# Focus on Extremely Late Relapses in Hodgkin Lymphoma: A Single Center Analysis

## TL;DR

This study explores Hodgkin lymphoma relapses occurring more than 20 years after diagnosis, finding they are less aggressive and have better outcomes.

## Contribution

First detailed analysis of extremely late relapses in Hodgkin lymphoma, identifying their incidence, characteristics, and favorable outcomes.

## Key findings

- Nine out of 270 patients experienced extremely late relapses after 20 years in remission.
- Patients with extremely late relapses had better outcomes and less aggressive treatment compared to those relapsing between 5 and 20 years.
- Omission of radiotherapy and mixed cellularity subtype were associated with higher risk of extremely late relapses.

## Abstract

Our study examined extremely late relapses (EXLRs) in Hodgkin lymphoma (HL), defined as relapses occurring after at least 20 years from initial diagnosis. We reviewed 270 patients with HL in continuous remission for at least 5 years and with follow-up data exceeding 20 years from initial diagnosis. Nine patients experienced EXLR. The cumulative incidence of EXLR gradually increased over time. Patients with EXLR generally had more favorable characteristics at relapse and were treated less aggressively compared to patients who relapsed between 5 and 20 years. Omission of radiotherapy at initial treatment and the histologic subtype of mixed cellularity were associated with a higher probability of EXLR. Patients with EXLR achieved a favorable disease control and survival after relapse, suggesting that these late relapses may represent a biologically different and less aggressive form of disease.

Background/Objective: Very late relapses (VLRs) in Hodgkin lymphoma (HL), occurring ≥5 years after initial treatment, have been well-recognized for decades. Recent studies have highlighted the persistent and linear risk of relapse extending well beyond 5 years, while also describing the incidence and risk factors. However, extremely late relapses (EXLRs) occurring ≥20 years after diagnosis remain poorly described and largely limited to case reports. In the present study, we focus on patients experiencing EXLRs after chemotherapy or combined modality therapy, aiming to define their incidence, clinical characteristics, and outcomes, and to compare them with patients with VLRs relapsing between 5 and 20 years from initial diagnosis. Methods: We performed a retrospective study of 270 patients with HL, who received chemotherapy ± radiotherapy (CT ± RT), remained in continuous remission at least 5 years from treatment initiation and had follow-up data exceeding 20 years from diagnosis. The primary endpoint was the cumulative incidence (CumInc) of VLR, considering death from any cause as a competing event. Results: EXLR occurred in 9/270 cases. The CumInc of EXLR at 25, 30 and 35.2 years was 2.23%, 4.80% and 7.87%, respectively. Compared to patients with VLRs (N = 61), patients with EXLRs had a lower incidence of anemia and a higher incidence of lymphocytopenia at diagnosis. At relapse, patients with EXLR tended to be older, had a lower frequency of extranodal disease, were more often managed with the same or similar salvage CT regimen as at initial diagnosis (reinduction), and were considered less frequently as candidates for autologous stem cell transplantation. In univariate analysis, the omission of RT at initial treatment and the histologic subtype of mixed cellularity (MC) were associated with a higher probability of EXLR. Compared to patients with VLRs, patients with EXLRs had a 10-year treatment to second failure (TT2F) of 88.9% versus 47.4%, a 10-year overall survival after relapse (O2S) of 77.8% versus 54.9% and a 10-year disease-specific survival (DSS) of 88.9% versus 70.9%. Conclusions: The study describes for the first time the incidence and characteristics of EXLRs in HL. These patients had excellent outcome despite having relapsing disease, suggesting that this subgroup of patients may have distinct biological characteristics.