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: Background: Over 4300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. A national collaborative program, PRecision Oncology For Young peopLE (PROFYLE), was created with the goal to develop and implement a pipeline providing access to tumor molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for CAYA with hard-to-treat cancers. Design: PROFYLE unites 21 institutions, building upon 3 pre-existing regional pediatric precision oncology programs (Personalized Oncogenomics (POG), SickKids Cancer Sequencing (KiCS), and Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood (TRICEPS)). PROFYLE nodes (genomics/bioinformatics, proteomics, modeling, biomarkers, data/biobanking, therapeutics, bioethics, policy, AYA) are unified by a shared governance structure. PROFYLE includes genomic and transcriptomic sequencing of paired germline/cancer fresh/frozen samples. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-treat cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling referral is provided to the treating oncologist. Results: To date, & gt;800 CAYA are enrolled in PROFYLE and POG, KiCS, TRICEPS. Cancer diagnoses: 35% sarcoma, 18% leukemia/lymphoma, 14% CNS tumor, 14% neuroblastoma, 19% other. At study entry, 44% of participants had not relapsed, 39% 1 relapse, 14% 2 relapses, and 3% 3+ relapses. 13% had a cancer-predisposing pathogenic/likely pathogenic germline variant, 39% had ≥1 potentially actionable somatic alteration, and 13% had a therapeutically targetable somatic alteration. The most frequent classes of alterations were RAS/MAPK, immune checkpoint, cell cycle, DNA repair, epigenetic, PI3K/AKT/mTOR, RTK. Of clinicians who reported the utility of results, 78% indicated the findings had the potential to inform a medical decision. Future Directions: We will build on PROFYLE's success by addressing the challenge of real-time availability of target-based therapies through innovative clinical trial strategies incorporating new drugs, off-label use, drug combinations, basket and single patient study designs to enable improved access to therapies for CAYA with actionable molecular targets. We will work on policy-relevant research to facilitate implementation of precision oncology care for CAYA in Canada. We will leverage knowledge developed by PROFYLE thus far by integrating omics, modeling and biomarkers research in the trials being developed. Citation Format: Stephanie A. Grover, Thierry Alcindor, Jason N. Berman, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, David D. Eisenstat, Conrad V. Fernandez, Paul E. Grundy, Abha Gupta, Cynthia Hawkins, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Michael F. Moran, Daniel A. Morgenstern, Shahrad R. Rassekh, Adam Shlien, Daniel Sinnett, Poul H. Sorensen, Patrick J. Sullivan, Michael D. Taylor, Anita Villani, James A. Whitlock, David Malkin, on behalf of the Terry Fox PROFYLE Consortium. PROFYLE: The pan-Canadian precision oncology program for children, adolescents and young adults with hard-to-treat cancer [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 636.

Abstract: Blinatumomab plus chemotherapy is safe, and improves outcomes for low-risk relapsed ALL in the marrow.

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: While survival in paediatric acute lymphoblastic leukaemia ( ALL ) is excellent, survival following relapse is poor. Previous studies suggest proteasome inhibition with chemotherapy improves relapse ALL response rates. This phase 2 Children's Oncology Group study tested the hypothesis that adding the proteasome inhibitor bortezomib to chemotherapy increases complete response rates ( CR 2). Evaluable patients ( n  = 135, 103 B‐ ALL , 22 T‐ ALL , 10 T‐lymphoblastic lymphoma) were treated with reinduction chemotherapy plus bortezomib. Overall CR 2 rates were 68 ± 5% for precursor B‐ ALL patients ( 〈 21 years of age), 63 ± 7% for very early relapse ( 〈 18 months from diagnosis) and 72 ± 6% for early relapse (18–36 months from diagnosis). Relapsed T‐ ALL patients had an encouraging CR 2 rate of 68 ± 10%. End of induction minimal residual disease ( MRD ) significantly predicted survival. MRD negative ( MRD neg; MRD 〈 0·01%) rates increased from 29% (post‐cycle 1) to 64% following cycle 3. Very early relapse, end‐of‐induction MRD neg precursor B‐ ALL patients had 70 ± 14% 3‐year event‐free ( EFS ) and overall survival ( OS ) rates, vs. 3‐year EFS / OS of 0–3% ( P  = 0·0001) for MRD pos ( MRD ≥0·01) patients. Early relapse patients had similar outcomes ( MRD neg 3‐year EFS / OS 58–65% vs. MRD pos 10–19%, EFS P  = 0·0014). These data suggest that adding bortezomib to chemotherapy in certain ALL subgroups, such as T‐cell ALL , is worthy of further investigation. This study is registered at http://www.clinical.trials.gov as NCT 00873093.

