The Addition of Brentuximab Vedotin to ESHAP Significantly Increases the Rate of Metabolic Complete Remissions Vs Chemotherapy Alone. in Patients with Relapsed/Refractory Classical Hodgkin's Lymphoma. Final Results of a Phase IIb Prospective Randomized Clinical Trial (BRESELIBET)
Authors: Sureda Balarí Anna Maria , Nuñez Cespedes Javier , Terol Castera María José , Hernandez Francisca Maria , Domingo Domenech Eva , De la Cruz Vicente Fatima , Moreno Miram , Amutio Elena , Gonzalez Ana Pilar , Cordoba Raul , Martinez Munoz Maria Carmen , Romero Samuel , Bastos-Oreiro Mariana , Rodriguez Izquierdo Antonia , Briones Javier , Greil Richard , Casanova Espinosa Maria , Rubio Araceli , Avivi Irit , Del Campo Raquel , Gómez Pilar , Vassilakopoulos Theodoros P. , Bašić-Kinda Sandra , Papageorgiou Sotiros , Noriega Concepcion Victor , Sanchez Blanco Jose , Sánchez-González Blanca , Zeberio Izaskun , García Ramon 
Published: December 2024

INTRODUCTION:
Autologous stem cell transplantation (auto-HCT) is still considered the standard of care for relapsed / refractory Hodgkin's lymphoma (RRHL) patients (pts) if the disease demonstrates to be chemosensitive to salvage treatment strategies. In fact, the achievement of a metabolic complete remission (mCR) before auto-HCT is the most important factor that impacts their long-term outcome. Best salvage treatment for RRHL is unknown; superiority of brentuximab vedotin (BV) + chemotherapy (CT) vs CT alone has never been tested in randomized trials although the potential benefit of adding BV in a sequential or concomitant mode to conventional salvage CT has been indicated in several phase I/II prospective clinical trials. It is also unknown if consolidation with BV could eventually spare auto-HCT in good risk RRHL pts. BRESELIBET (ClinicalTrials.gov ID: NCT04378647) is a phase IIb prospective clinical trial that evaluates the efficacy of BV-ESHAP vs ESHAP in RRHL, followed by BV consolidation in pts attaining a mCR.
METHODS:
Adult (age ³ 18 years) pts with RRHL after first line CT were randomized 1:1 to receive either BV-ESHAP (q21 days, 3 cycles) vs ESHAP (q21 days, 3 cycles). Those pts that achieved a mCR after 3 cycles continued with BV consolidation (13 or 16 cycles, respectively, 1.8 mg/kg iv q3wks). Pts with active disease went off protocol and were treated according to the responsible physician. Peripheral blood stem cells were collected after the 1st or 2nd cycle. Primary objective was to determine mCR (Deauville scores 1-3) after 3 cycles of therapy; key secondary objectives were 2-years progression free survival (PFS), 2-years overall survival in those pts in mCR who continued consolidation with BV, differences in hematological and non-hematological toxicities between BV-ESHAP vs ESHAP and stem cell collection yield in pts treated with BV-ESHAP vs ESHAP.
RESULTS:
160 adult pts with RRHL were included from 05/2020 to 10/2023 and 151 [88 (58.3%) males, median age of 39 years (18-65)] were randomized 1:1 between BV-ESHAP (n=76) and ESHAP (n=75).BV-ESHAP and ESHAP arms were well balanced; 53 pts (35.5%) were primary refractory, 79 pts (52.3%) had nodular sclerosis subtype, 79 (52.3%) relapsed in advanced stage (III-IV), 24 (15.9%) had &gt; 1 extranodal site, 13 (8.6%) bulky mass and 37 (24.5%), B symptoms. The primary endpoint was met: mCR was 69.7% in BV-ESHAP pts vs 48.0% in ESHAP (p=0.007). Final logistic regression model indicated that not only treatment arm (BV-ESHAP vs ESHAP, p=0.003) but also disease status (primary refractory vs early relapse vs late relapse, p=0.007) and extranodal disease (no vs 1 site vs &gt; 1 site, p&lt;0.001) were independent prognostic factors for mCR. 52 treatment-related adverse events (TRAE) grade 3-4 have been reported in the BRESHAP arm vs 63 grade 3-4 TRAE in ESHAP. No cases of grade 3-4 peripheral sensory or motor neuropathy were reported. 73 pts entered into the consolidation phase and received 13 (1-16) cycles of BV; there have been 11 relapses (15%) after 5 (2 - 16) cycles of BV, 9 of them during the first year. No relapses have happened during the follow up and 38 patients have finished BV therapy. Ten patients discontinued consolidation due to AE (9 polyneuropathy, 1 pneumonitis) and 11 due to disease relapse. With a median follow up of 10 (1 - 36.5) mo after the beginning of consolidation, PFS is 79.4% (95%CI 67.9 - 90.9) at 24 mo.
CONCLUSIONS:
BRESELIBET trial demonstrates that the association of BV to ESHAP results in a significantly higher proportion of mCR than ESHAP alone with no additional toxicity signals; BV consolidation might eventually substitute auto-HCT in patients that achieve a mCR after salvage therapy.