Raetz, Elizabeth A.

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Abstract Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).

Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD >0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD <0.1% as compared with AALL0434 which used a prednisone-based Induction (AALL1231 Arm A: 69.6%; Arm B: 72.2%; AALL0434: 64.6%; p = 0.02). However, this did not translate into improved survival. Indeed OS, but not EFS was worse on AALL1231 than AALL0434. On-going analyses are investigating the increased mortality on AALL1231, but preliminary analyses suggest a combination of increased toxic deaths and overall poor outcome in the VHR group. On AALL0434, 90.8% of T-ALL pts received CXRT. On AALL1231, 9.5% of subjects were scheduled to receive CXRT (CNS3 T-ALL/T-LL: 5.7%; VHR T-ALL: 4.1%). A comparison of AALL0434 pts that received CXRT with similar AALL1231 pts not receiving CXRT on AALL1231 demonstrated similar EFS (p = 0.14) and OS (p = 0.42) (Table 2). CNS relapse rates were higher in these pts on AALL1231 (4.5%) as compared with AALL0434 (1.7%), but overall relapse rates were the same (6.5% vs 6.4%). Notably the benefit of NEL in AALL0434 was due to reduction of CNS relapses. 128 AALL1231 pts came off protocol therapy after the study was closed for physician or patient/parent choice. Data collection is underway to understand the reasons for removal, including if it was to receive NEL. Conclusions: Outcomes for SR and IR pts with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT. Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of pts. Outcomes for VHR pts were dismal and worse on the bortezomib arm. T-LL pts had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. This is the first trial to demonstrate an OS benefit for de novo pediatric T-LL with a new agent; however, longer follow-up is needed. Therapy intensification allowed elimination of CXRT in the majority of pts without excessive relapse. These results should be interpreted cautiously as the 3-yr OS on AALL1231 was inferior to AALL0434. Nevertheless, incorporating bortezomib into standard therapy for de novo T-LL appears advantageous. Future COG T-ALL/T-LLy trials will build on the positive findings from AALL0434 and AALL1231, balancing intensity while mitigating toxicity to maintain high cure rates without routine cranial radiation. (MLL, SPH, EAR contributed equally) Disclosures Teachey: Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy; Sobi: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Galardy:Abbott: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shimano:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. McKay:Immunogen: Current Employment. Bollard:Mana Therapeutics: Other: IP. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. OffLabel Disclosure: Bortezomib for the treatment of acute lymphoblastic leukemia under an IND

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.

10520 Background: Outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are superior with pediatric-inspired therapy. CALGB 10403, the first US adult cooperative group prospective trial using a pediatric-inspired augmented BFM (ABFM)-based regimen, demonstrated feasibility and improved survival. We examined differences in drug delivery and targeted toxicities in AYAs who received the same therapy on C10403 vs the Children’s Oncology Group (COG) study AALL1131. Methods: The proportion of AYAs receiving full dose (within 10% of protocol- specified) vincristine (VCR) and pegaspargase (PEG) during induction (IND), consolidation (CON), and delayed intensification (DI); the likelihood of selected grade ≥3 adverse events (AEs); and the impact of patient characteristics were compared in AYAs 16-30 years. Targeted AEs with analogous reporting requirements in both studies included hyperbilirubinemia, pancreatitis, sensory neuropathy, and GI/intracranial hemorrhage. Thrombosis, transaminitis and hyperglycemia were not comparably captured. Fisher’s Exact test and logistic regression models were used for analyses. Results: After excluding AYAs removed from study after induction, 87 AALL1131 AYAs (accrued 2012-2016) and 188 C10403 AYAs (accrued 2007-2012) were analyzed with median ages of 17 (16-26) vs 22 (17-30) years, p < 0.001. There was no difference in the intensity of VCR delivery during IND, but in CON and DI, AALL1131 AYAs were more likely to receive all specified VCR (93.1% vs 81.9%, p = 0.02; 92.7% vs 72.1%, p = 0.01). Women were less likely to receive all specified VCR (OR 0.57, 95% CI 0.34-0.94, p = 0.03), and overweight/obese AYAs were somewhat less likely to receive all VCR compared to those considered normal weight (OR 0.88 and 0.59, p = 0.09). More C10403 AYAs were obese/overweight compared to AALL1131 AYAs (p = 0.04). There were no significant differences in dosing of PEG during IND/CON, but in DI AALL1131 AYAs were more likely to receive both doses (75.6% vs 57.1%, p = 0.03). No patient variables impacted delivery of PEG. There was no significant difference in grade ≥3 toxicities captured similarly on both studies. Conclusions: AYAs enrolled on AALL1131 were more likely to receive all protocol-specified VCR and PEG compared to those on C10403. Selected AE rates were comparable, suggesting that older AYAs do not tolerate doses of VCR and PEG for reasons other than toxicity, with body habitus as one potential variable. Further analyses to compare dose density, toxicities, and outcomes experienced by younger AYAs versus older are ongoing.

