Long-Term Follow-up Analysis of HD2000 Trial Comparing ABVD Versus BEACOPP Versus Copp/EBV/CAD in Patients with Newly Diagnosed Advanced-Stage Hodgkin's Lymphoma: A Study from the Fondazione Italiana Linfomi
Authors: Merli Francesco , Luminari Stefano , Mammi Caterina , Cascavilla Nicola , Bari Alessia , Stelitano Caterina , Scalone Renato , Baldini Luca , Angrilli Francesco , Polimeno Giuseppe , Gobbi Paolo G , Cervetti Giulia , Ilariucci Fiorella , Ruffini Alessia , Marcheselli Luigi , Federico Massimo 
Published: October 2019

Abstract
PURPOSE: The HD2000 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus the combination of cyclophosphamide, vincristine, procarbazine, prednisone (COPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [CEC]) in 305 eligible patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 41 months median follow-up had indicated that BEACOPP was associated with a significantly improved Progression Free Survival (PFS) compared with ABVD, with a predictable higher acute toxicity. At time of previous analysis none of the study arms resulted in a better Overall Survival (OS). We here report analysis of long-term outcome and toxicity.
PATIENTS AND METHODS: Three hundred and five eligible patients with stage IIB, III, or IV were randomly assigned to receive six courses of ABVD (n=103), four escalated plus two standard courses of BEACOPP (n=100), or six courses of CEC (n=102), plus a limited radiation therapy program; radiotherapy was administered in 46, 42, and 42 patients in the three arms, respectively. Study enrolment was completed in June 2007. In January 2014 we updated the study follow-up with the aim of providing data on survival and on late events.
RESULTS: At time of current analysis the median follow-up was 119 months (range 1-169) with 92% of patients with a last contact later than January 2012. In the prolonged observation period 23 additional failures (cumulative=82)were recorded, including 17 new relapses/progression (cum=71) and 6 deaths not related to lymphoma progression (cum=11). Additional relapses and progressions were observed in 5, 7 and 5 patients treated with ABVD (cum=31), BEACOPP (cum=17), and CEC (cum=23), respectively. No death unrelatedto lymphoma progression was recorded among patients treated with ABVD, while 8 (+4) and 3 (+2) events were documented among patients treated with BEACOPP or CEC, respectively. The 10-year PFS was 69%, 74% and 74% in the ABVD, BEACOPP and CEC arm, respectively (P=0.639). Using ABVD as reference, Hazard Ratio for PFS for BEACOPP and CEC was 0.73 (CI95% 0.43-1.25) and 0.80 (0.47-1.36); this result was adjusted by IPS. Overall 42 patients died (+19), 13 (+5) in the ABVD arm, 15 (+7) in the BEACOPP arm and 14 (+7) in the CEC arm. The 10-year overall survival rates were 84%, 84% and 86% for ABVD, BEACOPP and CEC, respectively (P =0.883). A total of 11 second malignancies were documented including 2 MDS/AML (1 BEACOPP and 1 CEC), 2 non-Hodgkin’s Lymphoma (1 BEACOPP and 1 CEC), and 7 solid cancers: 2 lung cancer (BEACOPP), 2 bladder cancer (2 CEC), 1 sarcoma (BEACOPP), 1 Kaposi sarcoma (BEACOPP) and 1 thyroid cancer (ABVD). The risk of second malignancy at 10-year was 6.7, 4.4 and 0.9 for BEACOPP, CEC and ABVD, respectively; the difference between BEACOPP and ABVD was statistically significant (P=0.027).
CONCLUSION : With the updated follow-up of the HD2000 trial we confirm that patients with advanced HL have similar high chances of survival when treated with ABVD, BEACOPP or CEC. With this long-term analysis we were not able to confirm the previously observed superiority of BEACOPP over ABVD in terms of PFS mainly due to a higher rate of secondary malignancies observed after BEACOPP.

Disclosures
No relevant conflicts of interest to declare.