Long-Term Follow-Up of BEACOPP_escalated Chemotherapy in Patients with Advanced-Stage Hodgkin Lymphoma on Behalf of the German Hodgkin Study Group.

The HD9 trial of the German Hodgkin Study Group (GHSG) compared two different doses (baseline and escalated) of the novel chemotherapy regimen BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in patients with advanced-stage Hodgkin lymphoma (HL). The previous analysis with a median follow-up of 5 years showed improved tumor control (FFTF) and overall survival (OS) for BEACOPP_escalated. Since BEACOPP_escalated had been associated with more toxicity as compared with ABVD we report the results of long-term follow-up of 1196 patients enrolled and randomized in that study. The median follow-up was 112 months; a total of 370 centres contributed. Patients received one of three chemotherapy regimens: 8 cycles of COPP (cyclophosphamide, vincristine, procarbazine, and prednisone) alternating with ABVD (doxorubicin, bleomycin, vinblastin, and dacarbazine), 8 cycles of standard-dose BEACOPP or 8 cycles of escalated-dose BEACOPP. At 10 years, FFTF rates were 64%, 70% and 82%, OS rates were 75%, 80%, and 86 for COPP-ABVD (arm A), BEACOPP_baseline (arm B), and BEACOPP_escalated, respectively (p < 0,001). Importantly, BEACOPP_escalated was also significantly better than BEACOPP_baseline in terms of FFTF (p < 0.0001) and OS (p = 0.0053). Death due to HL occurred in 11.5%, 8.1% and 2.8% in arms A, B, and C, respectively. 74 second malignancies were documented, including secondary acute myeloid leukaemias (1,7,14), Non-Hodgkin lymphoma (7,8,5), and solid tumors (7,16,9) in arms A, B, and C respectively. The corresponding overall secondary malignancy rates were 6.7%, 8.9% and 6.8%. Importantly, the risk of secondary AML (sAML), although increased in this study after BEACOPP_escalated, amounts to 0.9% in our follow-up study with BEACOPP_escalated (HD12) in 1502 advanced-stage HL patients randomized and four years median follow-up. Although the higher rate of secondary AML after BEACOPP_escalated in HD9 most likely occurred by chance, interestingly, 70% of patients in this group had additional radiotherapy whereas only 39% were radiated in HD12. Taken together, the 10 years follow-up of BEACOPP_escalated chemotherapy demonstrates a stabilized significant improvement in long-term FFTF and OS for advanced-stage HL. Although for formal prove the results of ongoing prospective randomized comparisons with 8 cycles of ABVD might be required, these results clearly challenge ABVD as standard of care for this patient population.