Combined escBEACOPP-ABVD Therapy for Advanced Hodgkin’s Lymphoma Patients with High IPS Score: An Effective Regimen and Low Positive Predictive Value of Early FDG-PET/CT Scan.
Authors: Avigdor Abraham , Bulvik Shlomo , Dann Eldad , Levi Itai , Perez-Avraham Galit , Shemtov Noga , Shimoni Avichai , Nagler Arnon , Ben-Bassat Isaac , Polliack Aaron 
Published: April 2020

Abstract
The expected 5-year freedom from progression of advanced stage Hodgkin’s lymphoma (HL) patients (pts) with IPS≥3, treated with COPP-ABVD, was reported as 55%. While the superiority of escalated (esc) BEACOPP regimen over COPP-ABVD was shown for all risk groups, it was more pronounced in pts with a poor IPS. However, pts receiving escBEACOPP had more acute and long-term toxicities including a higher incidence of MDS/AML. In an attempt to reduce this toxicity, while preserving improved initial tumor control in this high risk group of pts, we conducted a phase II study, which tested the feasibility, toxicity and efficacy of a regimen which utilized the combination of escBEACOPP and ABVD. Newly diagnosed HL pts, with unfavorable stage IIB or stages III–IV with IPS≥3 were initially received two cycles of escBEACOPP followed by reevaluation with FDG- PET/CT scans. When complete or partial response (CR, PR) was achieved, pts then continued to receive four cycles of ABVD, while pts who failed to obtain this response were planned to receive salvage therapy. Since starting in late 2001, 40 eligible pts received this regimen. Median age at diagnosis was 27 years (range 18–56) and 29 (73%) were males. Histology included nodular sclerosis (n=30), mixed cellularity (n=6) and unclassified (n=4). Stage IV, III and IIB were evident in 29 (73%), 8 (20%) and 3 (7%) pts, respectively and extranodal involvement was noted in 28 (70%). Following the first two cycles of escBEACOPP the overall response rate (CR+PR) was 100% and at the end of all therapy 36 (90%) pts were in CR, 2 (5%) in PR and 2 (5%) pts had progressive disease. After a median follow-up of 30 months (range 7–61), 38 pts are alive while two pts died from progressive HL. The estimated 5-year Progression free survival (PFS) and overall survival rates were 78% (95% CI, 64–92%) and 91% (95% CI, 78–100%), respectively. The 5-year cumulative incidence of relapse was 13% (95% CI, 5-33%). These survival rates are higher than those expected for ABVD containing regimens and comparable with the reported estimated long term survival rates achieved with the poor prognostic subgroup of pts, receiving eight cycles of escBEACOPP in the GHLSG HD9 trial. Furthermore, the estimated 5-year PFS rate for early PET negative pts (n=27) and for early PET positive pts (n=11) was 82% (95% CI, 66–98%) and 64% (95%, CI 35–92%), respectively (P=0.14) (in 2 pts early PET results were not conclusive). In terms of treatment failure, the positive predictive value was only 35%, while the negative predictive value was 85%. As expected, the incidence of acute hematologic toxicities was more common in the escBEACOPP than in the ABVD phase. Non hematologic adverse effects included grade III–IV infection (n=1), avascular necrosis of the hip (n=1) and cognitive impairment (n=1). In conclusion, combined escBEACOPP-ABVD therapy is well tolerated and may improve the outcome in pts with advanced HL who have high IPS scores. Larger scale randomized studies, comparing this combination regimen with previously reported dose-intensified chemotherapy regimens, are required in order to verify its true merit in this high risk subgroup of pts.