Abstract: Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design: induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), and interim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX. Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those 〈 13y received continuous DEX. In 10/2006 the study was amended due to an unexpectedly high ON incidence in patients 10–12y receiving continuous DEX (28% @ 18 months) compared with historical controls given discontinuous DEX (3.4%). Subsequently all patients ≥ 10y have received discontinuous DEX; it is too early to assess the impact of this change. A comprehensive interim ON analysis was completed 4/2008 (reported as 24-month cumulative incidences). Overall ON incidence is 10.4% (110/1647), and is higher for those age ≥ 10 vs. 〈 10y (15.2 vs 2.6%, p 〈 0.0001, RHR=6.38); 99/110 cases of ON occurred in the older cohort. Among all patients, ON incidence is higher in DEX vs. PRED regimens (11.6 vs 8.7%, p=0.014, RHR 1.64); rates are similar for Capizzi MTX vs. HD-MTX regimens (10.4 vs 9.8%). Among patients ≥ 13y, incidence is higher in DEX vs. PRED regimens (18.9 vs 9.9%, p=0.02, RHR 1.97). There is no difference between regimens for children 〈 10y. Among randomized RER patients ≥ 10y, incidence is higher in DEX vs. PRED regimens (17.2 vs 12.6%, p=0.006, RHR=1.79). For historical comparison, ON incidences by age cohort for RER patients on AALL0232 regimen PC (PRED + Capizzi MTX) vs. CCG-1961 regimen D (double DI with discontinuous DEX) were: 〈 10y 4.1±3.4 vs. 2.0±1.4%, 10–12y 21.9±10.6 vs. 7.1±2.8%, and ≥ 13y 7.1±10.1 vs. 6.6±3.8%. To address these findings, the study was amended 6/2008. Patients ≥ 10y will be non-randomly assigned to induction PRED; the induction steroid randomization will continue for younger patients. Patients of all ages will receive discontinuous DEX during DI and PRED pulses during maintenance. Of note, compared with CCG-1961 the AALL0232 augmented BFM backbone was non-randomly modified in several ways that may affect ON incidence, including the use of pegaspargase during induction, a higher 15 mg intrathecal methotrexate dose for those age ≥ 9y, and monthly DEX instead of PRED maintenance pulses. Heightened awareness among caregivers may also have led to increased recognition and reporting of this toxicity. Using CTCAE v3.0 criteria, clinical ON severity among the 110 patients is: 3% grade 1, 60% grade 2, 35% grade 3, and 2% grade 4. Data regarding surgical intervention are being collected. These findings will directly influence the design of future trials in an effort to lessen the incidence and burden of this toxicity.

Abstract: ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Abstract: First relapse of B-ALL in children and AYAs is a vexing clinical problem with high rates of subsequent relapse and death using conventional treatment approaches. This is especially true in patients with early relapse [high risk (HR), defined as marrow relapse 〈 36 months from diagnosis or isolated extramedullary relapse 〈 18 months from diagnosis] and those with late relapse and minimal residual disease (MRD) of ≥0.1% at the end of re-induction chemotherapy [intermediate risk (IR)] . Allogeneic hematopoietic stem cell transplant (HSCT) is considered the treatment of choice for this population, but many relapsed patients are not able to proceed to HSCT due to adverse events (AEs) from chemotherapy and/or inability to achieve the MRD-negative second remission known to be associated with optimal HSCT outcomes. The CD3-CD19 BiTE® blinatumomab has single agent efficacy in relapsed/refractory B-ALL (pediatrics and adults) and MRD-positive B-ALL (adults), and a favorable toxicity profile. The primary aim of this study was to compare disease-free survival (DFS) of HR/IR first relapse B-ALL patients aged 1-30 years randomized following re-induction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3; Control Arm A) or two 4-week blocks of blinatumomab, each followed by one week of rest (Blina cycles 1 and 2; Experimental Arm B). Patients with ≥25% marrow blasts after Block 1 were