# Severe toxicity-free survival following acute lymphoblastic leukemia in patients aged 1–45 years: a Danish cohort study

## TL;DR

This study shows that many survivors of acute lymphoblastic leukemia experience severe long-term toxicities, especially adults and older adolescents.

## Contribution

The study introduces and applies a new metric, Severe Toxicity-free survival (STFS), to real-world ALL data for the first time.

## Key findings

- Severe Toxicity-event-free survival was 78.4% at five years, significantly lower in adults than children.
- Severe osteonecrosis and disabling neurological conditions were the most common severe toxicities.
- Older adolescents (10–17 years) had similar risks of severe toxicities as adults.

## Abstract

With increasing survival in acute lymphoblastic leukemia (ALL), long-term toxicities have become a critical aspect. A novel measure, designated Severe Toxicity-free survival (STFS), was developed through international consensus to integrate the most severe, symptomatic organ toxicities in outcome evaluation. This measure has not been applied to real-world data before. We assessed the incidence of 21 predefined Severe Toxicities in a nationwide cohort of 506 ALL patients aged 1–45 years treated according to the NOPHO ALL2008 protocol. At five years, event-free survival was 84.4% (95% CI: 81.3–87.7%) and Severe Toxicity-event-free survival was 78.4% (95% CI: 74.9–82.1%), with significantly lower values in adults (aged 18–45 years) than children (61.6% [52.6–72.2%] vs 82.4% [78.8–86.2%]; log-rank p < 0.001). The most common Severe Toxicities were severe osteonecrosis limiting activities of daily function (N = 20) and disabling paralytic and neuropathic conditions (N = 16). Exploratory analyses showed that 10–17-year-olds had the highest risk of Severe Toxicities similar to that of adults. These findings highlight a burden of severe, long-term toxicities in ALL survivors overlooked by traditional outcome measures, also following frontline therapy only. STFS should be incorporated in future trials for meaningful outcome evaluation and international comparisons across treatment strategies.