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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.

Abstract Abstract 676 Although maintenance therapy has been shown to be of value in Acute Lymphoid Leukemia, its role in non M3 Acute Myeloid Leukemia (AML) has never been proven. Studies have been limited by issues related to efficacy as well as toxicity. 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 AML. Patients(pts) with AML in remission after requiring salvage therapy or over age 60 in first remission were eligible. A confirmatory bone marrow exam prior to randomization was required to demonstrate a complete remission (CR) or morphologic remission(MR). Absolute neutrophil count >1000/mm3, platelet count >=50,000/mm3, normal renal, and hepatic function were required. 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. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of the study was to compare disease free survival (DFS) in the two groups. The study was designed with 84% power to detect a 76% relative increase in the median DFS from 3.4 months to 6 months (mo). The final analysis was to take place when 111 events had taken place. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). The majority of pts enrolled on the study (67%) were in first CR. Seventy three pts were enrolled onto the treatment arm and 71 pts were enrolled onto the observation arm. When the study initially opened, tipifarnib was given at a dose of 400 mg BID with dose reductions and interruptions as per protocol for toxicity. Based on the first interim analysis, toxicity data, the starting dose was decreased to 300 mg BID. Significant hematologic toxicity was seen in patients at both 300 and 400 mg. The majority of patients experienced >=grade 3 neutropenia or thrombocytopenia. There was 1 episode of febrile neutropenia. Non-hematologic toxicities were minimal. At the time of 110 events (90 relapses and 100 deaths), the final analysis of the study was conducted. The relapse rate was 60.3% on tipifarnib vs 64.8% for observation. Median DFS and 10 and 12 mo DFS and overall survival (OS) are documented in Table 1. Kaplan Meier curves for DFS and OS are presented. As the difference in median DFS is not considered significant (9.3 vs 5.8 mo, log rank p value 0.21), in July 2011, pts and physicians were informed of the lack of evidence of benefit so they could decide if they wished to continue drug. However an unplanned analysis of the data demonstrates a statistically significant improvement in OS at 10 months in pts who received tipifarnib. (70% vs 48%, p=0.05). While the benefit is subsequently lost, given a median survival measured in months, an increase in the number of pts alive and/or without disease at 10–12 mo is of value, particularly in the absence of noteworthy toxicity. Future studies are needed to better determine the role of maintenance therapy in pts with AML. Tipifarnib Observation Median DFS (months) 9.3 (95% CI:5.7, 13.3) 5.8 (95% CI: 3.7, 8.8) p=0.21 OS rate at 10 mo 70% (95% CI: 58%, 79%) 48% (95% CI: 36%, 60%) p=0.05 OS rate at 12 mo 59% (95% CI: 47%, 70%) 44% (95% CI: 32%, 55%) p=0.07 DFS rate at 10 mo 47% (95% CI: 36%, 59%) 32% (95% CI: 21%, 43%) p=0.07 DFS rate at 12 mo 39% (95% CI: 28%, 50%) 30% (95% CI: 20%, 41%) p=0.26 Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Abstract Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 663 Introduction: The biology and outcome of adult t(4;11) ALL are poorly understood. We report here 85 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing outcome and identifying prognostic factors and optimal therapy. Patients and methods: 1914 adult patients (≥15 years) with ALL were registered on the UKALL XII/ECOG 2993 study in the UK or United States from 1993–2006. Cell lineage was classified by local institutions (UK) or central immunophenotyping (ECOG). Cytogenetic, FISH and RT-PCR analyses of pre-treatment samples were either performed locally and reviewed centrally or performed centrally. Results: The 85 patients with t(4;11) were predominantly female (68%). Median age was 38 years (vs 32 years in the non-t(4;11) group) and 42% were >40 years. They had high white cell counts with 87% >30 and 66% >100 × 109/l (vs 7% in the non-t(4;11) group). Among the 27 ECOG patients, 22 (81%) had the typical pro-B (CD10NEG) immunophenotype, compared to 12% in t(4;11)NEG patients. Aside from expression of myeloid antigens, CD65 and CD15, which is part of the pro-B immunophenotype, t(4;11)POS lymphoblasts showed a unique combination of stem cell antigens: lower expression of CD34 and CD105, but higher expression of CD133 and CD135 compared to t(4;11)NEG blasts (p<0.0001). Additional cytogenetic abnormalities (ACAs) were present in 31/75 (41%) evaluable cases. Most common ACAs were gain of chromosome X (n=13), i(7)(q10) (n=7) and abnormalities of 1p (n=4). Deletion of IKZF1 or CDKN2A/B was present in 18% of patients tested; neither affected outcome. Seventy seven evaluable patients attained complete remission (CR1, 93%). Treatment received in CR1 was either chemotherapy (n=46, 59%) or a myeloablative allograft (N=31, 16 matched sibling, 1 mismatched related and 15 unrelated donors UD). CR1 treatment received strongly correlated with age with the number of allografts