Obinutuzumab plus bendamustine for relapsed/refractory chronic lymphocytic leukemia and predictive and prognostic impact of genetic alterations: the phase II GABRIELL study

Abstract

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

Keywords:

• Bendamustine
• chemoimmunotherapy
• chronic lymphocytic leukemia (CLL)
• gene mutations
• obinutuzumab
• prognostic factors

Acknowledgements

The authors would like to thank the GABRIELL study investigators: Alicia Rodríguez Fernández, Hospital Universitario Virgen Macarena, Sevilla, Spain; Ana Muntañola Prat, Hospital Mutua de Terrasa, Barcelona, Spain; Alexia Suárez Cabrera, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain; José Manuel Puerta Puerta, Hospital Universitario Virgen de las Nieves, Granada, Spain; Miguel Fernández Zarzoso, Hospital Universitario Dr. Peset, Valencia, Spain; Mercedes Rodríguez, Hospital de Navarra, Pamplona, Spain; Juana Clavel, Hospital General de Castellón, Castellón, Spain; Maria Victoria Dourdil Sahun, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain; Christelle Ferra Coll, Hospital Universitario German Trias i Pujol, Barcelona, Spain; Ernesto Pérez Persona, Hospital de Txagorritxu, Vitoria, Spain; and Carmen Milagros Marrero Santos, Complejo Hospitalario Nuestra Señora de la Candelaria, Tenerife, Spain.

We are indebted to the patients who consented to participate in this study. We also would like to acknowl­edge Belen Fernandez-Cuevas, Sara Nova Gurumeta and Nuria Perez Sanz for their invaluable help with their technical support with FISH and IGHV sequenc­ing, and Roche Farma S.A for sponsoring the study.

Disclosure statement

J.A. Garcia-Marco has received honoraria for advisory board and speaker´s bureau from Mundipharma, Glaxo, AbbVie, Roche, Gilead, Astra-Zeneca and Janssen, and has received research support from Hoffman-La Roche, AbbVie and Janssen. P. Baltasar Tello has received speaker honoraria from Janssen and Abbvie and has served in an advisory board role for Roche and Janssen. E. Ríos-Herranz has received attendance fees and travel expenses for attending scientific meetings from Abbvie and Janssen, has served on the advisory board for Roche, Servier, and Takeda, has received financial support from Roche for attendance at educational and training programs, and has received speaker bureau honoraria. A. Ramírez Páyer has received speaker honoraria from Janssen, Takeda, Roche, BMS, Novartis, Pfizer, Abbvie and EUSA Pharma and has served on the advisory board role for Roche, Abbvie, Janssen, EUSA Pharma, Takeda, Novartis, BMS and Pfizer. M. Terol has received attendance fees and travel expenses for attending scientific meetings from Roche, Abbvie, Janssen, Takeda and Gilead, has served on the advisory board for Roche, Janssen, Takeda, Gilead and Abbvie, and has received speaker bureau honoraria from Roche Janssen and Abbvie, and research support from Gilead and Janssen. D. Champ is a Roche Farma employee (Medical Department). A. Medina has received speaker honoraria from Janssen, Roche and Abbvie and has served in an advisory board for Abbvie and Janssen. M. Gironella has received attendance fees and travel expenses for attending scientific meetings from Takeda, Roche and Janssen. M. Fernández Zarzoso has received honoraria for advisory board from Roche, Janssen and Takeda, has received honoraria as speaker in scientific meetings from Janssen and AbbVie, and has received attendance fees and travel expenses for attending scientific meetings from Takeda, Janssen and Roche. J. Bravo, R. Forés, and J. Delgado have no conflicts of interest to disclose.

Data sharing statement

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Additional information

Funding

Roche Farma S.A sponsored the study. Medical writing and editorial support were provided by Cristina Vidal and Antonio Torres-Ruiz from Dynamic Science S.L. (Spain), and was funded by Roche Farma S.A.