First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial - 29/05/24
, Arnon P Kater, ProfMD c, Sandra Robrecht, PhD a, b, Julia von Tresckow, MD d, Can Zhang, PhD a, b, Michael Gregor, MD e, Patrick Thornton, ProfMD f, Philipp B Staber, MD g, Tamar Tadmor, MD h, Vesa Lindström, MD i, Gunnar Juliusson, ProfMD j, Ann Janssens, ProfMD k, Mark-David Levin, MD l, Caspar da Cunha-Bang, MD m, Christof Schneider, MD n, Neta Goldschmidt, MD o, Elisabeth Vandenberghe, ProfMD p, Davide Rossi, MD q, Rudolf Benz, MD r, Thomas Nösslinger, MD s, Daniel Heintel, MD t, Christian B Poulsen, MD u, Ilse Christiansen, MD v, Henrik Frederiksen, MD w, Lisbeth Enggaard, MD x, Eduardus F M Posthuma, MD y, Djamila E Issa, MD z, Hein P J Visser, MD aa, Mar Bellido, MD ab, Nadine Kutsch, MD a, b, Jan Dürig, ProfMD ac, Alexander Stehle, MD ad, Matthias Vöhringer, MD ad, Sebastian Böttcher, ProfMD ae, Clemens Schulte, MD af, Florian Simon, MD a, b, Anna-Maria Fink, MD a, b, Kirsten Fischer, MD a, b, Emily E Holmes, PhD a, b, Karl-Anton Kreuzer, MD a, b, Matthias Ritgen, MD ag, Monika Brüggemann, MD ag, Eugen Tausch, MD n, Stephan Stilgenbauer, ProfMD n, Michael Hallek, ProfMD a, b, Carsten U Niemann, MD m, †, Barbara Eichhorst, MD a, b, †Summary |
Background |
In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available.
Methods |
GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0–2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1–2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1–3) and intravenous cyclophosphamide (250 mg/m2, days 1–3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax–rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2–6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2–6: 1000 mg on day 1). In the venetoclax–obinutuzumab–ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax–rituximab and the venetoclax–obinutuzumab group and between 12 and 36 cycles in the venetoclax–obinutuzumab–ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment.
Findings |
Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax–rituximab group n=237; venetoclax–obinutuzumab group n=229; and venetoclax–obinutuzumab–ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6–57·9]), patients in the venetoclax–obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32–0·69], p<0·0001) and the venetoclax–rituximab group (0·57 [0·38–0·84], p=0·0011). The venetoclax–obinutuzumab–ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19–0·47]; p<0·0001) and the venetoclax–rituximab group (0·38 [0·24–0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax–obinutuzumab–ibrutinib and venetoclax–obinutuzumab groups (0·63 [0·39–1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax–rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9–91·1; 37 [16%] events) in the venetoclax–obinutuzumab–ibrutinib group, 81·8% (75·8–87·8; 55 [24%] events) in the venetoclax–obinutuzumab group, 70·1% (63·0–77·3; 84 [35%] events) in the venetoclax–rituximab group, and 62·0% (54·4–69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax–rituximab group, 127 [56%] of 228 in the venetoclax–obinutuzumab group, and 112 [48%] of 231 in the venetoclax–obinutuzumab–ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter’s syndrome), none in the venetoclax–rituximab and venetoclax–obinutuzumab groups, and four (2%) in the venetoclax–obinutuzumab–ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy).
Interpretation |
With more than 4 years of follow-up, venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax–rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination.
Funding |
AbbVie, Janssen, and F Hoffmann-La Roche.
