Increased Rate of Pulmonary Toxicity in Pediatric Patients with Relapsed Hodgkin Lymphoma Receiving Brentuximab Vedotin

*Kelly E Faulk and Jenna Sopfe contributed equally to this work and are considered co-first authors.

Background: In pediatric patients with relapsed or refractory Hodgkin lymphoma, intensification of conventional chemotherapy and radiation has shown limited success with high rates of treatment-associated morbidity and highlighted the need for alternative, targeted approaches in this high-risk population. Brentuximab vedotin (Bv) is an anti-CD30 monoclonal antibody-drug conjugated to monomethyl auristatin E that has improved outcomes and reduced toxicity compared to standard salvage regimens. It is now approved for use in relapsed or refractory Hodgkin lymphoma and several ongoing pediatric clinical trials are underway to test the effectiveness of Bv as frontline therapy. In the existing literature, acute pulmonary toxicity has been described in adults with Bv but typically in the setting of concurrent administration with bleomycin, whereas the incidence of lung toxicity attributed to Bv alone has been reported at only 5% (Moskowitz 2015). There is little published data on lung toxicity of Bv in pediatric patients. This study aims to evaluate the prevalence of acute pulmonary toxicity among pediatric and young adult relapsed Hodgkin lymphoma patients and define risk factors for this complication, specifically examining the association of Bv with pulmonary toxicity when adjusting for other exposures.

Methods: We performed a retrospective cohort study of relapsed or refractory Hodgkin lymphoma patients who were originally diagnosed from 2006-2016 and treated at Children's Hospital Colorado. We examined demographic, clinical and treatment characteristics among patients who developed acute pulmonary toxicity (defined as hypoxemia, dyspnea or radiographic pneumonitis of ≥ grade 3 and/or newly abnormal pulmonary function testing occurring at any time from initiation of relapse therapy until 6 months off therapy) to determine potential risk factors. A Fisher's exact test was used to determine the statistical significance in the difference of the primary outcome (pulmonary toxicity) for those exposed and not exposed to Bv. Univariate and multivariate logistic regression modeling was performed to evaluate the association of Bv with pulmonary toxicity, adjusting for cumulative bleomycin and pulmonary radiation dose received as well other risk factors identified in univariate analysis.

Results : We identified 22 patients, age 6-24 years (median 15) at time of initial diagnosis, who underwent treatment at our institution. Twelve (52.2%) were male. Nine patients (40.9%) received Bv as a component of their relapse therapy regimen. On preliminary analysis, acute pulmonary toxicity was seen in 6 patients (27.3%). There was a statistically significant difference in pulmonary toxicity among patients who received Bv compared to patients who did not receive Bv (p=0.023); of patients who received Bv, 5/9 (55.6%) experienced acute pulmonary toxicity, compared to 1/13 (7.7%) patient who did not receive Bv. Further analyses of additional risk factors and calculation of odds ratios, adjusted for bleomycin and radiation exposure, are forthcoming.

Conclusions: At our institution, the administration of Bv in pediatric and young adult patients with relapsed or refractory Hodgkin lymphoma is associated with a higher rate of acute pulmonary toxicity than has previously been reported. Ongoing analysis will examine the magnitude of risk associated with Bv and the interaction of other known risk factors. As investigation into the use of Bv continues, this emerging safety and toxicity profile data will be important in understanding the risk of pulmonary toxicity and ensuring appropriate monitoring.