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Background: The CD22-directed antibody-drug conjugate inotuzumab ozogamicin (InO) is FDA-approved for adults with relapsed/refractory (R/R) CD22+ B-ALL and highly active in children with multiply R/R CD22+ B-ALL. Notable toxicities include cytopenias and hepatic toxicity, including sinusoidal obstruction syndrome (SOS) occurring primarily after subsequent hematopoietic stem cell transplantation (HSCT). The incorporation of InO into frontline ALL therapy for patients (pts) with CD22+ high-risk B-ALL who are not anticipated to require HSCT in first remission may optimize use of this effective agent without incurring significant SOS risk by minimizing relapse and therefore potential need for future HSCT. Methods: Children's Oncology Group (COG) AALL1732 is a phase 3 trial for pts 1-24 years of age with B-ALL who have high-risk features based on age, white blood cell count, or presence of extramedullary disease at diagnosis (Figure 1). Pts receive a 4-drug induction followed by augmented BFM consolidation. Those with surface CD22 expression on >20% of blasts at diagnosis and bone marrow minimal residual disease Results: Forty-eight pts continued on therapy after randomization, (Arm A: 25, Arm B: 23), with median age 12 years and body surface area 1.4m 2 on each arm (Table 1). There were no statistically significant differences in grade ≥3 ALT or bilirubin levels between Arms A and B through day 1 of DI. During DI, 4 pts on Arm B had grade 3 hyperbilirubinemia compared to none on Arm A, all in the setting of concurrent infection. The rates of SOS did not cross protocol-defined safety thresholds and were not statistically different between arms; on Arm A, 1/25 pts (4%, 1 grade 3 event) and on Arm B, 3/23 pts developed SOS (13%, 1 grade 4, 2 grade 2). The patient with grade 4 SOS discontinued protocol therapy. The duration of the IM1 block of therapy was significantly longer for patients on Arm B compared to those on Arm A (mean duration of 90 days (sd 15.3) versus 75.5 days (sd 14.4), p=0.002). Day 1 HD-MTX clearance to 14-day delay in the start of the second (Day 15) HD-MTX in 4/23 pts (17.4%) on Arm B compared to 0/25 on Arm A, p=0.046. In contrast, time to MTX clearance and rate of >96-hour clearance were not significantly different between the arms for the other HD-MTX doses (Days 15, 29, 43). Omission of oral 6MP occurred at a significantly higher frequency on Arm B compared to Arm A at several time points in IM1, with an association between HD-MTX clearance of >96 hours and the need to hold oral 6MP (p=0.011, p=0.018, and p=0.042 for days 1, 15, and 43, respectively). During DI, sepsis occurred more frequently in pts on Arm B. There were 6 (27%) Grade 3 events and 6 (27%) ≥Grade 4 events among 22 Arm B patients, including 3 pts with multiorgan failure and one death. In contrast, among 25 pts on Arm A, there were 2 (8%) Grade 3 sepsis events and no ≥Grade 4 events. The rate of sepsis was significantly higher on Arm B (12 of 22, 54%) compared to Arm A (2 of 25, 8%, p= 0.001). The majority of sepsis events were due to bacterial infections, and 8 of 12 events on Arm B occurred in the second half of DI. Conclusion: Planned safety phase analysis of the first 50 randomized pts demonstrated increased rates of delayed MTX clearance following the first HD-MTX infusion in IM1 and more sepsis events due to bacterial infections during DI in Arm B patients. Hepatic toxicity and SOS occurred infrequently and did not differ significantly between arms. We plan to amend AALL1732 to decrease the dose of InO by 20% and increase hydration for the first HD-MTX infusion. We will recommend prophylaxis with broad-spectrum antibiotics during periods of neutropenia in DI as well as monitoring of serum IgG levels, with replacement for IgG Figure 1 Figure 1. Disclosures McNeer: Jazz Pharmaceuticals: Other: Advisory Board Member. O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Wood: Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement; Pfizer, Amgen, Seattle Genetics: Honoraria. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees.

