Impact of body mass index on outcome, toxicity and pharmacokinetics in patients with acute lymphoblastic leukemia

Sammanfattning: Background: Overweight and obesity are growing health problems. Obesity has been associated with both a higher risk of contracting cancer and increased cancer-related mortality in adults. The impact in children with cancer, and more specifically with acute lymphoblastic leukemia (ALL), is less explored. Body mass index (BMI) may be an additional risk factor for poor outcomes that warrants consideration in risk stratification for ALL treatment assignment. This study aimed to retrospectively study the association between BMI and ALL treatment in children and young adults treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols and explore possible factors underlying adverse outcomes. Methods: Patients with B-cell-precursor (BCP) and T-cell ALL from the Nordic countries, Estonia and Lithuania were included. Detailed data on weight and height at diagnosis, as well as patient and disease characteristics, were retrieved from the NOPHO leukemia registries. In Study I, we used data collected retrospectively on children aged 2-<18 years and treated according to the NOPHO ALL92-, ALL2000, or ALL2008 protocols between 1992 and 2016, and for consecutive studies we included patients only from the NOPHO ALL2008 protocol (Studies II, III and IV) and also comprised of young adults (18-<46 years, Study V). In children, BMI was calculated and converted according to the International Obesity Task Force classification into BMI standard deviation scores (SDS), and age and sex-related BMI cut-offs for thinness, healthy weight, overweight, and obesity. The impact of BMI on the following outcomes in children and young adults were analyzed: event-free survival, relapse, overall survival, and treatment-related toxicity and mortality (Studies I, II and V). In children, mean BMI change between diagnosis and the end of treatment, together with identifying risk factors for weight gain were investigated (Study IV). Further, the relation between BMI and delayed high-dose methotrexate (HD-MTX) excretion was explored using data on HD-MTX pharmacokinetics gathered from medical charts from children treated in Stockholm and Uppsala (Study V). Results: In Study I (n =2558), we explored the impact of BMI on survival outcomes in children. Obese children aged 10-18 years at the time of their ALL diagnosis had higher relapse rate and consequently a more than six-fold increased risk of dying from their disease compared to healthy weight patients. Underweight and overweight were also associated with an increased risk of relapse, compared to healthy weight in this age category. However, BMI had no significant impact on outcomes in younger children aged 2-<10 years. In Study II, we compared the risk of specific severe adverse events and treatment delays in different BMI categories in a cohort of 1443 children with non-high-risk ALL. A similar age trend was observed in this study; only older obese children aged ≥10 years had a significantly increased incidence rate ratio for one or more specific severe adverse events, compared to healthy weight children. Older children also had a three-fold higher incidence rate ratio of asparaginase truncation, compared with older healthy weight children. Study III shows, that BMI SDS increased for many children during ALL therapy (n=765). An increase in BMI SDS was more prevalent in those who were young (2-<6 years) or underweight/healthy weight at diagnosis, compared to other age or BMI groups. To evaluate how BMI influences pharmacokinetics and associated toxicities, one cornerstone of the antileukemic treatment—HD-MTX—was explored in Study IV. The results, comprising 182 children and 1401 HD-MTX courses, indicate that children with substantial weight loss during induction had an increased risk of delayed methotrexate excretion. The results did not support changed pharmacokinetics of HD-MTX as a contributing factor to decreased survival in overweight and obese children. In Study V, the role of BMI on outcomes was further examined in young adults, to explore age-related differences in metabolic status and its impact on outcome. Out of the 416 young adults with non-high-risk ALL, only the severely obese patients (BMI ≥35 kg/m2, n=234) had inferior event-free survival due to relapses. Severe obesity had no effect on toxicity nor treatment delays compared to healthy weight patients. Conclusions: In obese patients, the poor outcomes are primarily linked to a higher risk of relapse, which may be related to undertreatment or chemotherapy resistance. When trying to improve survival, there is a fine balancing act between intensifying treatment in unhealthy BMI groups with the potential risk of Increased toxicity. For obese patients with ALL, novel strategies with individualized frontline therapy approaches are needed to reduce toxicity while further improving outcomes. Achieving optimal dosing strategies requires further exploration through pharmacokinetic trials. Furthermore, it is crucial to recognize that nutritional status is a modifiable risk factor, where physical activation and dietary interventions, possibly combined with drugs targeting the metabolic pathways, may contribute to better outcomes.