9513 Background: CD22, a 135kd protein restricted to B-cells, is expressed in > 90% of childhood B-precursor acute lymphoblastic leukemia (ALL). We conducted a feasibility/phase 2 study of epratuzumab, a humanized monoclonal antibody against CD22, with reinduction chemotherapy in children with relapsed CD22+ ALL. Methods: The feasibility portion (n=12) of the study is reported here. Patients with first or later ALL marrow relapse at any time following diagnosis, ± extramedullary disease, with = 25% blasts expressing CD22 and a presenting white blood cell count (WBC) of = 50,000/μl, were eligible. Therapy consisted of a 14-day single agent phase (epratuzumab 360 mg/m2 /dose IV twice weekly × 4 doses), followed by 4 weekly doses of epratuzumab in combination with standard reinduction chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin). Remission induction rates and minimal residual disease (MRD) by flow cytometry were determined at the end of this 6-week period. PK studies were performed by ELISA based immunoassay (prior + 30 minutes after infusions). Results: 12 evaluable patients, median age 10 years (range 3 - 18), were accrued. 9 pts were in 1st (n=5 early; n=4 late), and 3 pts in 2nd or later marrow relapse. The mean (±SD) trough epratuzumab concentration increased from 69±23 to 232±74 μg/ml during the initial 14 days. Surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration in all but one patient, indicating effective targeting of leukemic cells by epratuzumab. The most frequent toxicities were grade 1–2 infusion reactions (n=9). Two dose limiting toxicities occurred: one patient had a Grade 4 seizure of unclear etiology and one patient had asymptomatic Grade 3 ALT elevation. 9 patients achieved a complete remission following chemoimmunotherapy, of whom 7 were MRD-negative. Conclusions: Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and well tolerated in children with relapsed ALL, producing favorable early responses in the majority of patients. The phase II portion of the study is ongoing. [Table: see text]

Abstract Introduction B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor. Methods To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children's Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing. Results Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in "double/triple hit" lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion. We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL. Conclusions These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Disclosures McKay: ImmunoGen Inc.: Employment. Tallman:Orsenix: Other: Advisory board; AROG: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Relling:Shire Pharmaceuticals: Research Funding. Mullighan:Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.