ineligible for randomization. After randomized therapy, patients on both arms proceeded to HSCT. Secondary aims included comparisons of the following between Arms A and B: AEs, MRD response (by flow cytometry, central lab), overall survival (OS) and ability to proceed to HSCT. During a planned interim analysis (data cut-off 6/30/19) by the Data Safety and Monitoring Committee, the HR/IR randomization was stopped early. While the improvement in DFS for Arm B did not cross the predefined superiority threshold at the time of interim analysis, the combination of improved DFS, superior OS, lower toxicity, and superior MRD clearance for Arm B relative to Arm A was judged to provide sufficiently compelling evidence to establish a new standard of care. A total of 208 HR/IR patients were randomized (Arm A: 103, Arm B: 105). Baseline characteristics were comparable between arms (Table 1). With median follow up of 1.4 years, the intent-to-treat (ITT) 2-year DFS (% ± standard error) was 41.0 ± 6.2% for Arm A vs. 59.3 ± 5.4% for Arm B (p=0.05, 1-sided per pre-specified statistical plan)(Figure 1A). The ITT 2-year OS was 59.2 ± 6.0% for Arm A vs. 79.4 ± 4.5% for Arm B (p=0.005, 1-sided)(Figure 1B). Among patients with detectable MRD (≥0.01%) at the completion of Block 1 chemotherapy, the proportion that achieved undetectable MRD ( 〈 0.01%) after Block 2 (Arm A) vs. Blina cycle 1 (Arm B) was 21% vs. 79% (p 〈 0.0001)(Table 2). The rates of MRD response were similar with Block 3 or Blina cycle 2 (Table 2). Post-induction toxic deaths occurred in 4 patients on Arm A (all infections) vs. none on Arm B (p=0.05). Relative rates of CTCAEv4 grade ≥3 febrile neutropenia, infections, sepsis and mucositis were strikingly higher for Block 2/3 (Arm A) vs. Blina cycle 1/2 (Arm B): 44%/46% vs. 4%/0%, 41%/61% vs. 10%/11%, 14%/21% vs. 1%/2%, and 25%/7% vs. 0/1% respectively (p 〈 0.001 for all comparisons except mucositis for Block 3 vs. Blina cycle 2, p=0.16). For Arm B, the rate of selected blinatumomab-related AEs in cycle 1/2 were: Cytokine release syndrome (CRS) 22%/1% (grade ≥3 1%/0%); seizure 4%/0% (1%/0%); other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 14%/11% (2%/2%). All blinatumomab-related AEs fully resolved. The rate of patients successfully proceeding from randomization to HSCT (data cut-off 9/30/19) was strikingly different between arms. On Arm A, only 45% (44 of 98 who received randomized therapy) proceeded to HSCT. On Arm B, 73% (75 of 103 who received randomized therapy) proceeded to HSCT (p 〈 0.0001). In conclusion, for children and AYA patients with HR/IR first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as post-reinduction consolidation prior to HSCT, resulting in fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to HSCT and improved disease-free and overall survival. Patients remain in follow up, and prospectively defined analyses of longer-term outcomes will be forthcoming. Disclosures Brown: Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Borowitz:Beckman Coulter: Honoraria. Raetz:Pfizer: Research Funding. Zugmaier:Amgen: Employment, Other: holds stock, Patents & Royalties: & other intellectual property. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Pulsipher:Medac: Honoraria; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Lecture. Hunger:Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Jazz: Honoraria; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Investigational use of blinatumomab

Abstract: Background At initial diagnosis, sentinel cytogenetic (CG) abnormalities differ based on demographic/clinical features and are predictive of relapse risk in B-lymphoblastic leukemia (B-ALL). The relevance of CG at 1st relapse is not well defined. Children's Oncology Group (COG) AALL1331 enrolled non-BCR-ABL1+, non-Down syndrome 1st relapse B-ALL patients (pts) 1-30 years (yr) old. After a common chemotherapy induction (Block 1), pts were risk assigned as: High risk (HR): Early bone marrow (BM) relapse & lt;36 months from diagnosis or isolated extramedullary (IEM) relapse & lt;18 months; Intermediate