Population-Based, Cause-Specific Risk of Non-Lymphoma Deaths Among 20,491 Adults with Classical Hodgkin Lymphoma (cHL) Treated with Initial Chemotherapy in the United States, 2000-2015

Introduction: Advances in cHL treatment over the past 50 years have been fueled, in part, by recognition of long-term treatment-related complications that emerged after cure of cHL became a reality. While cHL-specific survival has continued to improve with time, premature death following diagnosis and treatment of cHL remains life-limiting. Most studies of cHL mortality have focused on long-term survivors and included patients treated with chemotherapy approaches and radiation techniques used in the past. Therefore, we sought to comprehensively quantify early and late cause-specific risks of death among U.S. adults with cHL treated with chemotherapy during a treatment era predominated by ABVD-based (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy.

Methods: We used data from 17 cancer registry areas of the Surveillance, Epidemiology, and End Results Program to quantify risks of death among individuals diagnosed with early (I/II) or advanced (III/IV) stage cHL between ages 20-74 years and treated with initial chemotherapy during 2000-2015. We calculated standardized mortality ratios (SMRs) and 95% confidence intervals to compare cause-specific risk of death following cHL to that expected in the general U.S. population and estimated absolute excess risks (per 10,000 patient-years) to quantify disease-specific death burden.

Results: Among 24,205 cHL patients, we assessed mortality among the 85% (n=20,491) treated with initial chemotherapy (37% of the 20,491 also received initial radiotherapy). With a mean follow-up of 6.7 years, we observed 3,230 deaths due to lymphoma (n=1,936), other neoplasms (n=273), noncancers (n=937), and unknown (n=84) causes. The risk of non-lymphoma deaths overall was significantly elevated 1.5- and 2.3-fold among adults diagnosed with early or advanced cHL, respectively, representing 20 (early stage) and 75 (advanced stage) excess deaths/10,000 patient-years. The most common causes of noncancer deaths were attributed to cardiovascular (n=284), respiratory (n=166), and infectious (n=119) diseases and accidents/falls/adverse events (n=121). The greatest increased risk of cardiovascular deaths was observed for heart disease <1-year after cHL which persisted 1-4 and >5 years after early and advanced stage cHL. Death from interstitial lung disease (ILD) significantly exceeded the expected rate by 14- and 24-fold in early and advanced stage cHL, respectively, most notably within the first year of diagnosis (SMR_early=90; SMR_advanced=128), with SMRs decreasing substantially after 1-year but remaining significantly increased in both stage groups. Patients were also prone to infection-related deaths irrespective of early (SMR_early=2.2) or advanced (SMR_advanced=3.9) cHL, both <1 or >1 year after diagnosis, with the greatest excesses occurring within the first year. Individuals with early (SMR_early=1.8) and advanced stage (SMR_advanced=4.2) disease had significantly elevated risks of death from adverse events (deaths coded as sequelae of drug, treatment, or other specified exposure), most notably <1 year after cHL diagnosis (SMR_early=7.5; SMR_advanced=17.5). Among non-lymphoma neoplasms, death from myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) was significantly increased among early (SMR_early=5.2) and advanced stage (SMR_advanced=8.6) cHL. No MDS/AML deaths occurred within 1-year of cHL, but risks increased to >9-fold among both stage groups 1-4 years after diagnosis, and excesses persisted at >5-years among those with advanced stage cHL (SMR_advanced=9.1). Lung cancer accounted for the majority of solid tumor deaths among those with early (SMR_early=1.4) and advanced stage (SMR_advanced=1.9) cHL, with heightened risks beginning at >5 years among early stage cHL and at 1-4 years among advanced stage disease.

Conclusion: Despite tailored treatment approaches in an ABVD-predominant era, risk of non-lymphoma deaths remains significantly elevated among cHL patients 20-74 years of age in the U.S., with early or advanced stage disease, and <1 or >1 year from diagnosis. Our data strongly support implementation of preventive and supportive measures following cHL diagnosis and continued refinement of treatment approaches to minimize premature deaths.