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Abstract Background: SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume SC injection that yields longer half-life and more extended DAC exposure than DAC IV infusion. A phase 1 clinical trial of SGI-110 demonstrated a differentiated pharmacokinetic profile from DAC IV, potent hypomethylation, and clinical responses in previously treated patients with MDS and AML (Kantarjian et al. 2012). Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles. Phase 2 is conducted to evaluate dose response between the BED and MTD in MDS patients. Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve or previously treated were randomized to either 60 mg/m2 or 90 mg/m2QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006 as well as transfusion-independence. Adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic biological activity as measured by Long Interspersed Nucleotide Element LINE-1 (an index of global DNA methylation) were also assessed. Patients are being followed for overall survival. Results: The study completed target enrolment with 102 patients: 53 who were refractory or have relapsed on prior treatment, and 49 previously untreated. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 8.2 months (range 1-21). Most baseline patient characteristics were well balanced between the 2 treatment arms with no significant differences in median age (71.7 vs. 72.5 y); male gender (70 vs. 61%); ECOG PS 2 (15 vs. 12%); HR MDS (28 vs. 37%); transfusion-dependence (57 vs. 55%), median baseline Hb (9.25 vs. 9.3 g/dL); platelets count (42.5 vs. 45 x109/L), and neutrophils count (1.19 vs. 1.16 x109/L) for the 60 and 90 mg/m2 QDx5 respectively. However, there were 15 CMML patients (28%) randomized to 60 mg/m2 vs. only 7 CMML patients (14%) randomized to 90 mg/m2(p=0.097). All but 2 patients in the previously treated group received one or more HMA. At the time of the data cutoff, 38 of 102 patients (37%) were still on treatment. Median number of treatment cycles was 4 for previously treated patients, and 5 for the treatment naïve group (range 1-22 cycles). CR+mCR were observed in 10/53 (19%), and 11/49 (22%) in the 60 and 90 mg/m2 arms respectively (p=0.8). CR was observed in 7/49 treatment naïve patients (14%) while CR+mCR were observed in 11/53 previously treated patients (21%) with no significant differences between 60 and 90 mg/m2 arms. Transfusion independence for at least 8 weeks was reported in 32% and 24% for platelets and RBCs respectively with no difference between the 2 treatment arms. Treatment naïve patients benefited from higher rate of transfusion-independence (58% and 46% for platelets and RBCs respectively). Potent demethylation was achieved in both treatment arms with a mean LINE-1 DNA demethylation of 27.3 and 30.5% for 60 and 90 mg/m2 respectively (p=0.12). Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 81 vs. 88% for 60 and 90 mg/m2 treatment arms respectively (p=0.42).There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (51 vs 38%) and pneumonia (20 vs. 13%) for the 90 mg/m2 arm compared to 60 mg/m2. Early 8-week any-cause mortality occurred in 3/102 patients treated (3%), 2 at 60 and 1 at 90 mg/m2. Follow up for survival is still ongoing. Conclusions: SC SGI-110 is a well-tolerated novel HMA with biological and clinical activity in the treatment of Int and HR MDS, and CMML patients with particularly promising activity in patients previously treated with azacitidine or decitabine. Clinical responses, transfusion independence, DNA demethylation as assessed by LINE-1, and Safety did not significantly differ between the 2 treatment doses. Disclosures Tibes: Astex Pharmaceuticals, Inc.: Research Funding. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Astex Pharmaceuticals, Inc.: Consultancy.