Abstract: Introduction: Over 4300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom will have refractory or metastatic disease or will relapse with a very poor prognosis. Most CAYA cancer survivors suffer significant late effects that impose an enormous burden to them, their family and the health care system. To address this urgent medical and socioeconomic need, a pan-Canadian collaborative program, PRecision Oncology For Young peopLE (PROFYLE), was created with the objective to develop and implement the first Canadian precision oncology pipeline providing access to tumour molecular profiling with the aim of identifying novel targeted therapeutic options in a clinically relevant timeframe for CAYA with hard-to-treat cancer. Design: Prior to PROFYLE, 3 programs (Personalized Oncogenomics Project (POG), SickKids Cancer Sequencing Program (KiCS), and Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood (TRICEPS)) constituted the bulk of childhood precision oncology efforts in Canada. PROFYLE was designed to unite and build upon them, and consists of interconnected nodes including: genomics/bioinformatics, proteomics, cancer modeling, biomarkers, biobanking/data repositories, therapeutics/clinical trial design and biomedical ethics; unified by a shared governance structure. There are 16+ institutions in the PROFYLE consortium. The PROFYLE profiling strategy consists of initial reporting from a & gt;800 cancer gene panel, followed by whole genome (paired germline/cancer samples) and whole transcriptome analyses. Eligibility criteria: ≤29y; treatment at a Canadian oncology center; diagnosis with a hard-to-treat cancer. Profiling results are reviewed by multidisciplinary Molecular Tumour Boards. A patient-specific molecular research report including summary of results and recommendations (actionable finding, potential targeted therapies, any open clinical trials which the patient may be eligible for, change of diagnosis, and/or referral for genetic counselling) is provided to the treating oncologist. Results: To date, 644 patients have taken part in PROFYLE (n=338) and POG, KiCS, TRICEPS. For the first 100 participants, cancer diagnoses include 43 sarcomas, 23 CNS tumors, 10 leukemia and lymphomas, 10 neuroblastoma and 14 other rare cancers. At study entry, 48% had not yet relapsed, 40% 1 relapse, 10% 2 relapses, and 2% 3+ relapses. 13 had a cancer-predisposing germline mutation and 82 had at least one potentially actionable somatic alteration. The most commonly mutated genes/pathways included TP53, CDNK2A/B, FGFR, MYC, and FLT1/3/4. 82% had results/recommendations from the MTB that informed a medical decision to alter diagnosis, prognosis, or treatment of their disease. In 71%, management recommendations were provided. Analyses of the complete dataset will be presented at the meeting. Conclusion: The goal of developing a national precision oncology pipeline has been realized through the establishment of the PROFYLE initiative. PROFYLE continues to grow through increased recruitment, additional institutions, contribution of new knowledge to the field of precision oncology, improving access to clinical trials for CAYA patients, and advocacy and partnerships on local, national and international scales. Citation Format: Stephanie A. Grover, Jason N. Berman, Jennifer A. Chan, Rebecca J. Deyell, David D. Eisenstat, Conrad V. Fernandez, Paul E. Grundy, Cynthia Hawkins, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Michael Moran, Shahrad R. Rassekh, Adam Shlien, Daniel Sinnett, Poul H. Sorensen, Patrick J. Sullivan, Michael D. Taylor, Anita Villani, James A. Whitlock, David Malkin, on behalf of the Terry Fox PROFYLE Consortium. Terry Fox PRecision Oncology For Young peopLE (PROFYLE): A Canadian precision medicine program for children, adolescents and young adults with hard-to-treat cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5413.

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.