decreasing with age: <25 years 12/17 patients; 24–39 years 13/29 and 40+ years 6/31 (p=0.001). At median follow up of 5.4 years, five year EFS was 34% (24–44%, 95% CI) and OS 35% (25–45%). Five year relapse rate was 45% (33–58%); only 1 relapsed patient survived, nearly all events had occurred by 2 years. The 46 patients who received chemotherapy had 24% survival and 69% relapsed but 5 year OS of patients who had sibling or UD allografts was 56% and 67% respectively (p=0.013) and only 3/31 relapsed. An allograft improved OS, EFS and relapse in the <40 year group. Age was also strongly associated with outcome (figure). Conclusions: This is the largest series of adult t(4;11) ALL patients treated uniformly. Allograft in CR1 from sibling or unrelated donors is an effective strategy. Current prospective trials of intensive pediatric-type regimens in younger patients will determine if CR1 allografts are necessary. Older patients have a poor outcome and different strategies such as reduced intensity allografting should be explored. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 169 The Philadelphia positive (Ph+) arm of the international adult acute lymphoblastic leukaemia (ALL) trial UKALL12/ECOG2993 opened in 1993 and is the largest single study of patients with Ph+ ALL, with a total of 441 participants. The first cohort of study patients was treated prior to Imatinib (N=266 “Pre Imatinib“) with 2 phases of induction therapy given over 2 months followed by matched sibling or unrelated donor myeloablative allogeneic haematopoietic stem cell transplant (alloHSCT) whenever possible. The treatment protocol and outcome for these patients has been published (Fielding et al, Blood 2009). Beginning March 2003, a second cohort of study patients had Imatinib 600mg daily added, as a consolidation block after the second induction chemotherapy, (N=86, “Late Imatinib”). From late 2005, a final cohort within the trial were given Imatinib earlier, in conjunction with the second phase of induction (N=89, “Early Imatinib”). Patients in both Imatinib cohorts resumed the drug for a further 2 years following alloHSCT, if tolerated. If alloHSCT was not possible, Imatinib was permitted for 2 years, with maintenance. The trial closed to recruitment in December 2006 (USA) and October 2008 (UK). All except 8 patients have now completed therapy. An earlier analysis of these data did not indicate a clear long-term advantage to receiving Imatinib. We now report 3-year follow-up, which shows large outcome differences between the 3 groups. There were no pre-existing differences between the 3 cohorts in terms of gender, presenting white blood cell counts and presence of central nervous system disease at diagnosis. However, the Pre-Imatinib cohort was younger than the two Imatinib cohorts, due to an increase in the upper age limit for study entry. Percentage complete remission (CR) rates and survival of induction therapy are shown in table 1. The total CR rate for the imatinib cohorts was significantly higher than for the pre-imatinib cohort (p=0.004). Table 1 Pre-Imatinib With Imatinib N=266 Total With Imatinib N=175 Part 1 Late Imatinib N=86 Part 2 Early Imatinib N=89 Died in induction<d56 5 5 3 7 Survived induction but never achieved remission 13 3 5 1 Total not achieving CR 18 8 8 8 CR on protocol induction 67 77 73 80 Total CR rate (includes those achieving remission later than post induction) 82 92 92 92 Pre- Imatinib, only 28% of patients went on to receive alloHSCT as per protocol. With any Imatinib, 44% of patients received alloHSCT as per protocol. Survival outcomes of patients in the 3 cohorts are shown in the table 2. Overall survival (OS), event free survival (EFS) and relapse free survival (RFS) are all at 3 years with 95% confidence intervals (CI) shown in brackets. The P values are for two comparisons - ** denotes the comparison between patients receiving any Imatinib and patients receiving none and ^ denotes the comparison between the Early and Late Imatinib cohorts. Table 2 Pre-Imatinib With Imatinib Total With Imatinib Part 1 Late Imatinib Part 2 Early Imatinib % OS (95% CI) (see also Figure 1) 25 (20–30) 42 (34–49) 34 (24–44) 48 (36–60) p=0.0001** p=0.05^ % EFS (95% CI) 19 (14–24) 36 (29–44) 29 (19–38) 45 (34–56) p=0.0001** p=0.04^ % RFS (95% CI) 36 (28–43) 54 (45–63) 45 (33–57) 62 (50–75) p=0.0001** p=0.02^ Figure 1 Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. Figure 1. Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. In conclusion, receiving any Imatinib during induction for Ph+ ALL significantly enhances CR rate and increase alloHSCT rate. This translates into a highly significant EFS, OS and RFS advantage to receiving Imatinib during therapy. An earlier start to Imatinib is significantly better than a later start. Though comparisons between study cohorts are not randomised, the large differences seen are unlikely to be explained by factors other than treatment. There can be no basis for omitting Imatinib from the initial therapy of adult patients with Ph+ ALL. However, our data show that the best outcome is seen when patients receive Imatinib followed by myeloablative alloHSCT, where nearly 60% of such patients survive 3 years from diagnosis. Disclosures: Goldstone: Roche: Honoraria, Speakers Bureau.