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)

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 1^st or 2^nd 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 > 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 > 1 site, p<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.