Abstract: 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 & gt;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 & lt;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

Abstract: 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: Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

Abstract: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children’s Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen. Patients and Methods COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase. Results AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%–89.5%) and 89.4% (95% CI, 85.7%–93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement. Conclusion AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Abstract: Nelarabine has shown impressive single agent clinical activity in T‐cell acute lymphoblastic leukemia (T‐ALL), but has been associated with significant neurotoxicities in heavily pre‐treated patients. We showed previously that it was safe to add nelarabine to a BFM‐86 chemotherapy backbone (AALL00P2). Children's Oncology Group (COG) AALL0434 is a Phase III study designed to test the safety and efficacy of nelarabine when incorporated into a COG augmented BFM–based regimen, which increases exposure to agents with potential neurotoxicity compared to the historical AALL00P2 regimen. Procedure AALL0434 included a safety phase to assess nelarabine toxicity. Patients with high‐risk (HR) T‐ALL were randomized to receive Capizzi‐style escalating methotrexate (MTX) plus pegaspargase or high dose (HD) MTX with/without six five‐days courses of nelarabine. We report results from 94 patients who participated in the initial safety phase of the study. Results There were no differences in the incidence of peripheral motor neuropathies, sensory neuropathies or central neurotoxicities among those randomized to the nelarabine (n = 47) and non‐nelarabine arms (n = 47). Conclusions The addition of nelarabine to COG‐augmented BFM chemotherapy regimen is safe and feasible. The ongoing AALL0434 Efficacy Phase will determine whether the addition of nelarabine treatment improves outcome for patients with T‐ALL. Pediatr Blood Cancer 2015;62:1176–1183. © 2015 Wiley Periodicals, Inc.

Abstract: AALL08P1 was designed to determine whether biweekly intensified pegaspargase (I-PEG) was feasible and safe in pediatric patients with newly diagnosed high-risk B-precursor lymphoblastic leukemia when given with Children’s Oncology Group hemiaugmented BFM therapy. High-risk average (HR-Avg) patients received standard pegaspargase dosing (6 doses), whereas high-risk high (HR-High) patients received I-PEG biweekly from the start of Consolidation until day 1 of Maintenance. Feasibility and safety were defined in advance as ≥65% of patients tolerating at least 8 doses of I-PEG and 90% requiring ≤49 weeks from day 1 of Consolidation to the initiation of Maintenance. Targeted toxicities included allergic reactions, anaphylaxis, pancreatitis, thrombosis, bleeding, central nervous system events, and sepsis. AALL08P1 enrolled 104 patients; 54 were classified as HR-Avg and 30 as HR-High after completion of induction therapy. Only 53% (16/30) of the HR-High patients received ≥8 total doses of I-PEG and 50% (15/30) took ≤49 weeks from start of Consolidation to the initiation of Maintenance. I-PEG did not significantly increase grade 2 to 5 targeted toxicities. I-PEG was not feasible or safe as defined in AALL08P1. Complete assessment of this regimen was limited due to removal of patients from I-PEG regimen and early closure of the study.

