Severe Toxicity Free Survival Following Childhood Acute Lymphoblastic Leukemia

Background:

Childhood acute lymphoblastic leukemia (ALL) is the most common childhood cancer comprising around 25% of all childhood cancers. Stepwise modifications of antileukemic therapy have led to a rise in 5-year survival probability from less than 30% in the 1970s to above 90% today. Cure, however, comes at a price; survivors are burdened by acute as well as long-term toxicities, that is, adverse effects of treatment. Among survivors, the cumulative incidence of severe, disabling, life-threatening, or fatal chronic health conditions was recently reported to be 21.1% at 20 years from ALL diagnosis, which is substantial, not least when considering the peak incidence of childhood ALL around the age of 3 years, meaning that many 20-year survivors are young adults. Hence, focusing on long-term health sequelae is more relevant than ever. Traditional cancer outcome measures consist of overall survival and cancer-related-event-free survival, but for cancers with high survival probability, such as for childhood ALL, these traditional outcome measures become insufficient since they ignore the burden of therapy. Severe, long-term toxicities should be considered in treatment outcome evaluation, but the lack of internationally standardized capturing and reporting of late effects is a barrier. To address this, an international collaboration of ALL consortia initiated a project aiming to select physician-defined severe toxicities following ALL treatment. This work resulted in consensus definitions of 21 severe health conditions named Severe Toxicities, which could each be considered an unacceptable price for cure. With examples as heart failure, brain damage, and chronic lung disease, the 21 conditions are of such severity that ALL treatment possibly would have been modified if the toxicity had been predictable at time of diagnosis. These Severe Toxicities should be integrated in treatment outcome evaluation alongside the overall survival and the cancer-related event-free survival for a more comprehensive evaluation of treatment protocols.

The occurrence of these 21 Severe Toxicities has not been evaluated before. This international study aims to quantify the occurrence of the Severe Toxicities in 5 large cohorts of childhood ALL patients from Europe, USA, and Australia. Even though the overall survival as well as the cancer-related-event-free survival for different cohorts may be similar, differences in the use and dose-intensity of steroids, chemotherapy, radiotherapy, and hematopoietic stem cell transplantation may lead to different toxicity patterns. The original Severe Toxicity definitions were recently modified to meet statistical requirements for valid analyses and to ensure that the Severe Toxicities can be classified uniformly and prospectively across different cohorts.

Comparing the prevalence and patterns of Severe Toxicities across different treatment protocols will potentially reveal modifiable treatment-related factors associated with risk of individual and/or multiple Severe Toxicities. A global decision to routinely report Severe Toxicity is essential for a more comprehensive knowledge of late effects, which may guide future research towards improved treatment strategies aiming to reduce toxicities, and hereby improving quality of life, without compromising cure.

The 21 Severe Toxicities include the following conditions: