Treatment-related circulatory diseases and mortality in Hodgkin lymphoma patients using multi-state modelling and relative survival
One of the most common late effects in Hodgkin lymphoma (HL) patients are diseases of the circulatory system (DCS). How much that can be attributed to HL therapy, while accounting for the competing risk of death, remains less understood. This study aimed to assess treatment-related incidence of DCS by sex and cumulative anthracycline dose in HL patients using novel methods in multi-state modelling and relative survival.
All patients with HL registered in the Swedish Lymphoma Register 2000-2018, aged 18-80 years at diagnosis, were included. DCS was identified in the Swedish National Inpatient Register (ICD-10 codes I00-I99). Sex-, year-, and age-specific incidence rates of DCS in the general population were retrieved from public records. Patients were followed from treatment through a series of states: Alive without DCS, alive with DCS, dead without DCS, and dead after DCS. Follow-up ended on death, emigration, or December 31st, 2019. All state transitions were modelled separately using flexible parametric survival models. A relative survival model incorporating the expected DCS rates was fitted to allow for estimation of excess DCS incidence, which was defined as attributable to HL therapy. Transition probabilities were predicted for specific patient groups.
A total of 1,929 HL patients were included (54% male, 49% treated with >200 mg anthracycline). The distribution of treatments was 66% ABVD, 20% CHOP-like, and 14% BEACOPP. During a median follow-up time of 7.6 years, 377 patients (20%) were diagnosed with DCS, 145 (7.5%) died without DCS, and 87 (5%) died following DCS.
Females had a lower non-DCS mortality rate than men (adj. hazard ratio=0.69, 95% CI: 0.49-0.97), as did patients treated with >200mg anthracycline compared to ≤200mg (adj. hazard ratio=0.28, 95% CI: 0.18-0.44). There were no differences in excess DCS incidence rates or post-DCS all-cause mortality rates.
Figure 1a shows the predicted transition probabilities for an advanced stage patient diagnosed in 2000 at age 50, treated with ABVD including >200mg cumulative anthracycline dose, by sex. Figure 1b shows the transition probabilities for a limited stage male patient diagnosed in 2000 at age 50, treated with ABVD, by cumulative anthracycline dose (≤200mg or >200mg).
Across almost two decades, females experienced more excess DCS compared to men, likely due to superior survival. The same was seen for high compared to low doses of anthracycline.