Abstract: Introduction: Salvage therapies in children and young adults with relapsed T-ALL are successful in 〈 10% of patients, thus relapse prevention is a first priority. Contemporary strategies have included the use of intensified multi-agent regimens, novel therapies, and alloHSCT. COG AALL0434 did not include an alloHSCT treatment arm. To mitigate the risk of relapse, some patients were taken off study and, at investigator discretion, referred for alloHSCT. We retrospectively collected data to identify which patients were taken off study, either during induction, or after end-induction risk assignment to receive alloHSCT, for reasons other than relapse. In particular, it was unknown how alloHSCT affected the outcomes for patients with specific subsets of disease, such as induction failure (IF) or with the early thymic precursor (ETP) phenotype. Patients and Methods: From 2007-2014, AALL0434 enrolled 1,895 patients (1,596 T-ALL) and included a 2 x 2 pseudo-factorial randomization using a COG-modified BFM regimen. Patients were randomized to receive escalating dose methotrexate without leucovorin rescue plus pegaspargase (CMTX) or High Dose MTX (HDMTX) with leucovorin rescue in a single Interim Maintenance phase, with or without six 5-day courses of nelarabine. No patients were risk stratified on the basis of ETP. Participants with ≥ 25% marrow blasts on day 29 of induction (IF) were assigned to receive HDMTX with nelarabine. All patients with intermediate risk (IR), high risk (HR) or IF received cranial irradiation. Results: Among 1385 eligible, evaluable T-ALL patients for whom survey information was available, 333 (24%) were taken off therapy during induction prior to randomization. Thirty-two (9.6%) of these 333 subsequently underwent alloHSCT (19 with M1, 9 with M2 and 4 with unknown Day 29 marrow status). At the end of induction, 1052 patients were risk stratified and consented to randomization. Of these, 43 patients (4.3%) were subsequently taken off protocol therapy for alloHSCT [0 low risk (LR), 2 IR, 21 HR and 20 IF]. For the 75 patients who were taken off protocol therapy during or after induction and underwent alloHSCT, time to transplantation from end induction ranged from 1 to 9 months (median 5) for the 20 IF patients, and from 1 to 30 months (median 4) for the 55 patients who achieved CR1. A variety of conditioning regimens were used, but most (80%) included total body irradiation. Five types of alloHSCTs were employed: matched unrelated in 37 (50%), matched related in 28 (38%), mismatched unrelated in 7 (10%), and mismatched related and unknown (1 each (1.4%)). Stem cells sources were bone marrow in 50 (67%), umbilical cord blood in 14 (19%) and peripheral blood in 11 (15%). Multivariate analyses on all 75 patients (adjusting for treatment arm and risk group, and using time-dependent covariates for time to HSCT) showed worse outcomes for those who received alloHSCT versus chemotherapy [Hazard ratio 3.46 (95% Confidence Interval 1.39 - 8.60); P = 0.008] . For IF patients, there was no difference in outcome for those receiving chemotherapy versus alloHSCT [Hazard Ratio 0.75 (95% CI 0.27-2.14); P = 0.60]. Centrally determined ETP status was available for 1123 (81%) of the subjects (Table), which were categorized as ETP (11%), Near ETP (17%) and Not ETP (72%) (Wood, BL: Blood 2014: [21] 1). Most patients were not taken off therapy during induction, but among those who were and had ETP/Near ETP, 21 of 28 (75%) received alloHSCT versus 71 of 251 (28%) who received chemotherapy alone (Fischer's exact test, P 〈 0.001). In multivariate analyses adjusting for ETP status, alloHSCT (n=66) was associated with inferior EFS compared to chemotherapy [Hazard ratio 2.81 (95% CI of 1.49-5.31); P = 0.001], and ETP status did not have a statistically significant impact on EFS [Hazard Ratio 1.36 (95% CI of 0.87-2.120; P = 0.18] . Conclusions: Our findings showed that only ~5% of participants in AALL0434 received alloHSCT, and that alloHSCT was employed in about half of those patients with IF. There was no EFS advantage for patients who failed induction and subsequently received alloHSCT. Patients were taken off protocol therapy and transplanted for a variety of reasons, which introduced heterogeneity. However, compared to those who received alloHSCT off therapy, we found that survival advantages favored those who received chemotherapy, regardless of ETP status. Table. Table. Disclosures No relevant conflicts of interest to declare.

