Extremes of Weight Are Associated with Increased Treatment-Related Toxicity in High-Risk Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group,

Abstract 3574

Intensification of therapy for acute lymphoblastic leukemia (ALL) has improved long-term survival but is associated with considerable treatment-related toxicity (TRT). While obesity has been shown to affect event-free survival (EFS) and overall survival (OS) in ALL, little information exists as to the effect of extremes of weight (underweight or obese) on morbidity due to TRT. To this end, we conducted a secondary analysis of 1,902 children treated on the Children's Oncology Group study CCG-1961 to determine whether weight extremes influence development of TRT and EFS/OS in children with higher risk ALL. CCG-1961 was a randomized study for patients 1–21 years old with National Cancer Institute High-Risk ALL (HR-ALL) that evaluated marrow response at day 7 of Induction and compared regimens of differing intensity and/or duration (for Rapid Early Responders, RER) or anthracycline used in Delayed Intensification (for Slow Early Responders, SER). Weight category was determined using the United States Centers for Disease Control and Prevention Z-scores for body mass index (BMI) by age (age ≥ 2 yrs) and weight by length (age <2 years). Extremes of weight were defined as underweight (< 5^th percentile) and obese (> 95^th percentile). At diagnosis, 107 patients (5.6%) were underweight and 264 were obese (13.9%). Multivariate linear and logistic regression analyses controlled for age, gender, race/ethnicity, payer type (as a surrogate for socioeconomic status), initial white blood cell count, presence of central nervous system disease, RER/SER status, and phase of treatment independent of regimen. All of the preceding predictors were independently significantly associated with development of grade 3/4 non-hematological toxicity in multivariate analysis (p<0.05). Data used for analysis were sourced from participating sites through routinely reported study forms (toxicity graded per Children's Cancer Group Toxicity and Complications Criteria).

Our results demonstrate statistically significant increases in toxicity for both extremes of weight. Weight category at start of each phase was predictive of developing grade 3/4 non-hematological toxicity during that phase (p<0.001). In comparison with healthy/overweight patients (5^th – 95^th%), underweight patients were at increased risk for developing fungemia (odds ratio [OR] 3.45, 95% confidence interval [95% CI] 1.25–9.50; p=0.017), fungal pulmonary infections (OR 2.54, 95% CI 1.05–6.11; p=0.040), and bacteremia (OR 1.33, 95% CI 1.04–1.71; p=0.020). Underweight patients also required significantly more hematopoietic support per phase with at least one transfusion of packed red blood cells (OR 1.62, 95% CI 1.31–1.99; p<0.001) or platelets (OR 1.42, 95% CI 1.16–1.75; p=0.001), as well as use of granulocyte colony-stimulating factor (OR 1.40, 95% CI 1.00–1.96; p=0.052). Underweight patients had slightly longer hospitalizations by 1 day per treatment phase (p<0.001). In contrast, obese patients had no increased risk of infection but exhibited increased toxicity of the liver as indicated by the presence of transaminitis or hyperbilirubinemia (OR 1.23, 95% CI 1.11–1.36, p<0.001) and increased incidence of pancreatitis (OR 1.30, 95% CI 1.08–1.56; p=0.005). There was no significant difference in the occurrence of other organ toxicities, including cardiac, renal, gastrointestinal and nervous systems. With a median follow-up of 7.1 years, healthy/overweight patients had an EFS of 71% as compared to EFS for underweight patients 63% (Hazard Ratio [HR] 1.33, 95% CI 0.95 – 1.87, p = 0.097) and obese patients 65% (HR 1.25, 95%CI 1.00–1.57, p=0.051). OS was not significantly different among the 3 weight classifications.

Our data indicate that for children with HR-ALL, extremes of weight are associated with significantly increased risk for TRT that is more infectious/hematopoietic in underweight patients and more hepatic/pancreatic in obese patients. With a median follow-up of 7.1 years, EFS was lower at both weight extremes versus healthy/overweight children, but in this analysis did not reach statistical significance. These findings provide insights into the nutritional status of children and adolescents with ALL that could lead to interventions designed to mitigate the impact of weight extremes upon their tolerance of therapy, quality of life and survival.