Treatability with ibrutinib plus venetoclax in patients with CLL in the real-world. the eric international thrive study

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.

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Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-6287
Primary Topic
Chronic Lymphocytic Leukemia Research
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article

Treatability with ibrutinib plus venetoclax in patients with CLL in the real-world. the eric international thrive study

Niki Stavrogianni, Miguel Arturo Pavlovsky, Enrico Derenzini, Fabiana Esposito et al.
Blood
Chronic Lymphocytic Leukemia Research
article

Treatability with ibrutinib plus venetoclax in patients with CLL in the real-world. the eric international thrive study

Niki Stavrogianni, Miguel Arturo Pavlovsky, Enrico Derenzini, Fabiana Esposito, Candida Vitale, Iulia Virginia Iancu, Isacco Ferrarini, Leonidas Benetatos, Maurizio Cavallari, Dominik Chraniuk, Klaudia Zielonka, Livio Trentin, Vanessa Innao, Maura Nicolosi, Sara Pepe, Massimo Gentile, Alessandro Bertolo, Tamar Tadmor, Marina Deodato, Riccardo Moia, Alexandros Machairas, Luca Laurenti, Lydia Scarfò, Anastasia Chatzidimitriou, Oana Stanca, Gian Matteo Rigolin, Francesca Cibien, Horia Bumbea, Ernesto Pérez Persona, Lucia Farina, Krzysztof Jamroziak, Andrea Visentin, Michael Doubek, Κώστας Σταματόπουλος, Laura Ballotta, Maria Ilaria Del Principe, Javier Loscertales, Maria Kislova, Roberta Murru, Mohamed A. Yassin, Thomas Chatzikonstantinou, Nilla Maschio, Antonio Cuneo, Mihnea Zdrenghea, Jacopo Olivieri, Enrico Lista, Anna Maria Frustaci, Giuseppe Petruzzellis, Anna Christoforidou, Marina P. Siakantaris, Marzia Varettoni, Eva Minga, Maria K. Angelopoulou, Paolo Sportoletti, Elżbieta Kalicińska, Paolo Ghia, Alessandro Sanna, Andrea Galitzia, Francesca Martini, Theodoros Vassilakopoulos, Carolina Pavlovsky, Ioannis Kyriakou, Annamaria Tomasso, Eva Gimeno Vázquez, Gianmarco Favrin, Persefoni Talimtzi, Giorgia Marcato
article en

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.

BloodVol. 146(Supplement 1)
Università Cattolica del Sacro Cuore (IT), University of Rome Tor Vergata (IT), University of Verona (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Udine (IT), University of Padua (IT), Carol Davila University of Medicine and Pharmacy (RO), University of Ioannina (GR), BioClinica (United States) (US), University of Ferrara (IT), Masaryk University (CZ), Medical University of Warsaw (PL), University of Perugia (IT), Agostino Gemelli University Polyclinic (IT), Wroclaw Medical University (PL), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale Santa Chiara (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Academia da Força Aérea (BR), Associazione Istituzione Libera Università Nuorese (IT), Institute of Oncology Prof. Dr. Ion Chiricuta (RO), University Hospital Brno (CZ), Azienda Ospedaliera di Cosenza (IT), Ospedale Garibaldi (IT), Istituto Oncologico Veneto (IT), Bnai Zion Medical Center (IL), Laiko General Hospital of Athens (GR), Azienda Ospedaliero-Universitaria Careggi (IT), Navarrabiomed (ES), Rappaport Family Institute for Research in the Medical Sciences (IL), National Center for Cancer Care and Research (QA), Botkin Hospital (RU), Gobierno de Navarra (ES), Hospital Universitario de La Princesa (ES), Hospital Del Mar (ES), Fundación para la Investigación, Docencia y Prevención del Cáncer (AR), IRCCS Ospedale San Raffaele (IT), Centre for Research and Technology Hellas (GR), University General Hospital Attikon (GR), Ospedale dell' Angelo (IT), Azienda di Rilievo Nazionale ed Alta Specializzazione (IT), Ca' Foncello Hospital (IT), Provincial Polyclinical Hospital in Toruń (PL), Policlinico San Matteo Fondazione (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Piedmont University (US), G. Papanikolaou General Hospital (GR), Azienda Sanitaria Universitaria Integrata di Trieste (IT), Azienda Ospedaliera G. Brotzu (IT), European Institute of Oncology (IT), Sapienza University of Rome (IT), Universidad de Navarra (ES)
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