Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)–CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.

Summary Background The ALLR3 trial investigated outcomes of children with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. We analysed long-term follow-up outcomes of these patients. Methods ALLR3 was an open-label randomised clinical trial that recruited children aged 1–18 years with B-cell precursor acute lymphoblastic leukaemia who had late bone marrow relapses. Eligible patients were recruited from centres in Australia, Ireland, the Netherlands, New Zealand, and the UK. Patients were randomly assigned from Jan 31, 2003, to Dec 31, 2007, and the trial closed to recruitment on Oct 31, 2013. Randomly assigned patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation; after randomisation stopped in Dec 31, 2007, all patients were allocated to receive mitoxantrone. After three blocks of therapy, patients with high minimal residual disease (≥10 −4 cells) at the end of induction were allocated to undergo allogeneic stem-cell transplantation and those with low minimal residual disease (<10 −4 cells) at the end of induction were allocated to receive chemotherapy. Minimal residual disease level was measured by real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements. The primary endpoint of the original ALLR3 clinical trial was progression-free survival of randomly assigned patients. The primary endpoint of this long-term follow-up analysis was progression-free survival of patients with late bone marrow relapses stratified by minimal residual disease level. Outcomes were correlated with age, site, time to recurrence, and genetic subtypes, and analysed by both intention to treat and actual treatment received. This trial is registered on the ISRCTN registry, number ISRCTN45724312, and on ClinicalTrials.gov , number NCT00967057 . Findings Between Feb 2, 2003, and Oct 28, 2013, 228 patients with B-cell precursor acute lymphoblastic leukaemia and late bone marrow relapses were treated. After a median follow-up of 84 months (IQR 48–109), progression-free survival of all randomly assigned patients was 60% (95% CI 54–70). 220 patients achieved second complete remission, and minimal residual disease was evaluable in 192 (87%). 110 patients with late bone marrow relapses and high minimal residual disease at the end of induction were allocated to undergo stem-cell transplantation, and 82 patients with low minimal residual disease at the end of induction were allocated to receive chemotherapy. In the patients allocated to undergo stem-cell transplantation, four relapses and three deaths were reported before the procedure, and 11 patients were not transplanted. Of the 92 patients transplanted, 58 (63%) remained in second complete remission, 13 (14%) died of complications, and 21 (23%) relapsed after stem-cell ...

The mainstay of therapeutic stratification in pediatric T-ALL is end-of-induction Minimal Residual Disease (MRD), but this is increasingly challenged by oncogenetic status. A NOTCH1, FBXW7, N/K-RAS, PTEN classifier had marked prognostic impact in the FRALLE2000T protocol but not in the UKALL2003 protocol, whereas we now show the reverse following relapse. We undertook a replication analysis to determine the reasons for this discrepancy. This showed that oncogenetic low-risk (gLoR) combined to MRD<10 -4 identified 33% of FRALLE2000T and 22% of UKALL2003 patients with a very low incidence of relapse (5y-CIR of 4% vs. 9%, respectively) whereas the UKALL2003 protocol led to better outcome for patients with MRD≥10 -4 and gHiR patients with MRD<10 -4 , mainly due to more widespread and effective intensification for patients with MRD≥10 -4 .Increasing stringency for MRD negativity will not lead to detection of all gHiR patients, since 10% (6/60) were totally MRD negative. Instead, future studies should integrate oncogenetic status into therapeutic stratification and avoid treatment reduction in gHiR, MRD<10 -4 /neg. patients. These data demonstrate the strength in comparing biomarker discrepancies between protocols as a means to identify optimal personalised therapy.

Background: Neurotoxicity during treatment for childhood acute lymphoblastic leukaemia (ALL) remains a significant problem. It can be acute as in methotrexate stroke-like syndrome, posterior reversible encephalopathy syndrome, or seizures, or may be subacute resulting in chronic neurocognitive defects. Symptomatic and asymptomatic neurotoxicity can affect long-term neurocognitive outcomes (e.g. attention, executive function). Worryingly, studies in patients 20-30 years post treatment suggest accelerated CNS ageing and the burden of neurological late effects may worsen over the next few decades. Thus, there is an urgent need to better understand the pathophysiology of neurotoxicity and develop ways of identifying children at risk. Previous reports suggest that treatment intensity, (particularly methotrexate exposure), age greater than 10 years and number of intrathecals may predispose to neurotoxicity but none of the studies have been sufficiently large to identify independent risk factors in multivariable analysis. In order to investigate clinical risk factors for neurotoxicity and its effect on outcomes in a large cohort of patients, we carried out a review of all neurotoxic serious adverse events (SAEs) reported for UKALL2003. Methods: Between Oct 2003 and June 2011, the UKALL2003 trial enrolled 3113 patients aged 1-24 years with ALL. The trial SAE database was interrogated for reports of seizures, encephalopathy or arachnoiditis. Cerebral venous sinus thrombosis, cerebral haemorrhage, miscellaneous encephalopathy secondary to systemic disorders and steroid psychosis (n=22) were excluded from this analysis due to their distinct aetiologies. Survival rates were calculated and compared using Kaplan Meier methods and log-rank tests. The association between neurotoxicity event and risk factors was investigated using χ2 test, univariate and multivariate logistic regression. All tests were conducted at the 5% significance level and the analyses were performed using Intercooled Stata. Results: There were 300 SAE reports of neurotoxicity in 254 patients (8.2% of all trial participants), 159 with encephalopathy, 86 with seizures and 9 other. These patients were compared to 2837 controls without any reported neurotoxicity. There was no significant difference in 5-year event-free survival, overall survival and relapse risk between the two groups. We observed a significant association between the neurotoxicity events and each of; treatment intensity, age, female sex, CNS status, T-cell immunophenotype and white cell count (Table 1). Multivariate analysis revealed that treatment allocation (regimen B/C v A, odds ratio (OR) 2.61 (95% CI 1.86-3.65), female sex (OR 1.42 (1.10-1.85), CNS status (CNS2/3/TLP v CNS1, OR 1.60 (1.14-2.24)) and age (OR 1.04 (1.01-1.07) per year) remained significant independent predictors of neurotoxicity. In order, to examine further the effect of age, we performed a stratified analysis by treatment group (regimen A v regimen B/C). Age remained significant in both groups: OR 1.15 (1.03-1.29) and 1.03 (1.01-1.06) per year, both p=0.01. Therefore, age was still a risk factor among patients receiving regimen A who were, by definition, under 10 years; despite lower methotrexate exposure. Discussion: This large study identifies treatment intensity as the main risk factor for developing acute neurotoxicity with female sex, age and CNS status having a significant modifying effect. CNS status may reflect increased intrathecal therapy given to non-CNS-1 patients. Females are more vulnerable to cranial radiotherapy induced neurotoxicity but this is the first report of female sex as a risk factor on contemporary chemotherapy treatment protocols. Reassuringly, the occurrence of acute neurotoxicity did not influence survival rates. These data provide an important benchmark for ongoing international deep phenotyping studies of chemotherapy-associated neurotoxicity. Disclosures Hough: University College London Hospital's NHS Foundation Trust: Employment. Vora:Amgen: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; Jazz: Other: Advisory board; Medac: Other: Advisory board. Halsey:Jazz Pharmaceuticals: Honoraria, Other: Support for conference attendance.