risk (IR): Late BM relapse ( & gt;36 months) with minimal residual disease (MRD) ≥0.1% at end Block-1 (EB-1); Low risk (LR): Late BM relapse with MRD & lt;0.1% at EB-1; Treatment failure (TF): M3 BM or failure to clear central nervous system at EB-1. The primary objective of the trial for HR/IR pts was to randomly compare post-reinduction therapy with 2 blocks of chemotherapy vs. blinatumomab, followed by allogeneic transplant. We previously reported the superiority of blinatumomab for HR/IR pts (Brown, ASH 2019). We hypothesized that CG would correlate with clinical features at relapse and response to therapy, enhancing relapse risk stratification. Methods CG data (karyotype and FISH) at relapse were centrally reviewed. CG groups were defined as: favorable (fav) (double trisomies (DT) or ETV6-RUNX1), unfavorable (unfav) (hypodiploid, KMT2A-rearranged (KMT2A-R) or iAMP21), and neutral (all others). Of 662 eligible pts, 130 IEM relapses were excluded, since CG data were not available due to lack of BM involvement. Of 532 BM relapses, CG data were available for 394 (74%); this group was used for associations of CG with clinical features and response to Block 1. Of 188 BM relapses risk assigned HR/IR and randomized, CG data were available for 147 (78%; 72 Arm A chemotherapy, 75 Arm B blinatumomab); this group was used for associations of CG with response to randomized post-reinduction therapy. CG distributions at initial diagnosis were based on data from over 16,000 pts enrolled on COG upfront trials from 1996-2014. Statistical comparisons used Pearson's chi-squared, Fisher's exact, Wilcoxon rank sum, or logrank test as appropriate. All p values are two-sided. Results As expected, unfav CG were more common at relapse compared to diagnosis (17% vs 7% p & lt;0.001), and the opposite for fav CG (22% vs 42% p & lt;0.001). Also expected was the younger age at relapse for the fav (median 8 yr) and KMT2A-R (median 2 yr) CG vs. others (median 12 yr, p=0.002). WBC at relapse was higher in the KMT2A-R (median 11k/uL), but similar in all others (median 5k/uL, p=0.041). Time from diagnosis to relapse differed by CG group, with late BM relapses comprising 79% of fav vs. 61% of neutral vs. 48% of unfav (p & lt;0.001). EB-1 MRD-negative rates were highest for fav (53%), intermediate for neutral (38%) and lowest for unfav (25%, p=0.002). Interestingly, in fav CG group, 62% of ETV6-RUNX1 vs. 40% of DT were EB-1 MRD-negative (p=0.043), suggesting that as for newly diagnosed pts, MRD clearance during relapse reinduction may be slower for DT than for ETV6-RUNX1. EB-1 risk assignments differed significantly by CG group, with rates for fav/neutral/unfav CG of 57%/35%/27% for LR, 16%/31%/34% for HR, and 3%/7%/7% for TF (p & lt;0.01). After 1st course of randomized therapy for HR/IR pts, the rate of EB-2 MRD negativity was (as previously reported) much higher for arm B (75%) vs arm A (25%, p & lt;0.001). Interestingly, EB-2 MRD clearance rates did not vary significantly by CG group for either randomized arm. There was, however, an influence of CG group on survival for arm B, but not for arm A. The 2 yr DFS/OS for fav CG on arm B was 77%/93%, vs. 49%/65% for neutral and 49%/49% for unfav (p=0.069 for DFS, p=0.035 for OS, univariate analysis). For arm A, DFS/OS was similar and consistently poor in all three groups (44%/52% fav vs. 49%/61% neutral and 39%/61% unfav, p=0.92 for DFS, p=0.62 for OS) (Table 1). Conclusions Pts with fav CG B-ALL relapse later and are more likely to achieve MRD negativity after reinduction chemotherapy, resulting in higher rates of LR risk assignment. Interestingly, while the superior MRD clearance with blinatumomab vs. chemotherapy is seen in all CG groups, this only translated into higher rates of DFS/OS in the fav CG group. Thus, the influence of CG on outcomes after 1st relapse may differ based on whether chemotherapy or immunotherapy is used as post-reinduction consolidation. Disclosures Gore: Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Brown:Jazz: Honoraria; Servier: Honoraria; Janssen: Consultancy; Novartis: Consultancy.