Abstract Abstract 573 Outcomes for children with relapsed ALL remain poor, especially when relapses occur early (<36 months) following initial diagnosis. A factor contributing to poor outcomes is much lower rates of successful induction of second remission (CR2). CD22 is almost universally expressed in children with B-cell precursor (BCP) ALL and we previously demonstrated the safety of adding the anti-CD22 monoclonal antibody, epratuzumab, to reinduction chemotherapy in children with first marrow relapse (Raetz et al, JCO 2008 26:3756-62) (COG ADVL04P2). The primary aim of the second part of the COG ADVL04P2 study was to determine if addition of epratuzumab to an established chemotherapy platform improves rates of CR2 in individuals with BCP ALL and early bone marrow relapse. Children, adolescents and young adults, ages 2–30 years with first early marrow relapse of BCP ALL, with or without extramedullary disease, were eligible for this study. The primary study endpoint was CR2 rate at the end of the first block of chemotherapy plus epratuzumab as compared to the 67% CR2 rate for historical controls (COG AALL01P2; Raetz et al, JCO 2008 26:3971-8) treated with the same chemotherapy without epratuzumab. For addition of epratuzumab to be deemed effective, an improvement in CR2 rate of 13% (67% vs. 80%) was required. Because there is a significant difference in CR2 rate between patients with very early (<18 months from diagnosis) vs. early (18 to <36 months from diagnosis) relapse, the statistical design used a model to account for potential differences in time to relapse between these studies. ADVL04P2 had several stages. In part A, epratuzumab was given alone for 4 doses twice weekly in an upfront window to assess safety and response, followed by AALL01P2 chemotherapy plus epratuzumab weekly during the first block of therapy. In part B, patients received the AALL01P2 3-block platform chemotherapy plus epratuzumab (360 mg/m2/dose) during block 1. Initially during part B, epratuzumab was administered weekly for 4 doses starting on day 1 based on pharmacokinetic (PK) data from adults with lymphoma. However, ADVL04P2 PK data showed that the half-life of epratuzumab was much shorter in children with ALL. Thus, ADVL04P2 was amended to give epratuzumab twice weekly for 8 doses, starting on day 1. This report focuses on ADVL04P2 part B and includes results of both the weekly (B1) and twice weekly (B2) epratuzumab dosing schedules. Between 1/07 and 1/11, 116 patients (114 eligible) were enrolled; 54 on B1 and 60 on B2, including 23 (B1) and 19 (B2) very early relapses. Median age at relapse was 10.2 years for the B1 cohort and 8.4 years for the B2 cohort. Concomitant extramedullary disease was present in 3 and 9 of the B1 and B2 patients, respectively. At the end of block 1, 48 B1 patients and 50 B2 patients were evaluable for response with CR2 achieved in (31/48) 65% of B1 and (33/50) 66% of B2 patients. Minimal residual disease (MRD) was measured by flow cytometry in a COG reference laboratory at the end of block 1. Among the 62 pooled B1 and B2 patients who achieved CR2 and had MRD data available at the end of block 1, 26 (42%) (14/31 B1 and 12/31 B2) were MRD negative (< 0.01%), which was significantly higher than the 25% with chemotherapy alone on AALL01P2 (one-sided p=0.001). The addition of epratuzumab to reinduction chemotherapy was well tolerated with no significant increase in the baseline toxicity observed with the platform regimen alone with either schedule. Toxic deaths occurred in 3 patients (2.6%) during block 1 in part B (2 in B1, 1 in B2), compared to 2.4% with block 1 chemotherapy alone. PK analyses in a cohort of B2 patients showed that the epratuzumab trough serum concentration steadily increased to 501 ± 149 mcg/mL before the final dose on day 25 (n=26). The mean serum half-life of epratuzumab was 17.0 ± 4.9 days (n=17) and was shorter than the value of 23 days observed in adults treated with epratuzumab for indolent non-Hodgkin lymphoma. No patient developed human anti-human antibodies. Epratuzumab, as given on the B1 and B2 schedules was tolerable in combination with chemotherapy in pediatric and young adult patients with early relapsed CD22-positive BCP ALL, but did not improve CR2 rates when compared to historical controls treated with chemotherapy alone. However, among patients who attained a complete remission, those treated with epratuzumab were significantly more likely to become MRD negative as compared to those treated without epratuzumab. Disclosures: Borowitz: BD Biosciences: Research Funding. Goldenberg:Immunomedics, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Wegener:Immunomedics: Employment.