Abstract: For children, adolescents and young adults with T-lineage acute lymphoblastic leukemia, event free survival (EFS) following relapse is 〈 10%. We recently showed that MLL-AF6, del3'MLL and other re-arrangements of the mixed lineage leukemia (MLL-R; KMT2A) molecular repertoire are associated with induction failure (IF) and an inferior EFS (Matlawska-Wasowska et al., Leukemia, 2016). However, we found that AF10 (MLLT10) gene structural alterations (AF10-R) did not confer a worse prognosis. While deregulation of HOXA9/10 is a hallmark of all MLL-R and AF10 lesions, its over-expression does not predict outcome or guide therapeutic decisions. Because there are currently no molecular features that inform treatment strategies in T-ALL, we hypothesized that supervised profiling of well-characterized cases might identify biologically relevant genes and signaling pathways for targeted T-ALL therapy. Using Affymetrix U133 Plus 2.0 microarray we performed a retrospective study of 100 T-ALL patients enrolled onto COG ALL0434. We performed a 3-way analysis of MLL-R Cases (n = 12), AF10-R Cases (n = 9), and Other T-ALL Cases (n = 79), and identified 330 probe sets that could discriminate between these groups. For the MLL-R Cases and AF10-R Cases, 258 and 40 probe sets, respectively, were uniquely different compared to Other T-ALL Cases. Within the MLL-R Cases group, the most deregulated genes included HOXA genes, MYO6, which encodesATP-dependent motor protein, SKAP2, a substrate of Src family kinases, transcriptional/translational regulators RUNX2, TCF4, SMAD1, CPEB2 ( 〉 3-fold, P 〈 0.05) and interestingly WHAMMP2/WHAMMP3, and GOLGA8I pseudogenes ( 〉 3-fold, P 〈 0.05). For the AF10-R cases, we found that MEIS1, HOXA3, 5, 7, 9/10, SPAG6, BMI1, and COMMD3 expression were deregulated, similar to the findings of others. We next identified genes that could discriminate between MLL-R and AF10-R cases. Among the most overexpressed genes, we identified MYO6, RUNX2, CPEB2, ZNF827 and TCF4 ( 〉 3-fold, FDR 〈 0.05) indicating that MLL-R encompass a specific biological subset, which collectively drive a unique oncogenic transcriptional program. The most downregulated gene in both MLL- and AF10-R cases was QKI, which encodes RNA-binding protein involved in alternative splicing ( 〉 3-fold, P 〈 0.05). Since MLL-AF6 confers an inferior outcome, we sought to determine which genes discriminate between MLL-AF6 (n = 5) and MLL-ENL (n = 5). Among the 26 discriminatory probes sets, we found two, MLLT4 and uncharacterized RP11-38P22 that were over-expressed and 24 were underexpressed, including SMAD1, CHI3L2, MYOM2 between AF6 and ENL, respectively ( 〉 10 fold change, FDR 〈 0.05). As an extension of the study we performed Gene Set Enrichment Analyses to assess functional networks. Genes that were differentially expressed in MLL-R cases were enriched in regulators of secretion and endocytosis (NES = 1.84, FDR = 0.06), actin binding and cytoskeleton function (NES = 1.7, FDR ≤ 0.25), embryonic development (NES = 1.98, FDR ≤ 0.25), and genes upregulated by hedgehog signaling pathways (NES = 1.73, FDR ≤ 0.25). Genes that were differentially expressed in AF10-R include those that activate cytokine production (NES = 1.90, FDR ≤ 0.25). Taken together, these pathways are commonly targeted by inhibitors of kinase signaling pathways and the proteosome. In summary, we have identified an extended repertoire of aberrant gene expression in MLL-R and AF10-R T-ALL. Our findings provide a mechanistic basis for additional pre-clinical testing of in classes of therapeutic agents that may hold promise for high-risk T-ALL. Disclosures Wood: Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement. Asselin:Sigma Tau Pharamceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy, Speakers Bureau. Loh:Abbvie: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Abstract: The early thymic precursor (ETP) immunophenotype was previously reported to confer poor outcome in T-cell acute lymphoblastic leukemia (T-ALL), requiring prospective confirmation using contemporary risk-adjusted therapy. Between 2009 and 2014, 1,256 newly-diagnosed children and young adults enrolled on COG AALL0434 were assessed for ETP status and minimal residual disease (MRD) using flow cytometry at a central reference laboratory. Subjects were categorized as ETP (n=145; 11.5%), Near-ETP (n=209; 16.7%) or Not-ETP (n=902, 71.8%). Despite higher rates of induction failure for ETP (6.2%) and Near-ETP (6.2%) than Not-ETP (1.2%) (P & lt;0.0001), all 3 groups showed excellent 5-year event-free survival (EFS) and overall survival (OS): ETP (80.4±3.9%; 86.8±3.4%), Near-ETP (81.1±3.3%; 89.6±2.6%) and Not-ETP (85.3±1.4%; 90.0±1.2%) (P=0.1679; P=0.3297). There was no difference in EFS or OS for subjects with day 29 MRD & lt;0.01% vs. 0.01%-0.1%. However, Day 29 MRD ≥0.1% was associated with inferior EFS and OS for patients with Near-ETP and Not-ETP, but not for those with ETP. Subjects with near-ETP and Not-ETP and a presenting WBC ≥200,000/microliter had inferior EFS and OS, but not for ETP. For subjects with Day 29 MRD ≥1%, end-consolidation MRD ≥0.01% was a striking predictor of inferior EFS (80.9±4.1% vs. 52.4±8.1%; P=0.0001). When considered as a single variable, subjects with all three T-ALL phenotypes had similar outcomes, and subjects with persistent post-induction disease had inferior outcomes regardless of their ETP phenotype. Although ETP status alone is not an independent predictor of outcome, future studies may provide additional insights into the mechanistic basis of resistant disease in stem-like T-ALL. Clinical trial is registered at AALL0434 (NCT00408005)