Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus

Summary

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.

Introduction

Acute lymphoblastic leukaemia accounts for 25% of all childhood cancers and has leapt from being universally fatal two generations ago, to having 5-year overall survival rates of more than 90% with the best contemporary treatment.¹ However, a substantial number of patients have severe, fatal, or lifelong toxic effects.² The frequency of these toxic effects varies widely across study protocols (appendix), which reflects not only the difference in treatment intensities, but also the diverse definitions of toxic effects and the strategies for their identification and reporting, making meaningful comparisons of the risks of toxic effects impossible.

The progressive intensification of acute lymphoblastic leukaemia treatment in the past three decades means that the chance of treatment-related death can now be equal to the chance of leukaemic relapse in low-risk patients.³ Accordingly, trials no longer aim only to introduce more powerful antileukaemic drugs, but also focus on minimising toxic effects. Evaluation of the success of this approach depends on robust measurement of the toxic effect burden within different groups in a trial, between different trials internationally, and between patient subsets defined by clinical features or germline DNA variants.⁴

Definitions for most organ toxic effects already exist, and the US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE)⁵ is widely used. However, the CTCAE describes many toxic effects in very general terms, and was not developed to meet the specific needs associated with childhood acute lymphoblastic leukaemia treatment. Additionally, the grades of toxic effects that are identified and reported vary across protocols. Finally, the scientific community uses various definitions for several toxic effects (appendix p 24) and there is a need for consensus definitions across paediatric acute lymphoblastic leukaemia protocols.

Recognising the need for international collaboration on this issue, the Ponte di Legno consortium (PdL) established a toxicity working group (PTWG) to address serious adverse events associated with childhood acute lymphoblastic leukaemia treatment (appendix), and thus improve the outcomes of children with the disease.¹ As a first step, the PTWG aimed to obtain consensus definitions of 14 prioritised acute toxic effects. We report the process and the final definitions that have been approved by the PdL acute lymphoblastic leukaemia groups. We hope these definitions will be valuable for reliable comparisons of data on toxic effects emerging from various treatments for acute lymphoblastic leukaemia, for collaborative research addressing risk factors including host genome variants, and for strategies for the prevention or treatment of toxic effects.