Despite the remarkable pace of characterizing the genomics of pediatric acute leukemias, the integration of real-time sequencing results into clinical practice has lagged. With increased availability of molecularly-targeted therapies, the promise of matching genetic lesions in patients' leukemia cells to treatment has not yet been fully realized. We established the first pediatric leukemia clinical genomics consortium in the United States, known as the Leukemia Precision-based Therapy (LEAP) Consortium, which includes 13 major pediatric cancer institutions. We hypothesized that it is feasible to identify and match, in real-time, actionable alterations with a targeted therapy for pediatric patients with relapsed, refractory or high-risk leukemias or myelodysplastic syndrome (MDS). Using a combination of a DNA-based next-generation sequencing panel and RNA-based gene fusion testing, followed by data review by our multidisciplinary molecular tumor board, we are conducting a clinical trial to test this hypothesis. To date, we have enrolled and reviewed data from 143 patients stratified by disease status: Cohort 1, patients with relapsed or refractory leukemias (n=93), and Cohort 2, patients with de novo high-risk leukemias or MDS (n=50). A matched targeted therapy (MTT) recommendation has been made for 72% (n=103) of patients, tiered based on the level of evidence linking the mutation to potential activity of targeted therapy in the context of each patient's disease (Tier 1: 11%, Tier 2: 4%, Tier 3: 41%, Tier 4: 6%, Tier 5: 10%). Of the 44 patients in Cohort 1 with clinical follow-up data, 5 (11%) had alterations in therapy made based upon sequencing results and MTT recommendation. These include the use of the MEK inhibitor trametinib for RAS mutant acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (n=2), dasatinib for B-ALL and T-ALL with NUP214-ABL1 translocations (n=2) and ponatinib for B-ALL with an ABL1 T315I mutation (n=1). In addition, this genomic data refined diagnosis and supported additional germline assessment in a subset of patients. In parallel to the genomic sequencing, we are conducting high-throughput drug sensitivity (HTS) assays to study in vitro anti-leukemia effects of a panel of up to 120 targeted inhibitors in the context of leukemia-associated genetic alterations. Of the initial 106 accrued patients, 40 (38%) had adequate amounts of blood or bone marrow for in vitro drug testing. All samples were tested in the inhibitor panel assay, and 65% of the samples yielded interpretable results. Inhibitor screening data was compiled for all 12 patients with genetic alterations resulting in Tier 1, 2 or 3 MTT recommendations. This subset of patients had leukemias with two distinct molecular profiles: 1) oncogenic RAS signaling pathway mutations or 2) oncogenic tyrosine kinase alterations. Our molecular tumor board recommended trametinib for the first group of patients and tyrosine kinase inhibitors (TKIs), specific to the mutation, for the second group of patients. In vitro HTS data analysis demonstrated dose-response sensitivity of leukemia cells with RAS pathway mutations to trametinib, many of which had half-maximal inhibitory concentration (IC50) less than 50 nM. Similarly, leukemia cells from patients with FLT3, ABL1 or KIT mutations generally showed dose-responses to relevant TKIs with low IC50s. Overall, HTS data were concordant with MTT recommendations informed by the sequencing results. This first in the US multi-institutional prospective leukemia genomics trial brings state-of-the-art clinical genetic testing, assessment of prognostic biomarkers, selection of patients for germline testing, and targeted therapeutic treatment recommendations to children and young adults with high-risk, relapsed or refractory leukemias or MDS. Our collaboration provides a unique opportunity to perform sophisticated patient-specific in vitro drug testing assays to impact MTT discovery efforts, which we plan to validate in vivo using patient-derived xenograft models where feasible. We believe that a model like the LEAP Consortium has the potential to transform precision medicine approaches for children with high-risk leukemias and to inform future genomics-guided therapeutic trials and drug discovery efforts. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Burke:JAZZ: Speakers Bureau; Shire: Speakers Bureau; AMGEN: Speakers Bureau. Tyner:AstraZeneca: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Array: Research Funding; Constellation: Research Funding; Gilead: Research Funding; Aptose: Research Funding; Incyte: Research Funding; Genentech: Research Funding.

