AUTHORS
Jennifer A Belsky, DO, MS, Karolina Breit, MS2, Lindsay A. Renfro, PhD3, Yue Wu, MS4, Cindy Im, PHD5, Aman Wadhwa, MD, MSPH6, Raymond Mailhot, MD, MPH7, Mallorie B Heneghan, MD, MS8, Justine M. Kahn, MD, MS9, Kara M Kelly, MD10, Angela Punnett, MD11, Susan Parsons, MD, MRP12, Sharon M Castellino Jr, MD, MSc13, Annalynn Williams, PHD14
AFFILIATIONS
1 Indiana University School of Medicine, Indianapolis, Indiana, United States, Riley Hospital for Children, Indianapolis, Indiana, United States
2 Division of Pediatric Hematology/Oncology Columbia University, New York, New York, United States
3 Children's Oncology Group, Monrovia, California, United States, University of Southern California, Los Angeles, California, United States
4 Children's Oncology Group, Monrovia, California, United States
5 University of Minnesota, Minneapolis, Minnesota, United States
6 University of Alabama, Birmingham, Alabama, United States
7 University of Miami Miller School of Medicine, Miami, Florida, United States
8 University of Utah, Salt Lake City, Utah, United States
9 Columbia University, New York, New York, United States
10 Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States
11 Hospital for Sick Children, Toronto, Ontario, Canada
12 Tufts University School of Medicine, Boston, Massachusetts, United States
13 Emory University, Atlanta, Georgia, United States
14 University of Rochester Medicine, Rochester, New York, United States
ABSTRACT
Background
Despite survival rates exceeding 90% in children, adolescents, and young adults (CAYAs) with classic Hodgkin lymphoma (cHL), treatment-related toxicity (adverse events, AEs) during therapy is of concern. These toxicities can negatively impact quality of life, lead to treatment delays or dose modifications, and may contribute to differences in survival outcomes across age groups. Prior studies in pediatric acute leukemia have demonstrated higher rates of treatment-related toxicity among adolescents compared to younger children, but whether similar age-related patterns exist in cHL remains unclear. A better understanding of how toxicity varies across the age spectrum may identify opportunities to tailor supportive care, improve treatment delivery, and reduce treatment-related morbidity for CAYAs with cHL.
Methods:
We performed a secondary analysis of patients with high-risk cHL (stage IIB +bulk, IIIB, IVA, or IVB) enrolled on the Children's Oncology Group trial AHOD1331. Patients were randomized to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (BV-AVE-PC) or doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Treatment-related adverse events (AEs) were assessed using clinician-graded Common Terminology Criteria for Adverse Events version 5.0 from enrollment through completion of therapy inclusive of radiation therapy. The primary outcome was the incidence of grade 3–5 non-hematologic AEs. Secondary outcomes included the incidence of any grade 3–5 AE, any grade non-hematologic AE, and any grade AE. Cox proportional hazards models estimated the risk of first AE while negative binomial regression estimated incidence rate ratios (IRR) considering the total AEs to compare the incidence rate (e.g., multiple AEs) among those ≥15 years old compared to those <15 years old at diagnosis, adjusting for trial arm, sex, stage, and histology. Sensitivity analyses compared those ≥12 to those <12 years of age. These thresholds were chosen based on prior associations with event-free survival.
Results:
A total of 586 patients were included in analysis; median age at enrollment was 15.6 (range 3.4-22.0 years; 59.4% ≥15 years). Of patients ≥15 years of age, 56% experienced at least one grade 3-5 non-hematologic AE compared to 50.8% of those <15 years. There was no difference in the adjusted risk of first grade 3-5 non-hematologic AE, or any other AE category as described above, among those ≥15 years old compared to those <15 years old (p’s >0.05).
However, the mean number of grade 3-5 non-hematologic AEs was greater among those age ≥15 years (mean [SD] 2.0[3.3]) compared to those <15 (1.4[2.3]; p=0.039), as was any grade non-hematologic AE (2.5[3.8] vs 1.8[2.7]; p=0.042). The adjusted incidence rate for multiple grade 3-5 non-hematologic AEs was two-fold higher among those who were ≥15 years old compared to those <15 years (IRR [95%CI] 2.09[1.53, 2.86]; p<0.001). Similarly, the incidence rate of any grade non-hematologic AE was also two-fold higher among those ≥15 (1.94[1.44,2.60]; p<0.001). The incidence rate of any grade AE was 1.6 times higher among those ≥15 (any grade 1.61[1.23, 2.11] p<0.001; grade 3-5 1.64[1.24,2.17] p<0.001).
When considering organ specific AEs, those ≥15 experienced higher incidence rates of grade 3-5 infection (1.65[1.16, 2.35]; p=0.005), cardiopulmonary (2.79[1.25, 6.26]; p=0.013), and gastrointestinal AEs (2.28[1.44, 3.61]; p<0.001). Although not statistically significant, patients ≥15 years old had twice the incidence rate of any grade neurologic AEs, including neuropathy, compared to those <15 (1.96[0.94, 4.06]; p=0.071). No differences were observed in rates of other organ-specific AEs of any grade. There were no significant differences in incidence rates for any outcome by age when using 12 years as the comparison cut point.
Conclusions:
Among CAYAs treated on AHOD1331, patients >15 experienced a significantly higher rate of multiple AEs compared with younger patients. These findings suggest that AYAs with cHL represent a particularly vulnerable population during therapy and may benefit from enhanced toxicity monitoring and supportive care interventions. Improved understanding of age-related toxicity patterns and impact on dose modification may inform future efforts to optimize treatment delivery and reduce treatment-related morbidity in pediatric and AYA cHL populations.
DISCLOSURES
Jennifer A Belsky, DO, MS: No relevant conflicts of interest to declare.