Treatability with ibrutinib plus venetoclax in patients with CLL in the real-world. the eric international thrive study
Abstract
Abstract Background. Clinical trials have documented the efficacy of ibrutinib in combination with venetoclax in CLL. Indeed, Ibrutinib plus venetoclax (I+V) is the first all oral fixed duration treatment approved for treatment naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) based on the results of the Captivate (phase II) and GLOW (phase III) trials. Discontinuation rates due to adverse events (AEs) were 5% in the Captivate trial, which enrolled patients with ≤70 yrs, and 10.4% in the GLOW trial, which included older and comorbid patients without del(17p). We hypothesized that, when appropriately selected, patients of all ages can tolerate and benefit from I+V. Methods. This is the interim analysis of a retrospective multicenter study aiming at investigating the safety and efficacy of I+V in the real-world setting. Patients with previously untreated CLL/SLL, 18 years or older, who have completed 3 cycles of I and started V were eligible for the study. Patients treated with I+V in clinical trials were excluded. All patients were scheduled to receive fixed-duration I+V. After 3 lead-in cycles of I (420mg once daily), V was added for 12 cycles with the standard weekly ramp-up (20-50-100-200-400mg). The primary objective of this study was to determine the rate of discontinuation due to toxicity of I+V. Secondary objectives included overall response (ORR), safety, baseline characteristics associated with treatment discontinuation, and survival analysis. Results. We gathered data from 220 patients (intention-to-treat population) from 45 institutions in 11 countries. At the time of data cut-off, 14 patients were still receiving I lead-in, and 4 discontinued I before initiating V [reasons for discontinuation: 2 atrial fibrillation (AF), 1 diarrhea, and 1 grade 5 infection]. Overall, 202 patients were included in the analysis (treated population). The median age at I+V initiation was 65 years [interquartile range (IQR) 56-70]. Most patients were males (121, 59.9%), and 24 (12.3%) had an ECOG performance status of 2 or higher. Regarding prognostic markers, 112/179 (62.6%) patients carried unmutated IGHV genes, and 29/148 (16.4%) and 7/192 (3.6%) had del(11q) and del(17p) (determined by fluorescence in situ hybridization), respectively. TP53 mutations were present in 7/171 (4.1%) cases. At the data cut-off (30 June 2025), 201 (99.5%) patients were alive, and 151 (82.1%) were still on treatment. Among the 190 with at least 6 months of follow-up available for response assessment, the overall response rate was 95.6%. AEs of any grade were present in 122 (61.6%) patients. Specifically, 86 (43.4%) experienced non-hematological AEs, of which 23 (11.3%) were grade 3 or higher (including, 9 infective events, including 2 febrile neutropenia; 4 arterial hypertension; 3 AF; 1 rash; 1 diarrhea; 1 ventricular arrhythmia). No fatal treatment-related AEs have been reported to date. Seven (3.6%) patients developed laboratory tumor lysis syndrome (TLS), but no clinical TLS occurred. One patient developed Richter transformation (large B-cell lymphoma variant). Regarding hematological AEs, grade 3 or higher neutropenia, anemia and thrombocytopenia occurred in 48 (64.8%), 9 (20.9%), and 6 (15%) of patients, respectively. One patient died after being diagnosed with lung cancer. Seven (3.4%) patients discontinued I+V due to toxicity. Reasons for discontinuation included: acute generalized exanthematous pustulosis; AF; ventricular arrhythmia; heart failure (I was discontinued but V was completed as per treatment plan); neutropenia and heart failure; recurrent urinary tract infections and diarrhea; AF and stroke. The median age of patients who discontinued I+V treatment was 64.5 years (IQR 64-74). Five (71.4%) had at least one comorbidity: the most common was arterial hypertension (3/7, 43%). The discontinuation rates for patients in a Captivate-like (aged ≤ 70 years) and Glow-like (≥ 65 years without del17p) subgroups were 3.2% (5/153) and 4.9% (5/102), respectively. Conclusions. We herein confirm the efficacy and tolerability of I+V in the real-world setting. Notably, the discontinuation rate of I+V in our study compares favorably with the discontinuation rate in pivotal clinical trials, even in elderly patients, suggesting that I+V is an appropriate treatment option in a broad patient population. Longer follow-up will allow the assessment of real-world progression-free survival and time to next treatment after I+V.