Introduction: There is no clear consensus regarding the optimal therapeutic approach for AYAs with HL. Prior registry data showed that HL AYA patients treated with ABVD had similar outcomes to their older counterparts (Foltz JCO 2006). However, SEER data have suggested that advances in HL survival among AYAs may be less robust compared with older populations (Bleyer NCI 2006). We sought to examine AYA patients treated on two recent, randomized pediatric and adult North American HL clinical trials (i.e., 17-21 years; the age group of those typically eligible for both pediatric- and adult-based HL clinical trials) by comparing outcomes of different age cohorts within E2496 as well as across the two different studies. Methods: We examined characteristics and outcomes of 114 newly diagnosed AYA HL patients aged 17-21 years treated on E2496 (ABVD vs. Stanford V [SV] chemotherapy, Gordon JCO 2013) trial and compared the failure free survival (FFS) and overall survival (OS) with patients ages >21 years. In addition, we compared presenting features, planned treatment, FFS, and OS of these ECOG AYA patients with 391 newly diagnosed AYA HL patients between ages 17-21 years treated on the COG AHOD0031 (ABVE-PC backbone, Friedman JCO 2014). Unstratified and stratified log-rank tests as well as propensity score analysis were utilized to compare differences in patient outcomes. Results: In E2496, the 5-year FFS and OS rates for AYAs were 68% and 89%, respectively, with significant variations identified by patient age (see Table). There was no FFS difference between ECOG AYAs treated with ABVD vs. SV (P =0.66). However, FFS in AYAs were inferior to those ages 21 to 44 years in E2496 (P =0.005; see Figure, sections A and B). Interestingly, AYA outcomes on E2496 appeared more similar to patients aged 45-59 years. In examining COG and E2496 AYA patient characteristics, there was no significant difference in sex, race, or histology. Due in part to trial design differences, a larger proportion of E2496 AYAs were stage III or IV vs. COG AYAs (63% vs. 29%, P Conclusions: AYA HL patients treated on E2496 had inferior outcomes compared with older patients (i.e., ages 22 to 44 years) treated within the same study, for unclear reasons, as well as to similarly matched AYA patients treated on COG AHOD0031. These outcomes may result from treatment regimen differences or dose-intensity, differing patient populations or risk profiles, biology, and/or other factors. Prospective examination of these issues in AYA HL patients is warranted. Table 1. Survival Outcomes Within E2496 by Age. PFS 3-yr 5-yr P 17-21 70% 68% 0.005 21-44 79% 76% 45-59 68% 68% >=60 56% 48% OS P 17-21 93% 89% =60 70% 58% Figure 1. Figure 1. Disclosures Smith: Pharmacyclics: Consultancy; Celgene: Consultancy. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Horning:Genentech: Employment. Shah:Seattle Genetics: Research Funding; Rosetta Genomics: Other: Grant support; Acetylon: Other: Advisory board; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Other: Advisory board, Speakers Bureau; Bayer: Honoraria; Celgene: Other: Advisory board, Speakers Bureau; DeBartolo Institute for personalized medicine: Other: Grant support. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Background: The success in treatment of B acute lymphoblastic leukemia (B-ALL) is partially attributable to careful risk stratification of patients, based largely on biology of disease and disease response to therapy. Recently, gene expression profiling and subsequent high-throughput sequencing of B-ALL has resulted in the identification of a novel high-risk subset of patients with an activated kinase signature similar to patients with Philadelphia chromosome (Ph)-positive ALL, which is currently known as Ph-like ALL (Mullighan et al Nature 2007, Den Boer et al Lancet Oncol 2009). Identification of patients with Ph-like ALL using standard diagnostic techniques will be of great clinical importance since the activated kinases present in these leukemias may be therapeutically