Background: Patients free of HL >5 years after first diagnosis are usually considered cured. Nevertheless, VLR occur and biology, clinical characteristics, therapeutic approaches and prognosis are currently poorly understood.
Methods: Cumulative incidence of VLR was retrospectively estimated in 5149 patients of the GHSG HD7-HD12 trials, who were observed and relapse-free for >5 years; risk factors were analyzed using Gray’s test and Cox regression. Standardized incidence ratio (SIR) was estimated using age- and sex-specific reference values for the German population. Overall and progression-free survival were estimated according to Kaplan-Meier from first diagnosis (OS/PFS) and date of relapse (OSr/PFSr), Hazard Ratios (HR) were obtained from Cox regressions adjusted for relevant risk factors such as age, sex and initial stage. Relapse localizations and therapies, OSr and PFSr were compared with a group of 487 patients having earlier relapse. Patient characteristics were analyzed descriptively.
Results: With a median observation time of 10.3 years, a total of 169 relapses >5 years were observed. Cumulative incidences at 10, 15 and 20 years were 2.8%, 5.1% and 8.6%, respectively, with an SIR of 97.1 (95% CI: 83.0-112.9). VLR were more frequently observed in patients with early-stage favorable than early-stage unfavorable or advanced-stage disease at first diagnosis (15-year cumulative incidence 8.0%, 4.4%, 4.2%, respectively, p<0.001). Male patients and those with nodular-lymphocyte predominant subtype were also found at increased risk for VLR. VLR occurred more frequently outside initially involved areas and radiation fields than earlier relapse. OS was significantly worse compared to non-relapse survivors (10-year OS: 95.9% vs. 88.5%, HR: 2.4, 95% CI: 1.7-3.4, p<0.001). For earlier relapse, we observed inferior 5-year PFSr and OSr compared to VLR (55.7% vs. 64.3% HR: 1.6, 95% CI: 1.1-2.4, p=0.03; 63.0% vs. 76.3%, HR: 2.1, 95% CI: 1.3-3.4, p<0.01, respectively).
Summary: Besides therapy-associated side effects, survivors after initially successful HL-therapy are at a 100-fold increased risk of re-occurrence of disease compared to German reference values. After modern risk-adapted treatment strategies especially in early-stage favorable HL, thorough regular follow-up is hence needed for timely detection. Prognosis of VLR seems favorable when compared to early relapses.