Efficacy and safety of vipor (P) in relapsed or refractory large B-cell lymphoma
Abstract
Abstract Background Relapsed and refractory large B-cell lymphomas (r/r LBCL) remain a therapeutic challenge, particularly after CAR-T cell therapy or bispecific antibodies, where prognosis is dismal with no standard treatment. VIPOR(P) is a biologically guided, multi-targeted regimen combining venetoclax (V), ibrutinib (i), prednisone (P), obinutuzumab (O), and lenalidomide (R) ± polatuzumab vedotin (P). The pivotal phase 1b/2 trial achieved an overall response rate (ORR) of 54% and a complete response (CR) rate of 38%, with preferential activity in ABC-DLBCL and high-grade B-cell lymphomas (HGBCL) harboring MYC and BCL2 rearrangements (Melani et al NEJM 2024). The use of multi-targeted agents prompted concerns about the real-world use of VIPOR(P) due to cumulative toxicity, particularly infections in late-line patients. Moreover, the potential of VIPOR(P) as a bridge-to-CAR-T, especially in chemotherapy-refractory patients, remains unexplored.MethodsWe conducted a retrospective, multicenter study of 56 patients with r/r LBCL treated with VIPOR (77%) or VIPOR(P) (23%) across 18 German and Austrian centers between March 2021 and December 2024 (intention to treat [ITT] cohort). Patients were analyzed in the ITT cohort (n=56), and two subcohorts: i) sustained therapy ≥2 cycles (n=24), and ii) bridge-to-CAR-T (n=17). Response assessment by CT/PET-CT, toxicities per CTCAE v5.0. Whole transcriptome and whole exome sequencing were performed to define cell-of-origin (COO) and genetic subtypes (DLBclass and LymphGen).ResultsWithin the ITT cohort, the median age was 60 years (28–76). Patients were heavily pretreated with a median of 4 prior lines (range 1–12) and poor prognostic features: stage III–IV in 91% and elevated LDH in 93%. Overall, 91% had IPI ≥3 before VIPOR(P), 82% were refractory to the last therapy, and 39% had prior CAR-T cell exposure. Histologies included DLBCL, NOS (57%, thereof 69% ABC, 31% GCB), HGBCL with MYC/BCL2 and/or BCL6 rearrangements (30%), HGBCL, NOS (11%), THRLBCL (2%) and transformed indolent lymphomas (27%, also in other histological subgroups as appropriate).Toxicity exceeded pivotal trial rates, reflecting the late-line, frail population, but was manageable with supportive care. Specifically, hematologic toxicity predominated: neutropenia (grade 3/4 56%), thrombocytopenia (grade 3/4 50%), anemia (grade 3/4 40%), and febrile neutropenia (30%, all grades). Grade 3/4 infections occurred in 25% (4 fatal). Two further patients died of a pulmonary embolism and renal failure. Non-hematologic toxicities included transaminitis (61%), hypokalemia (55%), and nausea (27%) and vomiting (28%).VIPOR(P) induced meaningful responses despite high-risk disease characteristics. ORR/CR rates were 45%/13% (ITT), 61%/22% (sustained), and 50%/0% (bridge-to-CAR-T). Molecular stratification underscored the selectivity of VIPOR(P) for specific LBCL subtypes: Responses were enriched in ABC-DLBCL: ORR 71% (ITT), 80% (sustained), and 100% (bridge-to-CAR-T), while no GCB-DLBCL patients responded. Transformed lymphomas demonstrated few delayed but durable responses exceeding 18 months (ORR: 22%). Among 18 WES-profiled patients, 11 pts had high-risk C2 DLBCLs, with biallelic TP53 inactivation and chemo resistance. A trend toward longer PFS was seen in HGBCL-BCL2 and triple-hit cases as well as transformed lymphoma, while HGBCL-NOS responded poorly.Median follow-up was 6 months; median progression-free survival (PFS) and overall survival (OS) in the ITT cohort were 4 and 5 months, respectively. Twelve-month PFS for imaging-assessed patients was 43% (95% CI: 28-67) (ITT), 55% (35-88) (sustained), and 55% (30-100) (bridge-to-CAR-T), and 12-month OS was 25% (95% CI: 13-46), 42% (22-80), and 42% (20-86), respectively. VIPOR(P) successfully bridged 36% of patients to CAR-T and 9% to allo-HSCT, and 22 patients remained alive at data cutoff.ConclusionsVIPOR(P) demonstrated clinically meaningful activity and a manageable safety profile in r/r LBCL refractory to chemo-immunotherapies. Responses dominated in ABC-DLBCL, aligning with the biologically guided design. Despite higher hematological toxicity observed in more heavily pretreated patients than in the pivotal trial, durable responses in sustained responders and successful bridging of chemo-refractory patients to CAR-T cell therapy highlight the relevance of multi-targeted, chemo-free combination therapies for the treatment of r/r LBCL. *contributed equally as first author
Article Details
Authors (54)
Thomas Oellerich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Rebecca Wurm-Kuczera
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Shashwat Sahay
Meng Wang
Salaheddine Ali
