need to develop standardized, evidence-based guidelines in this at-risk population. VTE: venous thromboembolism, AL: acute leukemia, SC: subcutaneous, TED: thromboembolic deterrant stockings, SCD: sequential compression device Figure 1. Practice patterns of VTE prophylaxis for AL patients during induction and consolidation therapies Figure 1. Practice patterns of VTE prophylaxis for AL patients during induction and consolidation therapies Disclosures Barbarotta: Celgene, BMS, Novartis: Speakers Bureau. Prebet:CELGENE: Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background: The results of the primary endpoint of the E2906 North American Intergroup phase 3 trial - demonstrating significantly inferior OS after single agent clofarabine versus standard intensive daunorubicin & cytarabine induction and consolidation - strongly support the use of intensive therapy for patients age ≥60 years with newly-diagnosed AML who are fit for treatment. This result was achieved despite similar CR rates (including CRi - CR with incomplete blood count recovery) and similar early (30- & 60-day) induction mortality between study arms, raising the question as to the importance of achieving CR as an endpoint. Therefore, we performed a follow-up analysis to address the factors that contribute to early mortality, the necessity for 2nd induction cycle to achieve CR, and to assess the survival impact of the quality of remission. Methods: E2906 design, study population and results for the primary objective were reported previously (ASH 2015, abstr. #217a). We performed this updated analysis to evaluate clinical risk factors for early mortality and re-induction, and to assess the impact of response quality on OS. Univariate comparisons were made with Fisher's exact test (category) and t-test (continuous variable), and logistic regression models were used to examine risk factors associated with early mortality, and with requiring a 2nd cycle of induction therapy. We performed a landmark analysis (beginning Day 60 after initiation of therapy) to determine the impact of response quality (CR/CRi, morphologic leukemia-free-state (MLFS), and treatment failure - i.e. residual/refractory AML) on OS. Survival comparisons were performed with log-rank test. Results: A total of n=727 patients were registered to E2906, the median age is 68 years (range 60-86) and the median follow-up of surviving patients is now 18.3 months. Adjusting for treatment, cytogenetic risk group, FAB subtype, WBC count, and secondary AML, increasing age (p=0.06) and performance status (PS) >1 (p=0.05) were associated with 30-day mortality and only PS >1 (p=0.06) with 60-day mortality. Treatment arm (p=0.003), adverse cytogenetic risk group (p=0.02), increasing age (p=0.03) and baseline WBC <10K (p=0.03) were each independently associated with higher risk of receiving 2nd cycle induction, but there was no difference in CR/CRi (44.2% vs. 42.2%, p=0.58) or in median OS (13.8 versus 12.0 months, p=0.11) for those receiving 1 vs. 2 induction cycles, respectively. We next performed a landmark analysis (day 60, n=608 evaluable patients) to evaluate OS in relation to the quality of response (Table). We observed an advantage in achieving CR and CR/CRi, although the benefit of CRi diminished greatly after 12 months, and OS after MLFS appeared more similar to treatment failure (Figure, p<0.001). The relative adverse impact of CRi and MLFS (vs. CR) was most pronounced for patients treated with clofarabine, where median OS was shorter for those achieving CRi (12.2m vs. 22.6m standard therapy, p=0.007) and MLFS (6.6m vs. 13.4m standard therapy, p=0.15). Conclusion: This follow-up analysis confirms the importance of CR regardless of the number of cycles of induction therapy required to achieve remission, and identifies risk factors associated with early mortality and with requiring re-induction. At longer follow-up the OS after CRi appears to be inferior to true CR, particularly after clofarabine. We hypothesize that this may be due to higher rates of minimal residual disease in CRi, and studies to determine this are being performed. MLFS is not associated with a better overall survival than frank treatment failure (i.e. residual disease) and therefore its value as a response category is uncertain. These results highlight the role of standard intensive remission induction therapy with the intent of achieving CR, which remains the standard of care for fit older adults. Table. Table. Figure 1. Figure 1. Disclosures Foran: karyopharm: Honoraria; novartis: Honoraria; medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Melnick:Janssen: Research Funding. Altman:Novartis: Honoraria; BMS: Honoraria; Janssen: Honoraria; Syros: Honoraria. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

Abstract Abstract 132 Late relapse in acute myeloid leukemia (AML) has been infrequently studied and variably defined in the literature. Two series have shown that late relapse of AML ≥5 years after first complete remission (CR1) is uncommon, with rates of 1.19–3% (Medeiros et al, Leuk Lymphoma 2007; Verma et al, Leuk Lymphoma 2010). We searched the long-term data available on 784 adults (<60 years-old) who were treated on 1 of 4 ECOG clinical trials (E3483, PC486, E3489, or E1900) and achieved CR1 for reports of late relapse (defined as recurrence of AML ≥3 years after CR1). Median follow-up for the 553 patients last known alive was 11.1 years. The longest median follow-up was 17.2 years on trial PC486. Outcomes We found that 11 patients (1.4%) relapsed late; of these, 2 were treated on E3483, 1 on PC486, 5 on E3489, and 3 on E1900. Seven patients with late relapse died from their disease and 4 were living at last known follow-up. Only 1 patient (0.13%) had recurrence of AML ≥5 years after achieving CR1. It is possible that more late relapses will occur on E1900 (a more recent study with ongoing follow-up). All of these trials except E3483 treated some patients with autologous hematopoietic cell transplantation (autoHCT) as part of post remission therapy. On PC486, no post remission consolidation chemotherapy was administered before autoHCT. Ninety-eight total patients on E3489 and PC486 received autoHCT, and there were no late relapses; on E1900, 2 of the 141 patients treated with autoHCT developed late relapse. No patients who underwent allogeneic (allo) HCT in CR1 experienced late relapse on any of the 4 clinical trials. Nine of the 11 patients with late relapse did not undergo HCT; of these, 5 were consolidated with high-dose cytarabine, 2 received maintenance with low-dose cytarabine and 6-thioguanine, and 2 received unknown post remission therapy. Of the 3 patients with late relapse on E1900, 2 received standard-dose and 1 high-dose daunorubicin with induction. Conclusions Across all 4 trials, only 2 of the 239 patients (0.8%) treated with post remission autoHCT experienced late relapse of AML (≥3 years after CR1), which reinforces previously published data that late relapse after autoHCT is uncommon (Cassileth et al, J Clin Oncol 1993). Furthermore, of the 35 patients treated with autoHCT on PC486, 11 relapsed early and no patients relapsed late, suggesting that post remission chemotherapy may not be necessary before autoHCT. Based on this large AML cohort of nearly 800 patients with long-term follow-up, patients who remain in CCR for at least 3 years have a very low risk of relapse and can be considered cured of their disease. Moreover, given that recurrent AML was extremely rare after 5 years or more of CCR (<0.2%), the risk of therapy-related AML from contemporary induction and post remission strategies including HCT appears to be minimal. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Extramedullary disease (EMD) of acute myeloid leukemia (AML) was described decades ago but the incidence of this phenomenon and its prognostic impact are not clear. It is also uncertain whether every site of EMD has the same significance. This study explored these questions using a large cohort of AML patients treated on consecutive Eastern Cooperative Oncology Group (ECOG) frontline clinical trials. Methods For AML patients enrolled into ECOG clinical trials, the presence of EMD was captured at baseline on case report forms. From patients with newly diagnosed AML, age 15 and above, who were treated on 11 consecutive different clinical trials, we identified those with or without EMD, defined by physical examination, laboratory findings and imaging, without necessarily a biopsy. We used descriptive statistics to summarize patient and disease characteristics. Univariate analyses of potential prognostic factors were done. The Kaplan-Meier method was used to estimate median overall survival (OS) within each prognostic category and differences were explored using the log-rank test. Cox proportional hazards models were used to examine the effect of one-unit increases in continuous variables on OS and for multivariable analyses. Multivariate models were built using backward selection. Factors (or groups of factors) significant at the 0.10 level in univariate analyses were tested for inclusion in the model, and retained if they were significant at the 0.05 level. Results Of the 3,522 patients enrolled in 11 different AML clinical trials, we excluded 281; for diagnosis of other types of leukemia (n=220), no EMD evaluation at baseline (n=41) or no survival data (n=20). The overall incidence of EMD was 23.8% (770 out of the remaining 3,241 patients). The sites involved were: lymph nodes 367 (11.3%) patients, spleen 234 (7.2%), liver 173 (5.3%), skin 146 (4.5%), gingiva 104 (3.2%), central nerve system (CNS) 32 (1%), peripheral nerve system (PNS) 8 (0.2%) and other sites 134 (4.1%). In 65 cases (8.4%) EMD was confirmed by biopsy. Most of the patients (64.4%) had only one site of EMD, 163 (21.2%) had 2 sites, 75 (9.7%) - 3 sites, 28 (3.6%) - 4 sites, and 4 patients (0.5%) each had 5 or 6 sites. EMD patients compared to those without EMD; tend to be younger (median age 45.7 vs 52.9 years); male (57.7% vs 52%); poorer ECOG performance status (76.4% with ECOG 0-1 vs 85.9%) and with higher white blood cell count (WBC) at diagnosis (median of 41.6/µl vs 10.2/µl). In univariate analysis, having EMD was associated with a shorter OS (P=0.006). Examination of individual EMD sites revealed that skin (P=0.002), spleen (P=0.0002) and liver (P=0.0007) but not CNS (P=0.35), PNS (P=0.53), nodal involvement (P=0.85) and gingival hypertrophy (P=0.14), were associated with poorer OS. Using proportional hazards models for continuous factors, each additional site of EMD conferred a 9.4% increase in the risk of death. In a multivariable model, after adjusting for known prognostic factors (such as: age, WBC count and cytogenetic risk group), the presence of EMD, number of EMD sites and any specific EMD site were not independently prognostic. Of 165 patients with known favorable cytogenetics EMD was present in only 22 patients (13%). This group appeared to have a worse prognosis, but the numbers are too small for a definitive assessment (figure 1). Conclusions Extramedullary disease is common in newly diagnosed AML with an incidence of almost 24%, but CNS involvement is very rare (0.95%). In contrast to published data, no site of EMD was found to have an independent prognostic impact in multivariate analysis. This large dataset emphasizes the importance of evaluating large number of patients and considering all known risk factors in the multivariate analysis. Disclosures: No relevant conflicts of interest to declare.

Abstract Acute lymphoblastic leukemia (ALL) has a high relapse rate in adults. While the biology of the patient may be responsible for the marked difference in survival seen in comparison to children, variable adherence to complex chemotherapy regimens may also play a role. However, there is very little understanding about the risk factors for delays in therapy and the impact of delays on survival. To study delays in newly diagnosed adult ALL patients, we conducted an observational study using data from ECOG 2993/ MRC_UKALLXII (Rowe, Blood 2005). We analyzed Ph- patients who started intensification after documented complete remission (CR). A long delay (LD) was defined as > 98 days from start of induction to start of intensification (IS), which was >2 weeks delay beyond the 84 days recommended per protocol. A Very Long Delay (VLD) was defined as a >4 weeks delay. Of 2109 patients enrolled, 1247 patients met inclusion criteria for analysis. Of note, 435 Ph- patients who achieved CR after induction but did not proceed to intensification were excluded. In univariate analysis, female sex (p<0.001), Black race (p=0.01), and older age (p<0.001) were associated with increased odds of LD. During induction presence of infection (p=0.01), dose reductions (p=0.001), duration of neutropenia (p=0.007), thrombocytopenia (p<0.001), and hospitalization duration (p<0.001) were associated with LD. In multivariate regression, age, female sex, dose reduction, Black race, and hospitalization duration were significantly associated with LD and VLD (Table I). At 2 years after diagnosis, 801/1247 (64.2%) patients were alive. Of the surviving patients, 181 (22.5%) had VLD, and 620 (77.4%), had delay <4 weeks, p=0.073. Of the alloHCT patients, 333 were alive: 57/333 (17%) had VLD, and 276/333 (83%) had been delayed <4 weeks (p=0.036). As of July 2014, 687/1247 (55%) patients have died, with a median time to death from start of intensification of 13.3 months (range 0.8-231). Survival analysis was stratified by post-remission therapy, with living patients censored at date last seen. Patients who received myeloablative allogeneic HCT (allo HCT) had poorer overall survival from start of intensification (OS-IS) and event free survival (EFS-IS) after LD or VLD. While OS-IS and EFS-IS were significantly worse for alloHCT patients after VLD (p=0.02 and p=0.03) respectively, survival was not worse for non-transplant patients after VLD (p=0.24 and p=0.10) (Figure I). In a multivariate Cox regression, adjusting for other high-risk disease features (age, cell lineage, and white cell count at diagnosis), patients who underwent allo HCT had significantly worse OS-IS (HR 1.4, p=0.02) and EFS-IS (HR 1.4, p=0.02) after experiencing VLD compared to alloHCT patients who experienced <4 weeks delay. When evaluating OS and EFS from diagnosis, VLD was still associated with