Real‐world data on treatment concepts in classical Hodgkin lymphoma in Sweden 2000–2014, focusing on patients aged >60 years

Abstract Treatment for patients > 60 years with classical Hodgkin lymphoma (cHL) is problematic; there is no gold standard, and outcome is poor. Using the Swedish Lymphoma Registry, we analysed all Swedish patients diagnosed with cHL between 2000 and 2014 (N = 2345; median age 42 years; 691 patients were >60 years). The median follow‐up time was 6.7 years. Treatment for elderly patients consisted mainly of ABVD or CHOP, and the younger patients were treated with ABVD or BEACOPP (with no survival difference). In multivariable analysis of patients > 60 years, ABVD correlated with better survival than CHOP (p = 0.027), and ABVD became more common over time among patients aged 61–70 years (p = 0.0206). Coinciding with the implementation of FDG‐PET/CT, the fraction of advanced‐stage disease increased in later calendar periods, also in the older patient group. Survival has improved in cHL patients > 60 years (p = 0.027), for whom ABVD seems superior to CHOP.

The CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) regimen has, during 2000-2017, been used to treat elderly cHL patients > 70 years in Sweden. In a small Norwegian retrospective single centre study, the CHOP regimen showed promising overall survival (OS) and progression-free survival at 3 years of 79% and 76%, respectively. [10] ABVD is a standard treatment for younger patients and has also been tried in older patients. When used to treat elderly patients ABVD has a higher incidence of toxicity, in particular bleomycinrelated pulmonary toxicity. [11] More intensive chemotherapy combinations like BEACOPP have been associated with unacceptable toxicity and are generally not recommended for patients > 60 years. [12] With the introduction of brentuximab vedotin and immune checkpoint inhibitors in relapsed patients, the option of moving those treatments into first-line has emerged. The B-CAP (brentuximab vedotin, cyclophosphamide, doxorubicine and prednisone) regimen is such an attempt. [13] Older patients and patients with severe comorbidities and social problems are often excluded from clinical trials. [14] Previous population-based studies of adult cHL patients have been performed in Sweden [15][16][17] and elsewhere. [18][19][20] In the study performed by Bjorkholm [24,25] from which survival data were obtained.

Survival analysis
Survival of patients diagnosed with cHL was estimated using univari-

RESULTS
A total of 2345 cHL patients (1257 men and 1088 women) were diagnosed in Sweden from year 2000 through 2014 (Table 1). Of all the patients, 294 were 61-70 years and 397 were ≥71 ( Table 2).
The median age at diagnosis was 42 years and increased over time

Chemotherapy regimens
Chemotherapy regimens by age, sex and calendar periods are presented in Table 5. In multivariable analysis of patients > 60 years, CHOP compared to ABVD was an independent adverse factor for OS (p = 0.039; Table 4, see also Figure 1F). When repeating the multivariable analysis only in patients aged 61-70 years, CHOP was still inferior to ABVD (HR, 1.72; p = 0.039). Only nine patients ≥ 71 years had received ABVD, why statistical significance could not be achieved (p = 0.097).  Patients ≤ 60 years with advanced-stage disease treated with BEA-COPP and ABVD showed identical OS in univariable ( Figure 1G) and multivariable analysis (adjusted for the same covariates as in Table 3;

RS
RS was stable between the calendar periods (Figures 2 and S2), except for an improvement in elderly women with advanced stage disease diagnosed between 2010 and 2014 ( Figure 2B; Table 1). CHOP seems inferior to ABVD in the older patient group, while BEACOPP was equal to ABVD in younger patients with advanced-stage disease (Figure 2), also after adjustment for clinical factors (Table 4).

DISCUSSION
Using Competing, non-significant factors: Histology, LDH, B symptoms (and, in the latter analysis, male sex). Abbreviation: CI, confidence interval; HR, hazard ratio; RR, relative risk.
bias. Agreeing with previous reports, [10,11,15,33] prognosis remains poor for patients > 60 years. This is due to their inability to tolerate BEACOPP [12] or ABVD, [11] higher co-morbidity [7] and differences in lymphoma biology (more mixed cellularity, Epstein-Barr virus positivity and infradiaphragmatic disease). [7] FDG-PET/CT was gradually intro-duced, and a stage migration was seen over time as increased number of patients presenting with stage IV disease in the last calendar period, also in the older patient group.
In Sweden, between 2000 and 2014 there was no improvement in survival except in patients > 60 years. Improved survival, especially Hence, ABVD is preferable for those fit to receive such treatment.
Given that ABVD provides better outcome than CHOP and that bleomycin toxicity is a major problem in older patients receiving more than two cycles of ABVD, [11,36]  In our material, patients ≤ 60 years with advanced-stage disease treated initially with BEACOPP-14/esc versus ABVD showed identical OS in univariable and multivariable analysis. These data indicate that a PET-guided ABVD approach is suitable for a proportion of the advanced-stage patients. However, the IPS score, available from June 2007, predicted OS (p < 0.00005), suggesting that a proportion of those with high-risk score might need a more aggressive approach from the start. Since BEACOPP was only given to high-risk patients, according to IPS, it could be argued that the identical OS might suggest that BEACOPP is beneficial for this group. For the patients > 60 years, no PET-guided approach is available due to the lack of any evidence-based escalation-regimen.
The strengths of our study are that it is population-based, consecutive and based on real-life data. No regional differences were seen in treatment or survival. One weakness is the bias in the selection of chemotherapy regimens used, especially for CHOP versus ABVD in stage IV disease, also in the older patient group (Table 1).