HD7 to HD12 trials – favorable prognosis found for Classical Hodgkin Lymphoma patients with late compared to early relapse

On 1^st May 2017 in the Journal of Clinical Oncology, Paul J. Bröckelmann from the University Hospital of Cologne, Cologne, Germany, and colleagues published a comprehensive, retrospective analysis of Late Relapse (LR) in 6,840 patients with Classical Hodgkin Lymphoma (cHL) who were included in the German Hodgkin Study Group HD7 to HD12 trials.

Patients who experienced relapse more than 5 years into remission were compared with patients in continued remission for more than 5 years and with those who experienced relapse less than 5 years after first diagnosis.

Key Highlights

• CR achieved by 4,935 pts after first-line treatment and were relapse-free for >5 yrs
• Median observation time = 10.3 years; 141 pts with LR >5 yrs after first diagnosis were observed
• 45/141 pts experienced their first relapse >10 years after initial diagnosis
• Cumulative incidence of LR at 10, 15, and 20 years were 2.5%, 4.3%, and 6.9%, respectively
• Standardized Incidence Ratio (SIR) = 84.5 (95% CI, 71.2–99.7) compared with age- and gender-matched general German population
• LR was more common in pts with early-stage favorable disease than early-stage unfavorable or advanced-stage disease at first diagnosis (15-year cumulative incidence, 5.3% vs. 3.9% and 3.9%, respectively; P = 0.01)
• Trend confirmed by multivariable analysis; also identified older and male pts at a higher risk of LR with HRs of 1.01 (95% CI, 1.00–1.03) and 1.6 (95% CI, 1.1–2.3) per year, respectively
• Pts with LR had worse OS vs. pts in long-term remission (HR, 2.5; 95% CI, 1.7–3.5; P < 0.001)
• LR was more common outside initially involved/irradiated areas than pts with earlier relapses (P < 0.05)
• Compared to pts with earlier relapses, fewer LR pts underwent SCT (44% vs. 49%; P = 0.03)
• More LR pts BEACOPP (20% vs. 13%) and ABVD (13% vs. 11%) than early relapse pts
• Progression Free Survival from date of first Relapse (PFSr) of LR pts was superior to pts who relapsed earlier (HR, 0.7; 95% CI, 0.5–1.0; P = 0.03)
• Multivariate analysis found significantly worse PFSr for early-stage unfavorable pts (HR, 2.1; 95% CI, 1.5–3.1) or advanced-stage disease at first diagnosis (HR, 2.6; 95% CI, 1.8–3.9)
• Similar results found for Overall Survival from date of first Relapse (OSr), with a HR of 0.6 (95% CI, 0.4–0.9, P = 0.01) for LR vs. earlier relapse
• By histologic subtype, LR pts had nodular sclerosis cHL (39%), mixed cellularity cHL (27%), cHL not otherwise specified (17%), and lymphocyte-rich cHL (8%)
• At relapse, 9 pts (10%) presented with nodular lymphocyte predominant HL
• Between first diagnosis and LR, a switch to another subtype or to not specified HL occurred in 30% of pts

The authors stated that “long-term survivors after initially successful therapy for cHL are at an 85-fold increased risk of recurrence of disease compared with German reference values.” The group recommend that patients are regularly and thoroughly followed-up by clinical examination after risk-adapted treatment, particularly in early-stage favorable HL patients, in order to detect LR as early as possible. Lastly, they concluded that HL patients with LR appear to have a favorable prognosis compared to early relapse patients.

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.