targeted. Here we report two patients with B-ALL who had residual disease after induction, neither of whom had a classic high-risk karyotype. Using chromosomal microarray analysis (CMA) we identified targetable kinase mutations in each patient that resulted in a change in therapy and eradication of minimal residual disease (MRD). Patient 1: An 11 year old female presented with fever, malaise, and decreased appetite. The initial WBC count was 28.2 K/µL with 65% blasts, hemoglobin was 5.9 gm/dL, and platelets were 46 K/µL. Flow cytometry confirmed B-ALL. Cytogenetic analysis revealed the following karyotype: 46,XX,add(5)(q13.3),add(6)(q13)[13]/46,XX[5]. She was started on four-drug induction chemotherapy, but at the end of induction, there were 90% blasts in the marrow, consistent with induction failure. Using CMA, multiple regions of copy number loss were detected, one of which was a microdeletion at 5q32-q33.3 with breakpoints located in the EBF1 and PDGFRB genes. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of a PDGFRB rearrangement. The deletion likely resulted in the EBF1-PDGFRB fusion, previously described in rare cases of high-risk B-ALL. Based on previous reports that hematologic malignancies with PDGFRB fusions respond to the addition of a tyrosine kinase inhibitor (TKI) to therapy, imatinib was added to the chemotherapy backbone, and then dasatinib for broader tyrosine kinase inhibition. At the end of 8 weeks of this consolidation treatment there was no morphologic or immunophenotypic evidence of residual leukemia. Patient 2: A 28 year old male presented with abdominal pain, fatigue, and weight loss. The initial WBC was 210.7 K/µL with 94% blasts, hemoglobin was 8.8 gm/dL, and platelets were 43 K/µL. Flow cytometry confirmed B-ALL, and cytogenetic analysis showed one abnormal clone: 45,X,-Y,del(9)(p13p24)[11]. The patient received a four-drug induction, and at the end of induction therapy, MRD was present at a level of 4%. After 8 weeks of consolidation chemotherapy, MRD remained at a level of 1.3%. Several aberrations were detected by CMA, including a 360 kb copy number gain within the 9q34.12-34.13 segment of the long arm of chromosome 9. It involved the chromosome segment between the NUP214 and ABL1 genes, likely resulting in formation of a NUP214-ABL1 fusion gene and upregulation of the ABL1 kinase activity. Dasatinib was added to the chemotherapy regimen, and eight weeks later the marrow had no evidence of MRD. Discussion: We successfully employed CMA to identify 2 patients with B-ALL and a targetable fusion gene. Until now, CMA has been used to identify submicroscopic genetic lesions in ALL, often in genes that drive leukemogenesis. It has not yet been used for identification of patients with Ph-like ALL. Based on these two index cases, we have now begun prospectively to analyze leukemic blasts of patients with B-ALL who do not have classically prognostic cytogenetics using CMA and a panel of selected FISH probes. Using this approach, we have been able to identify Ph-like genetic lesions, and we plan to utilize this information to tailor therapy with early introduction of an appropriate TKI in order to achieve MRD-negative remissions. Figure 1 Figure Legend: CMA results for patients 1 and 2. Top panel: Array plot showing the 8.6Mb 5q32-q33.3 deletion (red bar) in patient 1, that fuses exon 11 of the EBF1 gene with exon 15 of PDGFRB. Bottom panel: The 360kb duplication at 9q34 (blue bar) in patient 2, with the breakpoints within the ABL1 gene and the NUP214 gene, resulting in the NUP214-ABL1 fusion. Figure 1. Figure Legend: CMA results for patients 1 and 2. Top panel: Array plot showing the 8.6Mb 5q32-q33.3 deletion (red bar) in patient 1, that fuses exon 11 of the EBF1 gene with exon 15 of PDGFRB. Bottom panel: The 360kb duplication at 9q34 (blue bar) in patient 2, with the breakpoints within the ABL1 gene and the NUP214 gene, resulting in the NUP214-ABL1 fusion. Disclosures Off Label Use: Use of tyrosine kinase inhibitors as adjunct therapy in Ph-like B-ALL.