Le texte complet de cet article est disponible en PDF.Plan
Vol 25 - N° 6
P. 744-759 - juin 2024 Retour au numéro
Article précédent
- Long-term survival for lymphoid neoplasms and national health expenditure (EUROCARE-6): a retrospective, population-based study
- Milena Sant, Claudia Vener, Roberto Lillini, Silvia Rossi, Simone Bonfarnuzzo, Rafael Marcos-Gragera, Marc Maynadié, Kaire Innos, Keiu Paapsi, Otto Visser, Alice Bernasconi, Elena Demuru, Corrado Di Benedetto, Seyed Mohsen Mousavi, Marcel Blum, Philip Went, Diego Serraino, Damien Bennett, Maria-Jose Sánchez, Roberta De Angelis, EUROCARE-6 Working Group, Monika Hackl, Elizabeth Van Eycken, Nancy Van Damme, Zdravka Valerianova, Mario Sekerija, Vasos Scoutellas, Anna Demetriou, Ladislav Dušek, Denisa Krejici, Hans Storm, Margit Mägi, Kaire Innos, Janne Pitkäniemi, Michel Velten, Xavier Troussard, Anne-Marie Bouvier, Valerie Jooste, Anne-Valérie Guizard, Guy Launoy, Sandrine Dabakuyo Yonli, Marc Maynadié, Anne-Sophie Woronoff, Jean-Baptiste Nousbaum, Gaëlle Coureau, Alain Monnereau, Isabelle Baldi, Karima Hammas, Brigitte Tretarre, Marc Colonna, Sandrine Plouvier, Tania D’Almeida, Florence Molinié, Anne Cowppli-Bony, Simona Bara, Adeline Debreuve, Gautier Defossez, Bénédicte Lapôtre-Ledoux, Pascale Grosclaude, Laetitia Daubisse-Marliac, Sabine Luttmann, Andrea Eberle, Roland Stabenow, Alice Nennecke, Joachim Kieschke, Sylke Zeissig, Bernd Holleczek, Alexander Katalinic, Helgi Birgisson, Deirdre Murray, Paul M Walsh, Guido Mazzoleni, Fabio Vittadello, Francesco Cuccaro, Rocco Galasso, Giuseppe Sampietro, Stefano Rosso, Cinzia Gasparotti, Giovanni Maifredi, Margherita Ferrante, Rosalia Ragusa, Antonella Sutera Sardo, Maria Letizia Gambino, Monica Lanzoni, Paola Ballotari, Erica Giacomazzi, Stefano Ferretti, Adele Caldarella, Gianfranco Manneschi, Gemma Gatta, Milena Sant, Paolo Baili, Franco Berrino, Laura Botta, Annalisa Trama, Roberto Lillini, Alice Bernasconi, Simone Bonfarnuzzo, Claudia Vener, Fabio Didonè, Paolo Lasalvia, Lucia Buratti, Giovanna Tagliabue, Diego Serraino, Luigino Dal Maso, Riccardo Capocaccia, Roberta De Angelis, Elena Demuru, Francesco Cerza, Fabrizio Di Mari, Corrado Di Benedetto, Silvia Rossi, Mariano Santaquilani, Serenella Venanzi, Marco Tallon, Luca Boni, Silvia Iacovacci, Valerio Gennaro, Antonio Giampiero Russo, Federico Gervasi, Gianbattista Spagnoli, Luca Cavalieri d’Oro, Mario Fusco, Maria Francesca Vitale, Mario Usala, Walter Mazzucco, Maria Michiara, Giorgio Chiranda, Giuseppe Cascone, Concetta Patrizia Rollo, Lucia Mangone, Fabio Falcini, Rossella Cavallo, Daniela Piras, Anselmo Madeddu, Francesca Bella, Anna Clara Fanetti, Sante Minerba, Giuseppina Candela, Tiziana Scuderi, Roberto Vito Rizzello, Fabrizio Stracci, Massimo Rugge, Angelita Brustolin, Santa Pildava, Giedre Smailyte, Miriam Azzopardi, Tom Børge Johannesen, Joanna Didkowska, Urszula Wojciechowska, Magdalena Bielska-Lasota, Ana Pais, Maria José Bento, Ana Maia Ferreira, António Lourenço, Chakameh Safaei Diba, Vesna Zadnik, Tina Zagar, Carmen Sánchez-Contador Escudero, Paula Franch Sureda, Arantza Lopez de Munain, Marta De-La-Cruz, María Dolores Rojas, Araceli Aleman, Ana Vizcaino, Rafael Marcos-Gragera, Arantza Sanvisens, Maria Josè Sanchez, Maria Dolores Chirlaque Lopez, Antonia Sanchez-Gil, Marcela Guevara, Eva Ardanaz, Jaume Galceran, Maria Carulla, Yvan Bergeron, Christine Bouchardy, Seyed Mohsen Mousavi, Philip Went, Marcel Blum, Andrea Bordoni, Otto Visser, Sarah Stevens, John Broggio, Damien Bennett, Anna Gavin, David Morrison, Dyfed Wyn Huws
- Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis
- Huseyin Naci, Yichen Zhang, Steven Woloshin, Xiaodong Guan, Ziyue Xu, Anita K Wagner
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?