Real-World Evidence of Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, Lenalidomide with or without Polatuzumab (VIPOR(P)) for Relapsed/Refractory Large B-Cell Lymphoma
Authors: Wurm-Kuczera Rebecca , Kouidri Khouloud , Wang Meng , Ali Salahedine , Sahay Shashwat , Winkler David , Leskien Ann-Kristin , Pudasaini Samixa , Kauer Joseph , Krämer Isabelle , Teichert Marcel , Gebauer Niklas , Schnetzke Ulf , Weber Thomas , Frenzel Lukas Peter , Hund Anna-Carina , Shumilov Evgenii , Berisha Mirjeta , Rudzki Jakob Daniel , Scholz Christian W. , Mougiakakos Dimitrios , Lenz Georg , Wulf Gerald , Schmidt-Hieber Martin , von Tresckow Bastian , Dreger Peter , Dreyling Martin , Weigert Oliver , Ishaque Naveed , Keller Ulrich , Pott Christiane , Oellerich Thomas , Chapuy Björn 
Published: December 2024

Roughly 2/3 of patients with large B-cell lymphoma (LBCL) are cured using R-CHOP-like immunochemotherapies, CAR-T-cell therapies or T-cell-engaging bispecific antibodies. The remaining patients experience relapsed or refractory disease (r/r LBCL), with limited treatment options and a dismal prognosis. Molecular insights into the disease hold the promise to improve outcomes. DLBCL is a molecularly heterogeneous disease with recognized transcriptional subtypes, including germinal center derived B-cell (GCB)- and activated B-cell (ABC)-type, which exhibit subtype-specific survival pathways that are druggable.

Capitalizing on the synergistic potential to target these pathways in ABC-type DLBCLs, the ViPOR(P) regimen was designed, consisting of venetoclax, ibrutinib, prednisone, obinutuzumab, lenalidomide with or without polatuzumab vedotin. In the recently published pivotal trial (Melani et al, NEJM 2024), the efficacy of VIPOR was highly encouraging in ABC-type DLBCL, and in high-grade B-cell lymphoma (HGBL) with BCL2 and MYC translocations, with objective responses in 54% of 48 evaluable patients and complete responses in 38%.

In this retrospective, multicenter analysis, we enrolled 48 patients with r/r LBCL treated with ViPOR(P) (VIPOR, 40; VIPORP, 8) in an advanced treatment situation in 16 centers in Germany and Austria to evaluate the efficacy and safety. Patients were considered eligible for the analysis in the intention-to-treat (ITT) cohort, when they had received one cycle of VIPOR(P) and for the sustained treatment cohort (STC), when they had received ≥2 cycles of ViPOR(P).

From the 48 patients enrolled in the ITT cohort, 19 patients received more than 1 cycle and were analyzed in the STC. The main reasons for discontinuation of VIPOR(P) following 1 cycle of VIPOR included progressive disease (17 patients), end of treatment determined by the investigator as VIPOR(P) was used as bridging to CAR-T cell therapy (6 patients), infection-prevented further treatment (3 patients), death due to non-lymphoma reasons (2 patients), medication intolerance (1 patient).

The median age of the STC was 61 years (range:28-71) and most patients had an IPI ≥3 (IPI 3, 9; IPI 4, 6; IPI 5,1); 2/19 patients were GCB-DLBCL, 5/19 were non-GCB DLBCL, one was a T-cell/histiocyte-rich large B-cell lymphoma, six were HGBL with MYC and BCL2 and/or BCL6 translocations, three were DLBCL transformed from indolent lymphoma, one was a follicular lymphoma 3B and one was a classical follicular lymphoma. Seventy-nine percent of the STC were refractory to prior treatment and patients had a median of 4 prior lines of therapy, including 47% of patients that had received prior CAR T-cell therapy. Patients in the STC had received a median of two cycles (range 2-5).

Anemia, thrombocytopenia and neutropenia were present at 95% (18/19), 76% (16/19) and 70% (15/19) of patients, respectively. Grade 3 (26%[5/19]) and grade 4 (5%[1/19]) infections were present in 31% (6/19) of patients, with six patients experiencing fever in neutropenia; GCSF was used in 74% (14/19) of patients.; one patient died of a brain aspergilloses despite prophylactic therapy.

Overall, 60% (9/15) of patients with evaluable imaging-based response assessment responded to VIPOR(P), with 20% (3/15) achieving a CR and 40% (6/15) reaching a partial response. The median progression-free survival was 9 months (95%CI 4-14) and the median overall survival was 12 mo (95% CI 6-18). (26% [5/19]) or allogeneic stem cell transplantation (allo SCT) (11% [2/19]). In the STC, 53% (10/19) of patients remain alive (4 CAR-T, 2 allo SCT, 2 with no consolidation). Overall, 29% (14/48) of patients remain alive and without clinical signs of progression.

In this first real-world series, VIPOR(P) demonstrates promising effectiveness and a largely manageable safety profile in heavily pretreated r/r LBCL patients, expectedly not completely matching the favorable results of the pivotal trial. Nevertheless, this data underscores VIPOR(P)'s potential as a valuable addition to the therapeutic armamentarium for r/r LBCL patients. Most often in this heavily pretreated cohort, VIPOR(P) was used as successful bridging for subsequent consolidative therapies.