Background Adolescents and young adults (AYAs) with cancer face unique psychosocial challenges. Hematologic malignancies account for the greatest frequency of AYA cancers and a growing number of AYA cancer survivors; however, there remains a paucity of studies describing the early and late psychological impact of experiencing a life-threatening blood cancer as an AYA. How oncologists perceive the psychological burden of cancer in AYAs is also unknown; provider under-appreciation may in part contribute to the documented unmet desire for mental health support amongst AYA cancer patients. The aims of this study were therefore to describe the prevalence and severity of psychological morbidities in AYAs with hematologic malignancies, and to examine provider perceptions of psychological morbidity in their AYA patients. Methods Patients ages 15-40 years at diagnosis of acute leukemia, aggressive non-Hodgkin lymphoma, and Hodgkin lymphoma who were undergoing curative intent therapy (on-treatment cohort) or had completed therapy within 2 years and were in remission (early survivor cohort) underwent a one-time semi-structured interview that incorporated validated measures of anxiety (State Anxiety Inventory [SAI]), depression (Center for Epidemiological Studies Depression Scale [CES-D]), and post-traumatic stress (PTSD Checklist [PCL-C]). Frequencies of patient anxiety, depression, traumatic stress, and composite distress (impairment in ≥1 psychological domain) were determined using published instrument cut-points, and stratified by cohort (on-treatment versus early survivor). Following patient enrollment, providers completed a survey evaluating their perception of the subject’s anxiety, depression, and traumatic stress. Spearman correlation coefficients evaluated correlations between provider perceptions and AYA scores on the survey measures. Results Between October 2012 and May 2013, 61 (26 on-treatment, 35 early survivors) of 77 eligible AYAs completed the study and are evaluable. Median age at diagnosis was 26 years. 64% were male; 59% non-Hispanic white, 15% Hispanic, and 20% African American. 52% and 48% had lymphoma or leukemia, respectively. Median time from diagnosis to study interview was 13 months (range, 1-102). On-treatment versus early survivor cohort demographics differed only in median time from diagnosis to interview (5.4 months versus 13.6 months, p= .009). Of the 61 evaluable patients, 23% met criteria for anxiety, 28% for depression, and 13% for traumatic stress; 46% demonstrated PTSD symptomatology. 36% met criteria for impairment in at least one psychological domain. Psychological impairments were as frequent in the early survivors as the on-treatment cohort. Provider surveys were distributed for the first 30 patients enrolled; 48 surveys were returned for 27 of the 30 patients. Providers were 50% attending physicians, 44% nurses, and 6% fellows; 71% were female. Providers had, on average, 10-20 interactions with the patient. Provider perceptions of their AYA patient’s psychological morbidities varied substantially between providers, and did not significantly correlate with results obtained via patient surveys (anxiety: r=.11, p= .57; depression: r=.13, p= .53; traumatic stress: r=.004, p= .98). Conclusions Many AYAs with hematologic malignancies experience substantial psychological morbidities both while undergoing therapy as well as during the first two years following treatment completion, with over one-third of patients meeting criteria for anxiety, depression, or traumatic stress. This psychological burden does not appear to be accurately appreciated by their oncology providers, indicating a need for increased awareness among the hematology/oncology community. Additional studies will explore the long-term implications of these findings, as well as novel interventions aimed at reducing the psychological burden for AYAs with hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

Abstract 3535 Background: AYAs with ALL are increasingly recognized as a distinct population with unique biomedical and psychosocial characteristics. However, little is known about factors that may influence participation in, and compliance with, the challenging treatment regimens that are currently being tested in this patient population. U.S. Intergroup trial C10403 was designed to prospectively evaluate a successful pediatric treatment approach in AYAs with ALL, with an additional aim to assess demographics, social support, and potential barriers to care that may impact outcomes. We describe here for the first time the baseline characteristics of patients enrolled on C10403 in order to begin to understand the personal challenges they face during treatment. Methods: Self-administered surveys were conducted at specified time points over the course of treatment. Survey 1, which explored demographics, decision making, and social support, was administered to patients following completion of induction chemotherapy. Survey 2, which evaluated treatment delays and barriers to care, was administered after remission consolidation at about 6 months. Descriptive statistics were used to summarize patient demographics and responses to survey questions. Results: Between November, 2007 and July, 2012, 296 patients across the United States aged16–39 were enrolled on C10403; 269 signed consent to participate in the survey study. 