poorer OS (HR 1.34, p=0.04) and EFS (HR 1.34, p=0.03). There was no difference in OS or EFS in patients who received non-transplant post-remission therapy based on delay. In a comprehensive analysis of the largest adult ALL study ever reported, we identified significant risk factors predictive of LD and VLD (>2 and >4 weeks beyond mandatory rest period). Our findings highlighted that patients were delayed because of chemotherapy toxicity and also identified healthcare disparities. VLD was associated with poorer OS and EFS in patients undergoing alloHCT, but not in patients undergoing non-transplant post remission therapy. Further studies are planned to prospectively identify patient barriers to on-schedule treatment with a goal of earlier intervention. The ability to better predict and intervene on risk factors for delay can improve adherence to protocol and optimize long-term survival. Table I: Multivariate Regression for LD and VLD Risk Factors Variable Odds Ratio 95% Confidence Interval p-value Days in the hospital Phase I Induction 1.01 1.00-1.02 0.04 Duration of Thrombocytopenia, Phase I 1.02 1.01-1.03 0.001 Age by Decade 1.2 1.08-1.31 <0.001 Reduced Dose in Induction 1.54 1.08-2.22 0.019 Sex, Female 1.56 1.22-2.0 <0.001 Race, Black 3.4 1.41-7.96 0.006 Figure 1 Figure 1. p=0.023 Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3315 The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(Tipifarnib), as maintenance therapy for acute myeloid leukemia (AML). Patients (pts) with AML in remission after requiring salvage therapy (primary induction failure or second or subsequent remission) or over the age of 60 in first remission were eligible. A confirmatory bone marrow exam was required within 2 weeks prior to randomization. Pts were eligible if they were in a complete remission (CR) or morphologic remission (MR). Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Adequate blood counts (absolute neutrophil count >= 1000/mm3 and platelet count >=50,000/mm3), and normal renal, and hepatic function were required within 2 weeks of randomization. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of this study was to compare disease free survival in the two groups. Although the study has completed accrual, an insufficient number of events have been recorded at this point to allow for evaluation of the survival data. However, toxicity data are now available. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). Seventy-three pts (51%) were male and 135 pts (94%) were white. Seventy-three pts were enrolled onto the treatment arm (Arm A) and 71 pts were enrolled onto the observation arm (Arm B). When the study was initially opened, pts on Arm A were treated with tipifarnib at a dose of 400 mg BID with dose reductions and interruptions defined per protocol for toxicity. After the first planned interim analysis, based on toxicity data, the ECOG Data Monitoring Committee recommended that the starting dose be decreased to 300 mg BID. The majority of pts enrolled on the study were in first CR (CR1) (Table 2). Among the 30 pts treated with the initial 400 mg BID dose, 23 pts (77%) had their dose held or reduced to a lower dose in the subsequent treatment cycles. For the 41 pts whose initial dose was 300 mg BID, 61% required either dose modification (n=19) or discontinued (n=6) due to toxicity. Table 1: Baseline characteristics Arm A 400 mg BID n=31 Arm A 300 mg BID n=42 Arm B Observation n=71 CR1 16 (52%) 34 (81%) 47 (66%) >CR1 10 (32%) 8 (19%) 16 (23%) Unknown 5 (16%) 16 (11%) Table 2: Toxicity Toxicity Type Arm A 400 mg n=31 Arm A 300 mg n=41 Arm B Observation n=69 Grade (n) Grade (n) Grade (n) 3 4 3 4 3 4 Hemoglobin 1 1 6 1 1 2 Leukocytes 2 4 16 4 3 Neutrophils 5 8 3 7 1 Platelets 4 10 11 11 1 5 Cardiac-ischemia 1 Fatigue 1 Diarrhea 1 Nausea 1 Febrile neutropenia 1 1 Infection w/gr 3-4 neutrophils (ANC) 1 Infection Gr0-2 ANC 1 1 3 GGT 1 Hypokalemia 1 Confusion 1 Agitation 1 Neuropathy-sensory 1 Back pain 1 Worst degree Non Hematologic 4 2 9 1 1 While non-hematologic toxicity was acceptable, significant hematologic toxicity was seen in pts treated at an initial dose of either 400 mg or 300 mg BID (Table 2). Of note, hematologic toxicity was also seen on the observation arm although less frequently than with both treatment doses. Non-hematologic toxicity was much less frequent overall and there were no significant non-hematologic toxicities in the observation arm. Reduction of the initial dose did not ameliorate either the hematologic or non-hematologic toxicity seen on the treatment arms. There was however no fatal toxicity at either dose level. Results of the randomization with respect to efficacy remain essential to determining the utility of this agent as maintenance therapy in AML. Disclosures: No relevant conflicts of interest to declare.