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: Standard treatment of children and AYAs with LR first relapse of B-ALL [LR defined as bone marrow with or without extramedullary (BM±EM) relapse ≥36 months or isolated EM (IEM) relapse ≥18 months from initial diagnosis, and low ( & lt;0.1%) BM minimal residual disease (MRD) at the end of reinduction chemotherapy] consists of approximately 2 years of standard chemotherapy without hematopoietic stem cell transplant. The objective of this study was to compare survival [primary: disease-free (DFS); secondary: overall (OS)] of LR first relapse B-ALL patients aged 1-30 years randomized following reinduction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3) followed by continuation and maintenance chemotherapy of UKALLR3 (chemotherapy control) vs. the same except with integration of three 4-week cycles of blinatumomab, one replacing Block 3 chemotherapy and two added during continuation and maintenance (blinatumomab experimental). All patients with central nervous system (CNS) leukemia at relapse (isolated or combined with BM relapse) received additional intensified CNS-directed chemotherapy (intrathecal and systemic) and 1800 cGy of cranial radiation during maintenance. Patients with testicular leukemia at relapse that persisted after Block 1 reinduction received 2400 cGy testicular radiation during Block 2. A total of 255 LR patients were randomized: Blinatumomab: 127; Chemotherapy: 128. Selected baseline characteristics are shown in Table 1. With median follow up of 2.9 years (data cut-off 12/31/20), the intent-to-treat (ITT) 4-year DFS (%±standard error) was 61.2±5.5% for blinatumomab vs. 48.2±6.0% for chemotherapy (p=0.15, 1-sided stratified log-rank test per pre-specified statistical plan). The 4-year OS was 91.6±3.0% for blinatumomab vs. 83.3±4.5% for chemotherapy (p=0.096). Striking differences in DFS and blinatumomab efficacy were noted according to site of first relapse (Figure 1). For BM±EM relapses, 4-year DFS was 74.0±6.4% for blinatumomab vs. 51.8±7.9% for chemotherapy (p=0.016), and 4-year OS was 96.6±2.5% for blinatumomab vs. 84.4±5.6% for chemotherapy (p=0.013). Significant predictors of DFS in Cox multivariable regression for BM±EM relapses included treatment arm, age at relapse, and time from diagnosis to first relapse (Table 2). For IEM relapses, 4-year DFS was 34.2±8.6% for blinatumomab vs. 39.3±8.5% for chemotherapy (p=0.73), and 4-year OS was 81.7±7.0% for blinatumomab vs. 80.8±7.2% for chemotherapy (p=0.61). The only predictor of DFS in IEM patients was site of first relapse [hazard ratio for testes vs. CNS 0.19 (0.04-0.87), p=0.015]. The difference in DFS between BM±EM and IEM patients was driven by excess of second relapse in isolated CNS relapse patients (Table 3). Of 64 CNS relapses, 39 (61%) had a second relapse, of which 28 (72%) were also isolated CNS, with no difference by treatment arm. Of the 191 remaining patients, 35 (18%) had a second relapse [13 (14%) blinatumomab (6 BM±EM, 7 IEM), 22 (23%) chemotherapy (15 BM±EM, 7 IEM)] . Blinatumomab cycle 1 was better tolerated than Block 3 chemotherapy, with lower rates of CTCAEv4 grade ≥3 febrile neutropenia (3% vs. 47%, p & lt;0.001), infections (5% vs. 51%, p & lt;0.001), anemia (12% vs. 57%, p & lt;0.001) and mucositis (1% vs. 7%, p=0.018). The rate of selected blinatumomab-related adverse events (AEs) in blinatumomab cycles 1/2/3 (all grades) were: Cytokine release syndrome (CRS) 12%/7%/7%, seizure 3%/1%/3%; other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 19%/9%/5%. All blinatumomab-related AEs were fully reversible. In conclusion, for children and AYA patients with LR first relapse of B-ALL, while there was no significant difference in outcome for the entire population, the blinatumomab arm was superior to the standard chemotherapy arm for patients with BM±EM relapse, establishing this regimen as a new standard therapy for these patients. The blinatumomab arm was not superior in IEM relapse. Isolated CNS relapse patients had a strikingly high relapse rate on both arms; better treatments are urgently needed for this subset. Figure 1 Figure 1. Disclosures Brown: Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; KIte: Membership on an entity's Board of Directors or advisory committees. Borowitz: Amgen, Blueprint Medicines: Honoraria. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Gore: Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Mirati: Current equity holder in publicly-traded company; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; OnKure: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Sanofi Paris: Current equity holder in publicly-traded company. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Hunger: Amgen: Current equity holder in publicly-traded company. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Blinatumomab, used as post-reinduction consolidation without regard to MRD