183 (68%), 129 (48%), and 193 (72%) completed survey 1, survey 2, or either survey. Of the survey respondents, 61% were male, 73% white, 11% African American, and 11% Hispanic. Median age was 24 years (yrs) (range 17–39); 17%, 62%, and 22% were Regarding social support, 51% of AYAs still live with parents while 36% live with their own families, and 6% live alone. 97% of those AYAs report that referral to specific treatment centers was primarily initiated by a physician (78%) rather than self or family. After protocol initiation, 35% recall that some chemotherapy was missed or delayed; 43% report ≥2 treatment delays. Delays were primarily due to low blood counts (52%) or toxicity (27%); only 7% were due to modifiable patient circumstances. Most patients did not report barriers to receiving care; however 9% had childcare difficulties, 14% had conflicting commitments, 15% had trouble keeping track of appointments, 18% had difficulty with co-pays, 19% had transportation issues, and 59% report long clinic wait times. Conclusions: AYAs enrolled on C10403 tend to be white, of middle/low income, and to have been previously healthy. Contrary to what has been hypothesized about AYAs, in general, they self-report a strong social support structure, and do not perceive substantial barriers to receiving treatment. Older AYAs are more independent and report that they, rather than others, are most responsible for their own leukemia care. Additional surveys are being distributed at treatment completion that explore whether these findings persist throughout the 2–3 year period of ALL therapy and the post-treatment follow up period. Disclosures: No relevant conflicts of interest to declare.

Arsenic Trioxide (As2O3) has major efficacy in the treatment of acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the need for high intracellular concentrations to induce apoptosis. Prior work in our laboratory has demonstrated that the p38 MAP kinase (MAPK) pathway is activated following treatment of cells with As2O3 and exhibits negative regulatory effects on As2O3-induced apoptosis and growth suppression. In the current study, we sought to identify upstream effector mechanisms by which the p38 pathway is activated by As2O3 in leukemic cells. We found that the MAPK kinase kinase TAO2 (thousand and one amino acid protein kinase 2) is phosphorylated on Ser181 after treatment of NB4, NB4.306, and U937 cells with arsenic. Such phosphorylation was rapid, occurring as early as after 5 minutes of As2O3 treatment. In addition, our data indicate that such phosphorylation occurs downstream of As2O3-induced redox reactions, as demonstrated by increased phosphorylation in cells pretreated with the oxidizing agent buthionine sulfoximine (BSO) and decreased phosphorylation following pretreatment with the reducing agent dithiothreitol (DTT). Arsenic treatment of the cells also resulted in activation of the kinase domain of TAO2, as evidenced in in vitro kinase assay studies using ATF2 as an exogenous substrate. siRNA-mediated TAO2 knockdown resulted in inhibition of As2O3-induced p38 phosphorylation, suggesting that this kinase acts as an upstream effector of the arsenic-activated p38 MAPK pathway. Moreover, in studies to determine the functional relevance of TAO2 in the induction of As2O3-dependent antileukemic responses we found that siRNA-mediated TAO2 knockdown enhanced the suppressive effects of As2O3 on KT1-derived leukemic progenitor (CFU-L) growth in clonogenic assays in methylcellulose. Altogether, our data demonstrate that TAO2 is activated during arsenic treatment of leukemic cells lines and acts as an upstream activator of the p38 MAPK pathway. Such activation appears to occur in a negative feedback regulatory manner to compensate for the suppressive effects of As2O3 on leukemic cell growth. Importantly, these findings raise the possibility that targeting TAO2 may provide a novel approach to enhance the generation of the antileukemic properties of As2O3.