Relapse Risk and Loss in Expectation of Lifetime in Young Classical Hodgkin Lymphoma Patients - a Nordic Lymphoma Group Study of 2,582 Patients
Authors: Biccler Jorne Lionel , Glimelius Ingrid , Eloranta Sandra , Smeland Knut B. , Brown Peter de Nully , Jakobsen Lasse H. , Frederiksen Henrik , Jerkeman Mats , Fosså Alexander , Andersson Therese M.L. , Holte Harald , Bøgsted Martin , El-Galaly Tarec C. , Ekstroem Smedby Karin 
Published: October 2019

Abstract
Estimates describing the survival and relapse risk for young classical Hodgkin lymphoma (cHL) patients are of considerable interest. A recent population-based study from British Columbia focused on the evolution of the relative survival and relapse risk given that patients reached certain milestones such as two years of relapse-free survival (Hapgood et al. 2016). The study included patients diagnosed before the year 2000 who were treated with regimens that have since been refined. Using register-data from Denmark, Sweden, and Norway, we investigated cHL survivorship in the era of contemporary treatment by inspecting the evolution of relapse risk and loss in life expectancy.
Inclusion criteria were: age at diagnosis 18-49 years; diagnosis year between 2000 and 2013; and treatment with chemotherapy (CT) with or without involved node/field radiation therapy (RT). Event-free survival was measured as the time from diagnosis to progression, relapse, or death, whichever came first. The five-year relapse risks from diagnosis and conditional on reaching event-free survival (EFS) milestones were estimated while taking the censoring and competing risk, death, into account. As a measure of relative survival, we estimated the five-year restricted loss in expected lifetime (5y-RLEL), defined as the numeric difference in the number of days a healthy person and a patient with cHL are expected to survive within the next five years. The 5y-RLEL was estimated taking the censoring into account and was estimated for all patients and for those reaching one (EFS1), two (EFS2), or five (EFS5) years of event-free survival.
In total, 2,582 cHL patients were included (Denmark n=863, Sweden n=1,236, Norway n=483). The majority were treated with ABVD (n=1,932). Most limited stage (IA-IIA) patients were treated with 2-4 courses of CT and RT with dosage up to 30Gy The majority of the advanced stage (IIB-IV) patients were treated with 6-8 courses of CT +/- RT. A fraction of the patients (n=306) were treated with 6-8 BEACOPP 14 or escalated BEACOPP. Advanced stage patients receiving BEACOPP more often had adverse risk criteria including involvement of the bone-marrow (27% vs 6%) and/or other extranodal sites (60% vs 34%) than advanced stage patients treated with 6-8 cycles of ABVD. The five-year OS was 95.2% (95% CI 94.4 - 96.1) and the five-year risk of relapse was 13.4% (95% CI 12.1-14.8).
The dynamic evolution of the five-year relapse risk is shown in Figure 1A and the 5y-RLEL estimates in Figure 1B. For patients reaching the EFS2 and EFS5 milestones, five-year relapse risks were 4.2% (95% CI 3.8 - 4.6) and 0.8% (95% CI 0.8 - 0.9) (Figure 1A), respectively. From diagnosis, the five-year relapse risk for advanced stage patients was twice as high as for limited stage patients, however the difference decreased among patients reaching later EFS milestones and was small after EFS3 irrespective of stage (2.5% [95% CI 2.1 - 2.9] for advanced stage disease vs. 2.0% [95% CI 1.6 - 2.4] for limited stage disease) (Figure 1A). The five-year relapse risk for advanced stage patients treated with 6-8 courses of BEACOPP was comparable to that of advanced stage patients treated with 6-8 courses of ABVD despite more adverse risk criteria among the BEACOPP treated patients (Figure 1A). The 5y-RLEL was limited, e.g. within the first five years post-diagnosis the HL patients were expected to live 46 days (95% CI 35 - 54) less than what was expected for the background population (Figure 1B). Patients reaching the EFS2 milestone had a 5y-RLEL of 13 days (95% CI 7 - 20) and for patients reaching the EFS5 milestone, the 5y-RLEL was 8 days (95% CI 2 - 14) (Figure 1B). Limited stage patients who remained event-free two years post-diagnosis had a minimal 5y-RLEL of 2 days (95% CI -4 - 7) (Figure 1B).
By reporting five-year relapse risk and loss of life expectancy overall and conditioned on years in remission, we provide relevant patient-centred prognostic measures for young contemporarily treated cHL patients. The results are reassuring and indicate that limited stage patients who remain event-free two years post-diagnosis have a future life expectancy in line with HL-free individuals. Additionally, irrespective of risk group, the five-year relapse risk was minimal once three years of event-free survival was reached. This information should be taken into account in future surveillance programs.

Disclosures
Eloranta: Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Ekstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals.