Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.

We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] ‫؍‬ 2.2) and OS was 46% (P < .001; RHR ‫؍‬ 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18-to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.

EFS and survival appear to be directly related to histologic response to neoadjuvant chemotherapy.

• MRD measured by flow cytometry is prognostic in childhood B-ALL even with more effective high-dose methotrexate therapy.• Intensive therapy in MRDpositive patients altered the timing of relapse but did not overcome the poor prognostic significance of MRD.Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 3 2 factorial design to receive either highdose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ‡0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% 6 1% vs 74% 6 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% 6 5% 5-year disease-free survival vs 39% 6 7% for those with MRD ‡0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% 6 2% vs 58% 6 4% for MRD-negative vs positive C-MTX subjects; 88% 6 2% vs 68% 6 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725. (Blood. 2015;126(8):964-971) IntroductionMinimal residual disease (MRD) is highly predictive of relapse in children, adolescents, and young adults treated for acute lymphoblastic leukemia (ALL). [1][2][3][4][5][6] MRD is typically measured either by assessment of clone-specific markers of immunoglobulin and/or T-cell receptor gene rearrangements using polymerase chain reaction (PCR) or by flow cytometry, taking advantage of the fact that leukemic cells have phenotypes that allow them to be distinguished from normal cells. The Children's Oncology Group (COG) has been assessing MRD by flow cytometry at the end of 4 weeks of induction therapy in subjects with newly diagnosed ALL since 1999, and has previously demonstrated that this is the most powerful predictor of outcome in children, adolescents, and young adults with B-precursor ALL (B-ALL). Because MRD is known to be such a strong prognostic factor, most studies of childhood ALL use this to deter...