Abstract Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML. The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts. A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo. This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001). Disclosures Uy: Novartis: Research Funding. Off Label Use: Sorafenib for AML. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta Pharma BV: Research Funding. Stone:Celator: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; AROG: Consultancy; Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Juno: Consultancy; Agios: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Abstract Purpose: Clinical trials in APL have generally reported similar outcomes for children and adults. However, sub-group analysis of pediatric patients treated on 2 consecutive trials of the European APL group demonstrated that children <5 years (yr) had an increased risk of relapse (Bally et al., JCO, 2012). Here we report the effect of age < 5 yr on outcome for the North American Intergroup Study C9710. Methods: Outcomes were compared among young children (age <5 yr, n=16) to those of older age (5-12 yr, n=25 and 13-18 yr, n=45) enrolled on C9710. Treatment on C9710 included induction with daunorubicin, cytarabine and ATRA followed by two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Patients of age ≥15 yr were randomized to receive or not receive two 5-week cycles of arsenic trioxide (ATO) before the chemotherapy consolidation. However, analysis in this study of young children compared to those of older age was restricted to patients who did not receive ATO. Results: Clinical remission (CR) rates were similar between the 3 age groups (age <5 yr= 88%, age 5-12 yr= 80%, age 13-18 yr= 82%; P=0.93). Overall survival (OS) Kaplan-Meier estimates were not significantly different (log rank P=0.84), and 5 yr OS rates were 77% (age <5 yr), 80% (age 5-12 yr), and 84% (age 13-18 yr). Similarly, event-free survival (EFS) Kaplan-Meier estimates were not significantly different (log rank P=0.48), and 5 yr EFS rates were 56% (age <5 yr), 47% (age 5-12 yr), and 59% (age 13-18 yr). Young children did not have a higher relapse rate (5-yr cumulative incidence of relapse by age: <5 yr=29%, 5-12 yr=49%, 13-18 yr=29%). Conclusions: Results of this intergroup trial demonstrate that ATRA administration during induction, consolidation and maintenance leads to CR rates >80% and 5 yr OS rates >75%. These results are superior to recently published results of pediatric non-APL acute myeloid leukemia and confirm results from the prior APL intergroup trial (INT0129) that demonstrated that ATRA in induction and/or maintenance significantly improved outcomes for pediatric APL (Gregory et al., Ped Blood and Cancer, 2009). Our sub-group analysis showed no association of age with outcomes in children treated with this regimen. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

Abstract Purpose: Recent studies have demonstrated differential outcomes for adolescents and young adults (AYAs) vs. children treated for acute myeloid leukemia. Here we analyze outcomes by age group for APL patients treated on the North American Intergroup Study C9710. Methods: Patient characteristics and outcomes were compared between children (<15 yr, n=55) vs. AYAs (15-31 yr, n=42). To control for differences in treatment center, only young adults registered at Children’s Oncology Group (COG) treatment sites were included. Treatment included induction with daunorubicin, cytarabine and ATRA. All patients (pts) received two consolidation cycles with daunorubicin and ATRA and maintenance for one year with ATRA +/- mercaptopurine and methotrexate. Pts ≥15 yr were randomized to an additional two cycles of arsenic trioxide (ATO). Sub-group analysis was also performed to exclude pts ≥15 yr who received ATO and thus compare only patients <15 yr vs. ≥15 yr who had not received ATO. Results: Children and AYAs had similar characteristics of gender, race/ethnicity, Sanz risk grouping and M3v histology. Among all pts enrolled at COG sites on the study, complete response (CR) rates were similar (<15yr =85% vs. ≥15yr =81%, P=0.59). AYAs had improved 5 yr disease-free survival (DFS) from time of CR compared to younger pts (<15 yr =47% vs. ≥15 yr =70%, log rank P=0.05), and there was a trend toward difference in 5 yr event-free survival (EFS) (<15 yr =46% vs. ≥15 yr =63%, log rank P=0.13). Overall survival (OS) at 5 years was not significantly different (<15 yr =82% vs. ≥15 yr =75%, log rank P=0.47). Twenty-three of 42 pts ≥15 yr received ATO consolidation cycles, which may have contributed to their improved DFS and EFS. Thus, we analyzed outcomes by removing from the analysis patients ≥15 yr who received ATO consolidation cycles, and compared pts <15 yr who did not receive ATO (n=55) to pts ≥15 yr who were randomized to no ATO (n=19). CR rates were again similar (<15 yr =85% vs. ≥15 yr no ATO =84%, P=1.0). There was no significant difference in other outcomes including 5-yr DFS from time of CR (<15 yr =47% vs. ≥15 yr no ATO =63%, log rank P=0.31), 5-yr EFS (<15 yr =46% vs. ≥15 yr no ATO=53%, log rank P=0.89), or 5-yr OS (<15 yr =82% vs. ≥15 yr no ATO=79%, log rank P=0.78). Conclusions: The C9710 study demonstrated improved EFS, DFS and OS among adult patients receiving ATO consolidation compared to those who did not receive ATO (Powell et al., Blood, 2010). The current analysis of results for AYAs versus younger pediatric pts showed improved DFS among the whole AYA cohort (of which 55% received ATO consolidation) compared to pts <15 yr (of which 0% received ATO). When the analysis was restricted to AYA pts not receiving ATO, however, the results of this intergroup APL trial showed similar CR, DFS, EFS and OS for AYAs and younger pts. Thus, unlike other subtypes of AML, APL appears to have a consistent response across the pediatric and AYA age groups. The most recent COG clinical trial in APL is now evaluating whether pediatric patients can also benefit from ATO consolidation. Disclosures Off Label Use: Daunorubicin- labeled for use in AML for adults and for pediatric ALL (not pediatric AML) Arsenic Trioxide- labeled for use in relapsed/refractory APL (not de novo APL) Mercaptopurine and Methotrexate- labeled for use in pediatric ALL (not APL).

