Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia

Summary

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology–oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.

Introduction

Childhood cancer 5-year overall survival rates now surpass 80%; therefore, a research focus on long-term therapy-related toxicities is important.1, 2 Outcomes have previously been measured by overall survival and event-free survival, with events encompassing resistant disease, relapse, second malignant neoplasms, and death. However, detailed information regarding the rates of other severe toxicities is needed to address and further improve the quality of life among survivors.

In childhood acute lymphocytic leukaemia, the most common childhood cancer, the 5-year event-free survival now exceeds 85% and overall survival exceeds 90%, following the best available contemporary therapy.³ However, the compiled risk of severe and permanent adverse effects, such as end organ dysfunction and severe cognitive impairment, approaches or even surpasses those of resistant disease and relapse.4, 5, 6 Decades-long awareness of treatment-related morbidity has prompted stepwise modifications of acute lymphocytic leukaemia therapy, including a dramatic decrease in the use of radiotherapy, anthracyclines, and alkylating drugs, contributing to a marked reduction in late mortality among 5-year survivors of childhood cancer.⁵ Nevertheless, the risk of long-term severe toxicities persists.

Acute toxicities are monitored as part of cancer treatment trials and typically defined according to the US National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE)⁷ and, over the past 5 years, by international consensus definitions to enable reliable comparisons between cohorts.⁸ Yet, these definitions contain no guidance about severe long-term toxicities that would be beneficial to integrate into an overall measure of treatment outcome.

The Ponte di Legno Working Group (PdL)—which represents 17 major childhood acute lymphocytic leukaemia study groups and institutions across North America, Europe, Japan, Taiwan, and Australia—⁹ launched an initiative in May, 2019, to prioritise physician-derived severe toxicities for future reporting of severe toxicity-free survival (STFS) alongside the other reported outcome events.

The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with the traditionally reported outcomes.