Late Relapse of Classical Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group HD7 to HD12 Trials

Abstract

Purpose Clinical characteristics, therapeutic approaches, and prognosis of late relapse (LR) in patients with classic Hodgkin lymphoma (cHL) are poorly understood. We performed a comprehensive analysis of LR of Hodgkin lymphoma (LR-HL). Methods To estimate the incidence of LR-HL, we retrospectively analyzed 6,840 patients with cHL included in the German Hodgkin Study Group trials HD7 to HD12. Patients who experienced a relapse > 5 years into remission were compared with patients in continued remission for > 5 years and with those who experienced a relapse ≤ 5 years after first diagnosis. Results With a median observation time of 10.3 years, 141 incidences of LR-HL were observed. Cumulative incidences at 10, 15, and 20 years rose linearly and were 2.5%, 4.3%, and 6.9%, respectively. The standardized incidence ratio for HL with respect to age- and sex-matched German reference data was 84.5 (95% CI, 71.2 to 99.7). LR-HL was more frequently observed in patients with early-stage favorable than unfavorable or advanced stage at first diagnosis (15-year cumulative incidence, 5.3% v 3.9% and 3.9%, respectively; P = .01). Overall survival from first diagnosis was worse after LR compared with nonrelapse survivors (10-year estimate, 95.8% v 86.1%; hazard ratio, 2.5; 95% CI, 1.7 to 3.5; P < .001). In patients with LR-HL, survival was better compared with 466 patients with earlier relapse (hazard ratio, 0.6; 95% CI, 0.4 to 0.9, P = .01). Forty-four percent and 49% of patients with LR-HL and earlier relapse, respectively, received stem cell transplantations. Conclusion Apart from treatment-associated adverse effects, survivors after initially successful therapy for cHL are at an 85-fold risk for recurrence of disease compared with the general German population. After risk-adapted treatment strategies, especially in early-stage favorable HL, regular clinical follow-up is recommended for timely detection of LR-HL. With adequate treatment, prognosis of LR-HL is better compared with early relapses.

Balancing risk and benefit in early-stage classical Hodgkin lymphoma

“…During the quest to omit RT, the relevant chemotherapy-associated morbidity 29,30 and late relapses of HL occurring especially in patients with earlystage disease should be acknowledged. 31 In the 50604 phase 2 trial, patients with nonbulky stage I/II disease with a negative interim PET/CT after 23ABVD (Deauville score, 1-3; 131 of 144 evaluable patients) were treated with an additional 23ABVD without consolidative RT, whereas patients with a positive interim PET/CT (12 of 144 patients) received 23BEACOPP escalated plus 30-Gy IFRT. Estimated 3-year PFS rates of 92% and 66%, respectively, for the PET 2 and PET 1 cohorts were reported in an interim analysis.…”

No excess long‐term mortality in stage I‐IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy

“…These results contradict the rationale of accepting a higher risk of relapse to achieve less toxicity, such as in the design of the H10 (Andre et al , ) and RAPID studies (Radford et al , ), and as in the report from the BC Cancer Lymphoid Cancer Database (Villa et al , ), where RT has been omitted for selected patients. There is an almost total absence of late relapses in contrast to other cohorts (Brockelmann et al , ). The lack of excess mortality needs to be confirmed in other cohorts.…”

“…The rate of relapses occurring later than 5 years after diagnosis was low, with only two late relapses, equal to a cumulative incidence of <1% at 10 years. This outcome seems to differ from the long‐term outcome in the GHSG studies (Brockelmann et al , ). In contrast to the Nordic registry, the GHSG clinical trials included patients with B‐symptoms and treatment with 20 Gy.…”

Successful brentuximab vedotin monotherapy against late relapse of classical Hodgkin lymphoma 6 years after first remission

“…A late-relapse group had a better prognosis on survival than an early-relapse group within 5 years. 6 Early-relapse, defined as <1 year of a CR, is considered as a poor prognostic factor as well as refractory, B symptoms, extranodal involvement 8,9 and as a good indication for aPBSCT/HDT. Radman reported that in long-term results of conventional chemotherapy alone, a group showing a CR for more than 1 year showed better overall survival and relapse-free survival than a group showing a CR for <1 year (10-year overall survival of 37% vs 20% and relapse-free survival of 40% vs 18%, respectively; P < .01 and <.01, respectively).…”

“…A late-relapse group showing more than 5 years of a CR was also reported to have a better prognosis than an early-relapse group. 6 In the late-relapse group, a treatment option without aPBSCT/HDT would be reasonable, aiming for a sustained CR benefit and limiting toxicity and complications, including late nonrelapse mortality.…”