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 1038 The relationships of inherent disease-related characteristics and of treatment to the nature of APL cell clones that emerge at disease relapse are poorly understood. We studied these relationships in 45 patients who relapsed after ATRA/chemotherapy treatment on the non-arsenic trixoxide arm of intergroup phase III trial C9710 (Powell, et al. Blood, Epub). Four variably-expressed APL cell clonal markers were assessed: PML-RARA ligand binding domain mutations (LBD-M), FLT3 internal tandem duplication mutations (ITD), FLT3 receptor tyrosine kinase mutations (D835; RTK-M) and additional chromosome abnormalities (ACA), i.e., in addition to the hallmark t(15;17). The methods for mutation analysis of PML-RARA and FLT3 have been reported and were RNA transcript-initiated supplemented by selected quantitative FLT3 mutation analyses initiated from DNA. Karyotype data were derived by standard cytogenetic methods. Four patients were excluded from analysis because the sample level of PML-RARA, as determined by quantitative RT-PCR, was insufficient to exclude possible false-negative mutation results. In 41 evaluable patients, the marker incidences were: LBD-M, 44%; ITD, 37%; RTK-M, 12%; ACA (22 tested), 59%. At presentation, the corresponding incidences were: LBD-M, 0% (by high-sensitivity testing a minor subclone of the relapse mutation was found in 2/7 patients tested); ITD, 43% (37 tested); RTK-M, 22% (37 tested); ACA, 24% (34 tested). The low frequency of RTK-M impeded further analysis. The other markers, using relapse determinations, were assessed for potential associations between the markers and with the following parameters: age, sex, presenting WBC count, PML-RARA type, time to relapse, relapse on or off ATRA treatment (on = taking or within 30 days of discontinuing) and post-relapse survival. The most essential positive findings are summarized below:Association of Marker with Parameter or Other MarkerCases with ParameterCases without Parameterp-valuePretreatment parameters: LBD-M with WBC count < 5,000/uL12/18 (67%)7/23 (30%)0.030 ITD with WBC count >10,000/uL10/15 (67%)5/26 (19%)0.006 ITD with S-form PML-RARA15/15 (100%)10/26 (38%)<0.0001Relapse parameters: ITD with lack of ACA1/7 (14%)12/15 (80%)0.007 LBD with relapse On-ATRA11/18 (61%)7/23 (30%)0.064 Off-ATRA only: LBD with lack of ITD0/7 (0%)9/16 (56%)0.019 The results confirm reports, which tested pretreatment samples, of a strong association between FLT3ITD mutations present at relapse and high WBC count and S-form PML-RARA. At relapse, there was, also, divergent selection of ITD-harboring vs ACA-harboring clones. LBD-M occurred more frequently in patients with low presenting WBC counts. They, also, occurred in patients who relapsed while on ATRA, consistent with an ATRA selective role for clones harboring LBD mutations. A significant segregation of patients with LBD-M or ITD was observed after relapse off ATRA treatment (p = 0.019), while no segregation was observed in overall relapse patients (p = 0.346) or after relapse on ATRA (p = 0.316). In 2 patients who relapsed on ATRA, quantitative analysis indicated that LBD-M and ITD mutations must be present in the same APL cell clone. There were no significant survival differences related to any clonal marker (post-relapse survival = 66%). Although the small number of cases is cautionary, the overall data suggest that LBD-M may have an overriding, dominant APL clone selection role in relapse that occurs on ATRA therapy. Other inherent clinicopathologic characteristics of APL may predispose to divergent molecular pathways of disease progression and relapse in patients alternatively harboring clones with LBD-M or ITD after the termination of ATRA selection pressure. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

Abstract Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Abstract Novel treatment strategies are needed for older patients with acute myeloid leukemia (AML). This randomized phase 2 trial compared the efficacy and safety of 20 mg/m2 of IV decitabine on days 1 to 10 alone (arm A) with those of 1.3 mg/m2 of subcutaneous bortezomib (arm B) on days 1, 4, 8, and 11 for up to 4 10-day cycles followed by monthly 5-day cycles. Previously untreated AML patients age ≥60 years (excluding those with FLT3 mutations and favorable-risk cytogenetics) without restrictions in performance status (PS) or organ function were eligible. Median age was 72.4 years (range, 60.5-92.3 years); 31 patients (19%) had baseline PS ≥2, 35 (22%) had an antecedent hematological disorder, 58 had (39%) adverse cytogenetics, and 7 (5%) and 23 (14%) had abnormal cardiac or renal function. There were no statistically significant differences in overall survival (OS) or responses between the 2 treatment arms. The overall response rate (complete remission + complete remission with incomplete blood count recovery) was 39% (n = 64), with median OS of 9.3 months. Nineteen responders (31%) underwent allogeneic stem cell transplantation. The most common adverse event was febrile neutropenia, and there were no unexpected toxicities. Adding bortezomib to decitabine did not improve outcomes, but responses were better than those in previous trials using 5-day decitabine cycles. This trial was registered at www.clinicaltrials.gov as #NCT01420926.