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Rituximab plus bendamustine or chlorambucil in CLL
ria that were based on the prescribing information for flu- darabine at the time of study design; the Cumulative Illness Rating Scale scoring was not used. However, a recent randomized study comparing the efficacy of ibruti- nib with Clb used an age cut-off of 65 years as the only criterion for selecting “older” patients, and did not carry out any assessment of comorbidities.23
Although the efficacy of immunochemotherapy combi- nations such as R-B, Ofa-Clb, and G-Clb in CLL have been shown,7,11,19 obinutuzumab plus B (G-B) needs to be evalu- ated further, although it is likely that future clinical studies will focus more on the combination of anti-CD20 anti- bodies with novel agents such as ibrutinib, idelalisib, and venetoclax. Indeed, these agents have shown promising efficacy when combined with anti-CD20 monoclonal antibodies (including rituximab) in the relapsed/refractory CLL setting,24-29 and are now being evaluated in 1L.23 Furthermore, additional safety data for 1L B-cell receptor (BCR) signaling inhibitors are required. In March 2016, the US Food and Drug Administration alerted healthcare pro- fessionals about safety concerns with idelalisib when used in combination with rituximab or R-B in CLL and follicu- lar lymphoma. This was related to a high rate of viral and fungal infections that led the sponsor to discontinue six trials.30
However, given the economic burden associated with new agents and the fact that BCR inhibitors are not yet available in many European countries, immunochemother- apy combinations are likely to continue to be valuable treat- ment options for 1L patients with CLL.31
In conclusion, in fludarabine-ineligible CLL patients, 1L R-B treatment significantly improved CR rates and medi- an PFS versus R-Clb, and increased MRD-negativity rates, with no new safety signals reported. R-B may be a valu- able 1L option for fludarabine-ineligible CLL patients and this combination continues to be widely used in clinical practice in Europe, reinforcing the interest of this large randomized study.
List of MABLE investigators and centers
Seppo Vanhatalo, Satakunta Central Hospital, Pori, Finland; Kimmo Porkka, HUS/Medisiininen tulosyksikkö/Hematologian klinikka, Haartmaninkatu, Finland; Anne-Sophie Michallet, Centre Hospitalier Lyon Sud, Pierre-Bénite, France; Bruno Royer, Hôpital Sud, Salouel, France; Olivier Boulat, Centre Hospitalier Henri Duffaut, Avignon, France; Christian Berthou, Hôpital Morvan – CHU Brest, France; Dominique Bordessoule, CHU de Limoges, France; Jean-Claude Eisenmann, Centre Hospitalier de Mulhouse, France; Jean-Michel Karsenti, Hôpital Archet 1, Nice, France; Eric Jourdan, CHU de Nîmes, France; Véronique Leblond, Hôpital de la Pitié-Salpêtrière, Paris, France; Laurence Sanhes, Hôpital Saint Jean, Perpignan, France; Mourad Tiab, Centre Hospitalier Départemental Vendée, La Roche Sur Yon, France; Kamel Laribi, Centre Hospitalier du Mans, Le Mans, France; Régis Costello, Hôpital la Conception, Marseille, France; Lysiane Molina, Hôpital Nord – Michallon, La Tronche, France; Laurent Sutton, CH Victor Dupouy, Argenteuil, France; Abderrazak El Yamani, Centre Hospitalier de Blois, France; João Raposo, Centro Hospitalar de Lisboa Norte, Lisbon, Portugal; Emília Cortesão, Centro Hospitalar e Universitário de Coimbra, Portugal; Cristina João, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal; Joaquim Andrade, Hospital de São João, Oporto, Portugal; Ângelo Martins, Instituto Português de Oncologia do Porto Francisco Gentil,
Oporto, Portugal; José Antonio García Marco, Hospital Universitario Puerta de Hierro, Madrid, Spain; Marcos González Díaz, Hospital Universitario de Salamanca, Spain; Francisco Javier de la Serna Torroba, Hospital Universitario 12 de Octubre, Madrid, Spain; Carolina Moreno Atanasio, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain; José María Moraleda Jiménez, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; M. Pilar Giraldo Castellano, Hospital Miguel Servet, Zaragoza, Spain; Macarena Ortiz Pareja, Hospital Regional Carlos Haya, Málaga, Spain; Alicia Rodríguez Fernández, Hospital Virgen Macarena, Sevilla, Spain; José Ignacio Olalla Antolín, Hospital Sierrallana, Cantabria, Spain; Emilio Montserrat Costa, Hospital Clínic de Barcelona, Spain; Christelle Ferra Coll, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; Kristina Wallman, Falu Iasarett, Falun, Sweden; Birgitta Lauri, Sunderby Sjukhus, Luleå, Sweden; Maria Strandberg, Sundsvall County Hospital, Sweden; Peter Johansson, Uddevalla County Hospital, Sweden; Honar Cherif, The Academic Hospital, Uppsala, Sweden; Alicja Markuszewska-Kuczynska, Norrlands Universietetssjukhus, Umeå, Sweden; Lars Timberg, Medicinkliniken, Kristianstad, Sweden; Balkis Meddeb, Hôpital Aziza Othmana, Tunis, Tunisia; Ilhan Osman, Ankara University Medical Faculty, Turkey; Filiz Vural and Seckin Cagirgan, Ege University Medical Faculty, Izmir, Turkey; Yagci Munci, Gazi University Medical Faculty, Ankara, Turkey; Undar Buient, Dokuzeylul University Medical Faculty, Izmir, Turkey; Nilgun Sayinalp, Hacettepe University Medical Faculty, Ankara, Turkey; Melih Aktan, Istanbul University Medical Faculty, Turkey; Mehmet Turgut, Ondokuzmayis University Medical Faculty, Samsun, Turkey; Muzaffer Demir, Trakya University Medical Faculty, Edirne, Turkey; Ali Unal, Erciyes Universitesi Medical Faculty, Kayseri, Turkey; Zafer Gulbas, Anadolu Health Center, Kocaeli, Turkey; Marion Macheta, Blackpool Victoria Hospital, UK; Stephen Devereux, Kings College Hospital, London, UK; Anna Schuh, Oxford Radcliffe Hospitals, UK; Adrian Bloor, Christie NHS Foundation Trust, Manchester, UK; Saad Rassam, Maidstone and Tunbridge Wells NHS Trust, Maidstone, UK; Julie Blundell, Royal Cornwall Hospital, Truro, UK; Renata Walewska, The Royal Bournemouth & Christchurch Hospital NHS Foundation Trust, Bournemouth, UK; Claire Hemmaway, Queens Hospital, Romford, UK; Peter Hillmen, St. James’ University Hospital, Leeds, UK.
Acknowledgments
The authors would like to thank the patients and their families, and the study investigators, study coordinators, and nurses who assisted with the rituximab clinical program. We would also like to thank Mundipharma for provision of bendamustine for use in this study. AS is supported by the Oxford Partnership Comprehensive Biomedical Research Centre with funding from the Department of Health’s National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. The views expressed in this publication are those of the authors and not nec- essarily those of the UK Department of Health. MABLE was sponsored by F. Hoffmann-La Roche Ltd, with provision of ben- damustine and financial support from Mundipharma. Third- party medical writing assistance, under the direction of the authors, was provided by Susan Browne, PhD, of Gardiner- Caldwell Communications (Macclesfield, UK) and funded by F. Hoffmann-La Roche Ltd.
Funding
This work was funded by F. Hoffmann-La Roche Ltd.
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