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
Authors: Dores Graca M. , Curtis Rochelle E. , Dalal Nicole H. , Linet Martha S. , Morton Lindsay M. 
Published: November 2019

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 (SMRearly=90; SMRadvanced=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 (SMRearly=2.2) or advanced (SMRadvanced=3.9) cHL, both <1 or >1 year after diagnosis, with the greatest excesses occurring within the first year. Individuals with early (SMRearly=1.8) and advanced stage (SMRadvanced=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 (SMRearly=7.5; SMRadvanced=17.5). Among non-lymphoma neoplasms, death from myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) was significantly increased among early (SMRearly=5.2) and advanced stage (SMRadvanced=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 (SMRadvanced=9.1). Lung cancer accounted for the majority of solid tumor deaths among those with early (SMRearly=1.4) and advanced stage (SMRadvanced=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.

Disclosures
No relevant conflicts of interest to declare.