Abstract: Introduction: Vincristine intensification has the potential to improve outcomes in ALL, but severe neurotoxicity has prohibited escalation beyond standard capped doses. Vincristine sulfate liposome injection, VSLI (Marqibo®) is a liposomal formulation of aqueous vincristine that optimizes pharmacokinetics, prolongs circulating half-life, increases tissue penetration, and may be better tolerated than standard vincristine. VSLI received accelerated FDA approval for adults with relapsed/refractory (r/r) ALL, at a dose of 2.25 mg/m 2/dose without a dose cap. A phase I trial of VSLI in children and young adults with r/r ALL demonstrated safety, tolerability, and evidence for single-agent activity (Shah NN, et al. Pediatric Blood Cancer, 2016). Studies of VSLI with combination chemotherapy in children have not been conducted. With emerging data supporting improved outcomes for patients (pts) with r/r ALL who proceed to immunotherapy with low-burden disease, identifying safe and effective reinduction regimens to reduce disease burden remains a priority. Methods: This multicenter pilot study conducted through the TACL consortium was designed to assess safety and feasibility of VSLI as replacement for standard vincristine with combination chemotherapy for individuals between the ages of 2-21 years with r/r ALL. Two dose levels of VSLI were utilized without a dose cap: Dose level 1 (DL1) 1.5 mg/m 2/dose; and Dose level 2 (DL2) 2.0 mg/m 2/dose. Treatment success was determined by both 1) the absence of a dose-limiting toxicity (DLT) (as defined by any & gt; Grade 3 regimen related non-hematologic toxicity which precluded completion of the pre-specified treatment course or from proceeding to subsequent therapy within 7 weeks) and 2) completion of the prescribed treatment regimen. Adverse event grading was based on CTCAE v4.03. Bone marrow aspirate was used for standard morphologic assessment of response with central flow cytometric analysis for minimal residual disease (MRD) determination with a cut-off of & lt;0.01% of mononuclear cells considered as MRD negative. This analysis reports the toxicities and feasibilities for Cohort A which constituted the 4-drug UK ALL-R3 induction regimen consisting of VSLI, dexamethasone, mitoxantrone, and asparaginase (pegaspargase or Erwinia). Results: A total of 10 pts with r/r B-ALL, median age 13.4 (range 5.0-17.3 years) were treated on Cohort A. Pts were heavily pre-treated, with 3 having relapsed after prior allogeneic stem cell transplantation; 8 of 10 had an M3 marrow ( & gt;/= 25% blasts). The first 4 pts were treated at DL1. All 4 were evaluable for toxicity and response and met the criteria for treatment success, facilitating dose escalation to DL2. At DL2, 4 pts were treated, with 2 experiencing DLT, including one grade (Gr) 5 event (Table 1). Two additional pts were subsequently treated at DL1 and achieved treatment success, confirming safety and feasibility of DL1 with a VSLI dose of 1.5 mg/m 2 in combination with UK ALL-R3 4-drug induction. Nine of 10 (90%) pts achieved a morphologic complete remission (CR), 5 of which were MRD negative. The median VSLI dose administered at DL1 was 2.3 mg (range, 1.8-3.2 mg) and at DL2 was 2.2 mg (range, 1.5-3.3 mg) demonstrating the feasibility of dosing beyond the standard vincristine dose-cap of 2 mg. Transient aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were seen in 8 pts, 6 of whom had a grade 1-2 toxicity. Gr 3 hepatic toxicities were seen in 3 pts: 1 each with ALT elevation and hyperbilirubinemia; ALT and AST elevation; gamma-glutamyl transferase elevation. Toxicities were generally consistent with the UK ALL-R3 regimen. Conclusions: In children with r/r ALL, the combination of UK ALL-R3 with VSLI was highly effective with an acceptable safety profile. DL1 (1.5 mg/m 2/dose) was found to be the maximum tolerated dose in combination with this intensive re-induction regimen. The trial continues to enroll at DL1 in the expansion phase to obtain additional safety and response data with this 4-drug regimen. Additionally, 2 cohorts have been added to gain further experience with VSLI in combination with 3-drug induction (Cohort B: UK ALL-R3 without mitoxantrone) and with ALL maintenance chemotherapy (Cohort C: dexamethasone, methotrexate, mercaptopurine). VSLI has potential as a vincristine dose-intensification strategy in combination with reinduction chemotherapy for r/r ALL in pediatric patients. Figure 1 Figure 1. Disclosures Hermiston: Novartis: Consultancy; Sobi: Consultancy. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Wayne: Spectrum/Acrotech: Research Funding; KITE/Gilead: Research Funding.