Abstract Background: Children with DS and B-ALL have historically experienced excessive TRM, primarily from infection. Here we provide an interim report on TRM in children with DS and newly diagnosed B-ALL enrolled on Children's Oncology Group (COG) trials for NCI standard risk (SR) (AALL0932) and high risk (HR) B-ALL (AALL1131). Methods: As of 06/30/2015, 203 SR DS-ALL patients have completed Induction on AALL0932 with 146 receiving post-Induction treatment on AALL0932. Eighty-eight HR DS patients have completed Induction on AALL1131, with 80 receiving post-Induction treatment on AALL1131. An additional 26 SR DS patients with poor early response received post-Induction therapy on AALL1131. Adverse events were graded according to NCI CTCAE v4.0, with enhanced data collection for targeted toxicities including infectious toxicities, and enhanced supportive care recommendations. Results: Patient characteristics are summarized in Table 1. TRM on AALL0932 occurred during Induction in 2/203 (1.0%) and post-Induction in 3/146 (2.1%), compared to 17/5528 (0.3%) and 12/3119 (0.4%) in non-DS SR patients (Fisher exact p=0.14 for Induction and p=0.03 for post-Induction). TRM on AALL1131 occurred during Induction in 4/88 (4.5%) and post-Induction in 5/106 (4.7%), compared to 34/2116 (1.6%) and 13/1258 (1.0%) in non-DS AALL1131 patients (p=0.06 for Induction and p=0.01 for post-Induction). Timing, cause, and other circumstances surrounding TRM are provided in Table 2. Gram-negative organisms accounted for the majority of fatal bacterial infections in patients with HR DS-ALL. Conclusion: TRM continues to be higher on current COG trials for patients with DS-ALL compared to non-DS patients. Most of the toxic deaths occur during intensive treatment phases due to infection in the context of profound neutropenia. Patients with HR B-ALL have a higher incidence of toxic death, notably in patients over 15 years of age. Based on our findings, hospitalization and antimicrobial prophylaxis during intensive treatment phases should be considered in children with DS-ALL due to their increased risk of infection-related mortality. Table 1. Patient Characteristics AALL1131 AALL0932 DS-ALL Non-DS ALL DS-ALL Non-DS ALL N 117 2689 207 5619 Median Age at Diagnosis (Years) 10.5 10.3 4.8 4.5 Gender Male 62 1511 117 2981 Female 55 1178 90 2637 Table 2. Treatment-Related Mortality Case Characteristics Case Age Gender Treatment Phase Site of Infection Organism AALL1131 (High Risk) 1 15 F Induction D#29 (RER) Pneumonia, ARDS HMPV (pre-treatment) 2 21 F Induction D#29 (SER) Sepsis 3 17 F Induction D#22 (SER) Sepsis, typhlitis Escherichia coli 4 12 M Induction D#16 (RER) Sepsis, pneumonia (+baseline CHD, AV canal s/p repair 2003) Influenza B 5 19 M Consolidation D#18 Sepsis Citrobacter 6 2 F Delayed Intensification D#101 ARDS/capillary leak (+baseline CHD) Rhinovirus 7 15 F Delayed Intensification D#45 Sepsis, pneumonia Klebsiella, enterovirus, rhinovirus 8 27 M Delayed Intensification D#52 Sepsis Gram negative bacillus 9 14 M Delayed Intensification D#22 Sepsis AALL0932 (Standard Risk) 1 7.3 M Induction Febrile neutropenia, hypotension, cardiorespiratory failure None reported 2 3.0 F Induction Febrile neutropenia, sepsis, liver failure Viridans group Strepococcus coagulase negative staphylococcus HSV, EBV and HHV 3 3.4 M Consolidation Meningitis, brainstem infarction None reported 4 9.7 F Interim Maintenance I Sepsis, Stevens Johnson syndrome/TEN None reported 5 7.2 M Interim Maintenance II Death NOS None reported RER, rapid early responder; SER, slow early responder; CHD, congenital heart disease; AV, atrioventricular; ARDS, acute respiratory distress syndrome; HMPV, human metapneumovirus; TEN, toxic epidermal necrolysis; HSV, herpes simplex virus; EBV, Epstein-Barr virus; HHV, human herpesvirus. Disclosures Hunger: Sigma Tau: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Spectrum Pharmaceuticals: Consultancy.

Abstract Despite improvements in front-line therapy for acute lymphoblastic leukemia (ALL), treatment after relapse remains a critical challenge. Examination of outcome after relapse in a large, recently treated, and unselected population provides a useful benchmark for evaluating new approaches. Survival after relapse was tracked on Children’s Cancer Group (CCG) ALL trials. Relapses were categorized by site (isolated or combined bone marrow relapse (MR); isolated central nervous system relapse (CNSR); isolated testicular relapse (TR)), and time from diagnosis to relapse (early < 18 months; intermediate between 18 and 36 months; late > 36 months). We examined the impact of age, sex, ethnicity, initial risk assignment (standard risk (SR) or higher risk (HR)), immunophenotype, length of first remission (CR1), and site of relapse on outcome in multivariate analyses. A total of 9,585 infants, children, and adolescents with newly diagnosed acute lymphoblastic leukemia were enrolled on CCG trials conducted between 1988 and 2002. We examined survival after relapse for 1,874 children with MR, CNSR, or TR. Survival after relapse by site and time to relapse Site MR CNSR TR Time to Relapse n *survival(%) n *survival(%) n *survival(%) *3-year survival Early 498 10 175 49 15 50 Intermediate 378 23 179 73 35 57 Late 488 53 52 77 54 70 Overall survival for any bone marrow relapse was best for late MR and worst for early MR. Early MR was linked to HR presenting features and T-cell disease. Survival after intermediate or late MR was superior for SR patients (p <.05). Survival was better for CNSR or TR than for MR. Older age at diagnosis, male sex, T cell immunopheno-type, and CNS disease at presentation were significant adverse factors for survival after adjustment for site and time to relapse in multivariate analyses (p<.05). Importantly, in the same multivariate analysis, patients treated on more contemporary trials (CCG1952CCG1953CCG1961, and 1962) had inferior survival rates after relapse when compared to patients treated on earlier trials (CCG 1881CCG 1882CCG 1883CCG 1891CCG 1901, and 1922) (p<.001). Importantly, these data from the analysis of a large, unselected group of patients indicates that features at initial presentation and prior therapy influences outcome following relapse. The inferior survival rates of those relapsing on more intensive protocols likely reflects particularly aggressive and chemoresistant disease leading to poor salvage. Increasing the intensity of retrieval therapy is unlikely to improve after relapse and novel therapeutic approaches that target these resistant leukemias are urgently needed for successful treatment of relapsed ALL.