3Charité - University Medical Center Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
Nazli Serin
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center
Khouloud Kouidri
1Weill Cornell Medicine, Medicine, New York, United States
Donika Tahiri
7Department of Medicine 2, Hematology and Oncology, University Medical Center Frankfurt, Goethe University, Hematology and Oncology, Frankfurt, Germany
Sebastian Scheich
Department of Medicine 2, Hematology/Oncology, University Medical Center Frankfurt, Goethe University
Uta Brunnberg
10University Medical Center Frankfurt, Goethe University Frankfurt, Department of Medicine 2, Hematology and Oncology, Frankfurt, Germany
David Winkler
11Charité - Charité-Universitätsmedizin Berlin, Campus Mitte, Institute for Pathology, Berlin, Germany
Samixa Pudasaini
12Ludwig-Maximilian-University (LMU) Hospital, Munich, Department of Internal Medicine III. German Cancer Consortium (DKTK), Munich, and German Cancer Research Center (DKFZ), Heidelberg, Germany., Munich, Germany
Zoi Saxonis
6Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Dept. of Hematology, Stem Cell Transplantation, Oncology and Palliative Medicine, CVK, Berlin, Germany
Atef Abdelhafez
6Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Dept. of Hematology, Stem Cell Transplantation, Oncology and Palliative Medicine, CVK, Berlin, Germany
Tatiana Borodina
13Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Genomics Technology Platform, Berlin, Germany
Ulrike Krueger
13Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Genomics Technology Platform, Berlin, Germany
David Böckle
29Charité -University Medical Center Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
Corinna Leng
29Charité -University Medical Center Berlin, Campus Benjamin Franklin, Department of Hematology, Oncology, and Cancer Immunology, Berlin, Germany
Joseph Kauer
14Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany, Heidelberg, Germany
Isabelle Krämer
14Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany, Heidelberg, Germany
Konstantinos Christofyllakis
1José Carreras Center for Immuno- and Gene Therapy and Department of Internal Medicine I, Saarland University Medical School, Homburg, Germany
Marcel Teichert
1Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany, Essen, Germany
Niklas Gebauer
17University Hospital Schleswig-Holstein, Campus Luebeck, Department for Hematology and Oncology, Lübeck, Germany
Ulf Schnetzke
2Klinik für Innere Medizin II, Abteilung für Hämatologie und Iinternistische Onkologie, Universitätsklinikum Jena, Jena, Germany
Thomas Weber
Lukas Frenzel
20University of Cologne, Faculty of Medicine and Cologne University Hospital, Cologne, Germany
Anna-Carina Hund
21University Hospital Goettingen, Department of Hematology and Medical Oncology, Goettingen, Germany
Evgenii Shumilov
1University Hospital Muenster, Department of Medicine A, Hematology, Oncology and Pneumology, Muenster, Germany
Thomas Melchardt
Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology, and Rheumatology, Cancer Research Laboratory of the Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria
Florian Eisele
2Universitätsklinikum Würzburg, Internal Medicine II, Würzburg, Germany
Mirjeta Berisha
26Otto-von-Guerike University Magdeburg, Dept. of Hematology, Oncology, and Cell Therapy, Magdeburg, Germany
Jakob Rudzki
27University Hospital Innsbruck, Department of Internal Medicine II (Hematology and Medical Oncology), Innsbruck, Austria
Christian Scholz
6Vivantes Klinikum Am Urban, Berlin, Germany
Martin Schmidt-Hieber
27Department of Hematology and Oncology, Medical University Lausitz–Carl Thiem, Cottbus, Germany
Dimitrios Mougiakakos
Johannes Duell
16Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany
Gerald Wulf
1University Medical Center Göttingen, Department of Hematology and Medical Oncology, Göttingen, Germany
Christian Schmidt
Medical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases
Georg Lenz
Bastian von Tresckow
1Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, University of Cologne, and German Hodgkin Study Group, Cologne, Germany
Hans Christian Reinhardt
Richard Greil
Lorenz Thurner
Peter Dreger
Martin Dreyling
LMU Hospital, Munich, Germany
Christiane Pott
6University Hospital Schleswig-Holstein, Department of Internal Medicine II, Kiel, Germany
Martina Rudelius
10Hospital of the Ludwig-Maximilians-University (LMU), Institute of Pathology, Munich, Germany
Oliver Weigert
1University Hospital, LMU, Department of Medicine III, Munich, Germany
Phillipp Strubel
13Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Genomics Technology Platform, Berlin, Germany
Roland Eils
Antonia Busse
Ulrich Keller
Naveed Ishaque
Björn Chapuy
Department of Hematology, Oncology and Tumor Immunology, Charité University Medical Center