Abstract: Background: Chimeric antigen receptor T-cells (CAR-T) have emerged as a promising treatment for children with relapsed/refractory acute lymphoblastic leukemia (ALL). While CAR-T outcomes have been published, little data exist on how to manage these patients for the weeks to months between T-cell collection and CAR-T infusion. Unlike stem cell transplant (SCT), where higher burden of disease is associated with poor outcomes and is often a contraindication, successful outcomes for children with high disease burden pre-CAR-T have been demonstrated. Thus, traditional high-intensity chemotherapy for relapsed ALL that aims to minimize disease burden but carries significant morbidity may not be the best option for pre-CAR-T populations. We thus compared our population-based experience in using high vs. low-intensity chemotherapy regimens to bridge patients in terms of toxicity, inpatient days, and success in reaching CAR-T infusion. Methods: The Hospital for Sick Children (Sickkids) is the provincial referral centre for cellular therapy for children in Ontario, Canada. All Ontario children referred to Sickkids between 2014-2018 for first T-cell collection with intent to proceed to CAR-T therapy were included and followed until CAR-T infusion, decision to pursue alternative therapy, or death. Bridging regimen details were collected and classified as low vs. high intensity based on whether such therapy was likely associated with 〉 7 days of neutropenia. Disease and outcome variables were compared between high vs. low intensity regimens using Chi squared, Fisher's exact, or Wilcoxon tests. Results: The cohort included 32 patients with a median age of 9.7 years at the time of first T-cell collection [interquartile range (IQR) 6.0-12.3]. The median number of previous relapses was 2 (IQR 1-2), 14 (44.0%) had undergone prior SCT, and 4 (12.5%) had Down syndrome. The vast majority of patients (28, 87.5%) were successfully bridged to receive CAR-T therapy with a median time to infusion of 81 days (IQR 60-105). Two patients experienced manufacturing failure and pursued SCT instead, 1 died of toxicity, and 1 was still awaiting infusion at the end of the study period. Low-intensity bridging regimens were used following collection for 19 (59.4%) patients, most often based on low-dose intravenous methotrexate, 3-drug induction (vincristine/steroids/asparaginase), or maintenance therapy. The most common high-intensity regimens included cyclophosphamide/etoposide, high dose cytarabine, or 4-drug induction (vincristine/steroids/asparaginase/anthracycline). Patients receiving high-intensity therapy did not seem to have more aggressive disease prior to starting bridging treatment (as indicated by peripheral blasts, number of previous relapses, prior SCT) that would have justified choosing high-intensity treatments. Patients receiving initial high-intensity regimens were however more likely to have been collected in first half of the study period (Table 1). Patients receiving initial high-intensity regimens also developed more microbiologically documented infections and experienced a greater number of inpatient days (Table 1). Excluding patients ex periencing manufacturing failure or still awaiting CAR-T at the end of the study period, the likelihood of receiving CAR-T also did not vary [high-intensity regimen - 11/12 (91.7%) vs. low-intensity regimen - 17/17 (100%); p=0.41]. Conclusions: We demonstrate in our population-based cohort of heavily pre-treated and high-risk patients that initial low-intensity chemotherapy had a very high likelihood of successfully bridging children to CAR-T infusion. Low-intensity bridging regimens were associated with lower rates of toxicity and higher quality of life as indicated by fewer inpatient days. Low-intensity regimens should be considered the first line option in this population. Disclosures