US population-based cohort study on the mortality causes of patients with cHL between 2000–2016

The introduction of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy in the 1970s and the subsequent reduction in patients being treated with radiation alone has significantly increased the survival outcomes of patients with classical Hodgkin lymphoma (cHL).¹ Nevertheless, a large-scale cause-specific mortality analysis has not been performed for patients with HL treated over the last four decades.¹ For this reason, Graça Dores et al.¹ published, in the Journal of Clinical Oncology, a population-based cohort study reviewing the reasons of death for patients with cHL between 2000–2016 and evaluating the disease-associated mortality burden. The results of this study are summarized below.

Study design

• US population-based cohort study with registry data from 20,007 patients with primary cHL, aged 20–74, who received initial chemotherapy between 2000–2015 and were followed through to 2016.
• Although registry data did not specify the initial chemotherapeutic regimen, ABVD was considered the standard primary chemotherapy regimen in the US between 2000–2016.
• Standardized mortality ratios (SMR) and excess absolute risks (EAR) per 10,000 person-years were calculated for the cohort.
• The key baseline characteristics of the patients included in the study are shown below in Table 1. Of note, 40% of patients had Stage III–IV cHL and 32% of them were 10-year survivors

Table 1. Key baseline characteristics of the cHL cohort for patients aged 20–74¹

cHL, classical Hodgkin lymphoma; NOS, not otherwise specified. *This group includes patients for whom it was unknown whether radiation was administered.
Baseline characteristic	cHL cohort (N = 20,007)
Male patients, %	53
Age (years), % 20–44 45–59 60–74	66 21 14
Histological subtype, % Nodular sclerosis Mixed cellularity Lymphocyte-rich Lymphocyte-depleted cHL, NOS	65 12 3 1 20
Ann Arbor stage, % I II III IV	14 46 22 19
Initial therapy, % Chemotherapy only* Chemotherapy & radiation	65 35

Key results

Risk of any-cause mortality

Cohort data analyses showed that, of 20,007 patients, 3,380 died due to

• lymphoma: 59%
• non-cancer causes: 31%
• other neoplasm: 9%
• unknown causes: 2%

Any-cause mortality was higher among male patients (62%), patients with nodular sclerosis (52%), or those treated with chemotherapy alone (80%). After 12 years of follow-up

• the cumulative mortality rates for patients with cHL were higher than those of the general population, for all age groups studied (Table 2).
• the cumulative mortality rate of lymphoma was higher than that of non-cancer deaths only for patients in the 20–44 age group (Stages I–II and III–IV) and for those with advanced-stage cHL (Stage III–IV), irrespective of age (Table 2).

Table 2. Cumulative mortality rates after 12 years of cHL diagnosis¹

cHL, classical Hodgkin lymphoma; CI, confidence interval. Significantly different comparisons (p < 0.05) are indicated in bold font.
Cumulative mortality, % (95% CI)	cHL cohort (N = 20,007)
cHL Stages I–IV, all causes of death Age 20–44 years Age 45–59 years Age 60–74 years	11.7 (11.1–12.4) 28.3 (26.4–30.1) 59.8 (57.2–62.4)
General population, all causes of death Age 20–44 years Age 45–59 years Age 60–74 years	2.4 (2.4–2.4) 10.6 (10.5–10.6) 30.2 (30.1–30.22)
cHL, Stage I–II, age 20–44 years Lymphoma Non-cancer	5.2 (4.6–5.7) 2.0 (1.6–2.4)
cHL, Stage I–II, age 45–59 years Lymphoma Non-cancer	9.4 (7.9–10.9) 7.8 (6.3–9.3)
cHL, Stage I–II, age 60–74 years Lymphoma Non-cancer	22.3 (19.4–25.2) 22.7 (19.5–26.0)
cHL, Stage III–IV, age 20–44 years Lymphoma Non-cancer	12.9 (11.8–14.1) 4.0 (3.2–4.7)
cHL, Stage III–IV, age 45–59 years Lymphoma Non-cancer	19.3 (17.1–21.4) 13.1 (11.0–15.3)
cHL, Stage III–IV, age 60–74 years Lymphoma Non-cancer	34.6 (31.8–37.4) 22.4 (19.6–25.1)

Cause-specific risk analysis revealed a 1.8 (95% CI, 1.7–1.9)-fold increase in the risk of death from any cause, except for lymphoma, in patients with cHL when compared with the general population. This risk was higher for patients with advanced Stage III–IV lymphoma (SMR = 2.2; 95% CI, 2.0–2.4) than those with early-stage (Stage I–II) lymphoma (SMR = 1.5; 95% CI, 1.4–1.6; p < 0.001).

Non-cancer causes of mortality

Excluding lymphoma, the majority of deaths were due to non-cancer causes, with a particularly higher risk of death among patients with advanced stage cHL (SMR = 2.4; 95% CI, 2.2–2.6; p = 0.001 when compared with patients with early cHL).

Patients with advanced stage cHL:

• The highest SMR was related to interstitial lung disease (ILD; SMR = 22.1; 95% CI, 16.6–28.8). Other common risk causes were benign hematological diseases, treatment-related adverse events (AEs), and infections, including gastrointestinal, septicemia, pneumonia and influenza.
• The greatest non-cancer death burden was due to heart disease (EAR = 15.1), infections (EAR = 10.6), ILD (EAR = 9.7), and AEs (EAR = 7.4).

Patients with early-stage cHL (Stage I–II)

• The most frequent SMR was due to ILD (SMR = 13.1; 95% CI, 9.2–17.9), followed by infections, benign hematological diseases, and AEs.
• The non-cancer death burden was most frequently associated with heart disease (EAR = 6.6), ILD (EAR = 3.7), infections (EAR = 3.1), and AEs (EAR = 2.5).

When looking at mortality rates according to patient subgroups, risk of death due to cardiovascular disease remained increased at all examined time points following cHL diagnosis, with the highest heart disease mortality rate and risk at < 1 year after disease diagnosis and then at ≥ 5 years after diagnosis. Risk of death from ILD, infections, or AEs was the highest at < 1 year since cHL diagnosis.

 With the exception of infections and AEs, which led to higher mortality in female patients with advanced stage cHL, no other cause-specific risk was different among males and females.

 Increasing age seems to lead to decreased mortality rates for ILD but increased rates for AEs, with a particularly high risk in patients aged 60–74 with either early- or advanced-stage cHL. Moreover, deaths due to heart disease were particularly high in the 60–74 patient age group, irrespective of follow-up period or disease stage.

Conclusion

 The results of this US population-based cohort study indicate that, despite the reduction in the use of radiation or older less safe chemotherapy regimens, a significant proportion of patients with cHL treated between 2000–2016 died from non-lymphoma related causes. These included heart disease, ILD, AEs, and infections, especially in patients with advanced-stage cHL or in their first year since disease diagnosis. The high rate of non-cancer mortality related to ILD is consistent with the use of bleomycin as part of the ABVD regimen, while heart disease as the most prominent non-cancer cause of death is very likely be related to the use of anthracyclines and radiation. These findings indicate the need for continuous research and evolution into treatments for cHL patients that will limit non-cancer-related toxicities and mortality, particularly for patients with advanced stage cHL.