Article Details
Authors (68)
Andrea Visentin
8Hematology Unit, Department of Medicine, University of Padova, Padova, Italy
Thomas Chatzikonstantinou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Lydia Scarfò
School of Medicine, Università Vita Salute San Raffaele, Milan
Persefoni Talimtzi
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Maria Angelopoulou
2Department of Haematology, University of Athens, Laikon General Hospital, Athens, Greece
Tomas Arpas
5Department of Internal Medicine - Hematology and Oncology, Faculty of Medicine, Masaryk University and University Hospital Brno, Brno, Czech Republic
Laura Ballotta
6Azienda Sanitaria Universitaria Giuliano Isontina Ospedale Maggiore, Trieste, Italy
Leonidas Benetatos
7Department of Hematology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
Ana Margarida Bertolo
8Hospital de Forca Aerea do Galeao HFAG, Rio de Janeiro, Brazil
Horia Bumbea
9University of Medicine and Pharmacy Carol Davila, Emergency University Hospital Bucharest,Romania, Bucarest, Romania
Maurizio Cavallari
10Hematology Section, Ospedale dell'Angelo, Venice Mestre, Italy
Anastasia Chatzidimitriou
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Dominik Chraniuk
11Hematology Ward, Wojewodzki Szpital Zespolony im. L. Rydygiera, Torun, Poland
Anna Christoforidou
12Hematologist of Hematology Department, Bioclinic Salonica, Thessaloniki, Greece
Francesca Cibien
13Hematology Unit, Ca' Foncello Hospital, Treviso, Italy
Antonio Cuneo
1University of Ferrara
Maria Ilaria del Principe
15Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Marina Deodato
16ASST Grande Ospedale Metropolitano Niguarda, Niguarda Cancer Center, Milan, Italy
Enrico Derenzini
17Oncohematology Division, IEO European Institute of Oncology IRCCS, Department of Health Sciences, University of Milan, Milan, Italy
Michael Doubek
19Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University; CEITEC MU, Brno, Czech Republic, Brno, Czech Republic
Fabiana Esposito
15Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Lucia Farina
1Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
Gianmarco Favrin
University of Pavia, Pavia, Italy
Isacco Ferrarini
21Hematology unit, Department of Engineering for Innovation Medicine Section of Biomedicine, University of Verona, Verona, Italy
Annamaria Frustaci
26ASST GOM Niguarda, Milano, Italy
Andrea Galitzia
22Struttura complessa di Ematologia, Ospedale S Francesco, ASL Nuoro, Nuoro, Italy
Massimo Gentile
Azienda Ospedaliera Annunziata, Cosenza, Italy
Iulia Roxana Iancu
24Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Vanessa Innao
25UOC di Ematologia, Azienda Ospedaliera di rilievo nazionale di alta specializzazione, ARNAS-G-Garibaldi di Catania, Catania, Italy
Krzysztof Jamroziak
Medical University of Warsaw, Warsaw, Poland
Elżbieta Kalicińska
Maria Kislova
27Department of Hematology, Oncology, and Chemotherapy, S. P. Botkins City Hospital, Moscow, Russian Federation
Ioannis Kyriakou
29Hematology Department and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece
Luca Laurenti
2Department of Diagnostic Imaging, Oncological Radiotherapy and Hematology, Agostino Gemelli University Hospital Foundation IRCCS, Rome, Italy
Enrico Lista
31Division of Hematology. Santa Chiara Hospital. APSS Trento, Trento, Italy
Javier Loscertales
Hospital Universitario La Princesa, Madrid
Alexandros Machairas
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Giorgia Marcato
33Oncoematologia Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
Francesca Martini
Dipartimento di Chimica e Chimica Industriale
Nilla Maschio
33Oncoematologia Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
Eva Minga
1Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece
Riccardo Moia
32Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
Roberta Murru
11Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS “G. Brotzu”, Cagliari, Italy
Maura Nicolosi
36Hematology Division A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
Jacopo Olivieri
9Azienda Ospedaliera di Udine, Udine, Italy
Carolina Pavlovsky
38FUNDALEU, Clinical Research Center, Buenos Aires, Argentina
Miguel Pavlovsky
6Fundaleu, Buenos Aires, Argentina
Sara Pepe
39Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
Ernesto Perez Persona
40Hospital Universitario de Navarra, Navarra, Spain
Giuseppe Petruzzellis
37Division of Hematology and Stem Cell Transplantation, University Hospital ASUFC, Udine, Italy
Gian Matteo Rigolin
16St. Anna University Hospital - Department of Medical Sciences, University of Ferrara, l, Ferrara, Italy
Alessandro Sanna
41Hematology Unit, AOU Careggi, University of Florence, Florence, Italy
Marina Siakantaris
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Paolo Sportoletti
Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy
Oana Stanca
44Carol Davila University of Medicine and Pharmacy, Coltea Clinical Hospital- Hematology, Bucharest, Romania
Niki Stavrogianni
41Hematology Department and HCT Unit G. Papanicolaou Hospital, Thessaloniki, Greece
Tamar Tadmor
Bnai Zion Medical Center, Technion, Haifa, Israel
Annamaria Tomasso
30Università Cattolica del Sacro Cuore, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
Marzia Varettoni
4Division of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy
Theodoros Vassilakopoulos
18Hematology, University of Athens, Laikon General Hospital, Athens, Greece
Eva Gimeno Vazquez
47Department of Hematology Hospital del Mar, Barcelona, Spain
Candida Vitale
42Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
Mohamed Yassin
Mihnea Zdrenghea
24Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Klaudia Zielonka
26Department of Hematology, Transplantation and Internal Medicine Medical University of Warsaw, Warsaw, Poland
Livio Trentin
Hematology Unit, Department of Medicine, University of Padua
Kostas Stamatopoulos
Institute of Applied Biosciences at the Centre for Research and Technology Hellas
Paolo Ghia
School of Medicine, Università Vita Salute San Raffaele, Milan