Grupp: Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 3076 Poster Board III-13 Background Despite improvements in survival rates for pediatric ALL and AML, many children still relapse with dismal outcomes. It is critical to develop non-anthracycline containing salvage regimens that induce remission and allow for hematopoietic stem cell transplantation (HSCT). Clofarabine is a nucleoside analog that potently inhibits ribonucleotide reductase and DNA polymerase αa. The biochemical modulation of cytarabine by clofarabine via inhibition of ribonucleotide reductase is well established, and this combination has been studied in adults with relapsed AML. Study Design The Children's Oncology Group instituted a Phase I/II study testing the combination of clofarabine and cytarabine in pediatric patients with AML in first relapse and ALL in second or subsequent relapse. We report on the toxicity profile in the Phase I portion of the study. Cytarabine was administered on days 1-5 at a dose of 1 gm/m2 and clofarabine was administered on days 2-6 in varying doses. Cytarabine was given 4 hours after the start of clofarabine to optimize the biochemical modulation of ara-CTP. Patients could receive up to 2 cycles on study. The Phase I portion of the study consisted of a single dose escalation/de-escalation of clofarabine with a fixed dose of cytarabine. For each dose level, 10 patients were enrolled. The first cohort of patients received clofarabine at 40 mg/m2/day (the adult single-agent MTD). Based on safety data on the first cohort, the dose of clofarabine would either be escalated to 52 mg/m2/day (single-agent pediatric MTD) or deescalated to a dose of 30 mg/m2/day. The MTD determined in this dose finding phase would determine the dose for the Phase II efficacy portion of the study. Results Of the 10 patients enrolled on the first cohort, 8 patients had ALL (6 in second relapse, 2 refractory to reinduction) and 2 had AML. Ten patients completed one cycle and 5 patients completed two cycles. In both cycles, the most common toxicities ≥ Grade 3 were fever/neutropenia (7/15 occurrences), infection (6/15), transaminitis (5/15), abdominal pain (3/15), and hypokalemia (4/15). Two ALL patients with prior HSCT had dose-limiting toxicities (DLT's): one with grade 4 fungal infection and pneumonitis and another with grade 4 fungal infection. Neither patient was on antifungal prophylaxis. The MTD was not met, and 10 patients were enrolled on the second cohort (52 mg/m2): 3 patients with ALL in second relapse and 7 with AML. Ten patients completed cycle 1 and 7 completed two cycles. In both cycles, the most common toxicities ≥Grade 3 were diarrhea (3/17), nausea (3/17), febrile neutropenia (5/17), infection (10/17), hyperglycemia (3/17), and hypokalemia (3/17). In this cohort, one AML patient experienced DLT's of prolonged bone marrow aplasia, Grade 4 hypokalemia, Grade 3 nausea, and Grade 3 dehydration. The table below summarizes count recovery data at both dose levels. The median cycle length for patients without ANC and platelet recovery at the 40 mg/m2 level was 22 and 30 days respectively after one course and 19 and 17.5 days respectively after 2 courses. At the 52 mg/m2 dose level, the median cycle length for patients without ANC and platelet recovery was 20 days for each after one course and 23 and 25 days respectively after 2 courses. These numbers suggest that patients without marrow recovery had progressive disease, received alternate chemotherapy, or proceeded to HSCT prior to count recovery, rather than drug-induced prolonged bone marrow aplasia. Conclusions The combination of clofarabine and cytarabine is safe and tolerable in pediatric patients with relapsed acute leukemia. The MTD of clofarabine in combination with cytarabine in pediatric patients with relapsed acute leukemia is 52 mg/m2/day. Disclosures Whitlock: Genzyme: Consultancy.