Changes in body composition during early phases of treatment and subsequent risk of relapse in childhood Hodgkin lymphoma

Abstract

Abstract Introduction: About 15% of children with intermediate/high-risk Hodgkin lymphoma (HL) suffer a relapse; salvage requires high-intensity treatment and is associated with substantial morbidity. Early response to treatment (negative PET scan after two cycles: PET2) is a significant predictor of durable remission and is used to inform subsequent intensification of therapy. Nonetheless, relapses are observed in PET2 negative patients, presenting a need to identify novel predictors of relapse that could improve risk stratification and reduce relapse risk. Body composition (skeletal muscle, adipose tissue mass) is a predictor of disease-free survival in adult-onset cancer (Caan, JAMA Onc 2018). Using abdominal CT scans obtained as standard of care at HL diagnosis, we have found an association between extremes of adipose tissue (but not body-mass index) at HL diagnosis and positive PET2 (Wadhwa, CEBP 2025). However, rapid changes in body composition are observed after initiation of therapy; whether a change in body composition during the first two cycles is associated with relapse in children with HL remains unknown. Methods: This report included 951 patients with HL enrolled on COG trials AHOD0031 and AHOD0831 with abdominal CT imaging at baseline and after cycle 2. Body composition analysis used commercial software (sliceOmatic, Tomovision). Skeletal muscle area (SMA [cm2]) and total adipose tissue (TAT [cm2]) were calculated at baseline and after cycle 2 and median change (increase or decrease) in SMA and TAT was used to group patients with gain (change in SMA or TAT > median overall increase), loss (change in SMA or TAT > median decrease), or stable SMA or TAT (all other patients). COG Statistics/Data Center provided details including age at diagnosis, sex, race/ethnicity, stage, histology, presence of ‘B’ symptoms and bulk disease, as well as disease status (remission, relapse, subsequent neoplasm), and vital status (alive, dead), along with dates. Primary exposures were change in TAT and change in SMA. Primary outcome was relapse stratified by PET2 status. Proportional sub-distribution hazard regression models determined the association between change in SMA or TAT and relapse treating non-relapse-related death as competing risk and adjusting for prognosticators including baseline SMA and TAT. Period at risk started at the end of cycle 2. Results: PET2 negative (n=663): Median age at diagnosis was 15.2y (3.5-21.8), 54% were male and 65% were non-Hispanic White. Bulk disease was present in 72% and 29% had ‘B’ symptoms. Majority (87%) were treated on AHOD0031. Change in SMA: Median decline in SMA was −4.6 cm2/m2 (−94.2 to 40.1 cm2/m2); 34% experienced loss in SMA, 16% experienced gain, 50% had stable SMA. Change in TAT: Median increase in TAT was 11.5 cm2/m2 (−225.6 to 189.6 cm2/m2); 14% experienced loss in TAT, 35% experienced gain, and 50% had stable TAT. Change in body composition and hazard of relapse: Over a median follow-up of 6.8y, 13% relapsed. Patients with gain in TAT had a 1.77-times higher hazard of relapse (95%CI=1.1-2.8, P=0.01; ref=stable TAT). Loss in TAT was not associated with relapse (hazard ratio [HR]=1.01, 95%CI=0.5-2.1, P=0.9; ref=stable TAT). Change in SMA was not associated with relapse (gain: HR=1.12, 95%CI=0.6-2.0, P=0.7; loss: HR=0.80, 95%CI=0.5-1.3, P=0.4; ref=stable SMA). Gain in TAT was associated with a significantly higher hazard of relapse among males (HR=2.53, 95%CI=1.3-5.0, P=0.007; ref: stable TAT) and patients ≥12y at diagnosis (HR=1.94, 95%CI=1.2-3.1, P=0.006; ref: stable TAT) but not among females or those <12y. PET2 positive (n=288): Neither change in SMA (gain: HR=1.22, 95%CI=0.7-2.3, P=0.5 or loss: HR=1.17, 95%CI=0.7-2.0, P=0.6) nor change in TAT (gain: HR=0.84, 95%CI=0.5-1.4, P=0.5 or loss: HR=0.69, 95%CI=0.3-1.5, P=0.4) were associated with relapse. Conclusions: Gain in adipose tissue during early phases of treatment of childhood HL (likely due to steroids) is associated with a greater hazard of relapse among patients with negative PET2. Rapid gain in adipose tissue during this period may affect chemotherapy bioavailability or tumor microenvironment, thereby compromising outcomes among the PET2 negative patients. However, gain in adipose tissue does not overcome the effect of aggressive disease biology among those with positive PET2. Further studies are ongoing to understand underlying mechanisms to inform interventions.