Lina Hamadeh

Abstract 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.

Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus.

Abstract 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.