ALBI Grade Enables Risk Stratification for Bleeding Events and Refines Prognostic Prediction in Advanced HCC Following Atezolizumab and Bevacizumab

Bernardo Stefanini,1,2 Claudia Angela Maria Fulgenzi,1,3 Bernhard Scheiner,1,4 James Korolewicz,1 Jaekyung Cheon,5 Naoshi Nishida,6 Celina Ang,7 Thomas U Marron,7 Y Linda Wu,8 Anwaar Saeed,9 Brooke Wietharn,10 Lorenza Rimassa,11,12 Angelo Pirozzi,11,12 Antonella Cammarota,12 Tiziana Pressiani,12 Matthias Pinter,4 Lorenz Balcar,4 Yi-Hsiang Huang,13,14 Aman Mehan,1 Samuel Phen,15 Caterina Vivaldi,16,17 Francesca Salani,17,18 Gianluca Masi,16,17 Dominik Bettinger,19 Arndt Vogel,20,21 Martin Schönlein,22 Johann von Felden,23 Kornelius Schulze,23 Henning Wege,23 Adel Samson,24 Peter R Galle,25 Masatoshi Kudo,6 Giulia Francesca Manfredi,1,26 Ciro Celsa,1,27 Nichola Awosika,1 Alessio Cortellini,1,3 Amit G Singal,15 Rohini Sharma,1 Hong Jae Chon,5 Francesco Tovoli,2,28 Fabio Piscaglia,2,28 David James Pinato,1,26,* Antonio D’Alessio1,* 1Department of Surgery and Cancer, Imperial College London, London, UK; 2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 3Division of Medical Oncology, Policlinico Universitario Campus Bio-Medico, Rome, Italy; 4Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 5Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea; 6Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan; 7Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York, NY, USA; 8Division of hematology/oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 9Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh (UPMC), Pittsburgh, PA, USA; 10Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS, USA; 11Department of Biomedical Sciences, Humanitas University, Milan, Italy; 12Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Italy; 13Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 14Institute of Clinical Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan; 15Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 16Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; 17Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; 18Sant`Anna School of Advanced Studies, Pisa, Italy; 19Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; 20Hannover Medical School, Hannover, Germany; 21Longo Family Chair in Liver Cancer Research, Division of Gastroenterology and Hepatology, Toronto General Hospital, Medical Oncology, Princess Margaret Cancer Centre, Schwartz Reisman Liver Research Centre, Toronto, Canada; 22Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 23Department of Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 24Leeds Institute of Medical Research at St James’s (LIMR), School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’s University Hospital, Leeds, UK; 25University Medical Center Mainz, I. Department. of Internal Medicine, Mainz, Germany; 26Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; 27Gastroenterology and Hepatology Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy; 28Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy*These authors contributed equally to this workCorrespondence: Antonio D’Alessio, Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0HS, UK, Email [email protected] and Aims: Atezolizumab and bevacizumab (A+B) are recommended for treating unresectable hepatocellular carcinoma (HCC). Although highly effective, A+B can lead to potentially life-threatening adverse events including bleeding. We investigated whether albumin-bilirubin (ALBI) grade identifies patients with a higher risk of bleeding and its impact on prognosis than the Child-Pugh (CP) score.Methods: We performed a multicenter retrospective study of 15 tertiary referral centers that consecutively treated patients with A+B. We analyzed the association between the ALBI grade and gastrointestinal bleeding using the χ 2 test. Overall survival (OS) stratified by ALBI was estimated using the Kaplan-Meier method and the predictive value for the 6-months OS landmark with ROC curves.Results: Of the 368 patients included in the analysis, 163 (44.3%), 192 (52.2%) and 13 (3.5%) had ALBI 1, ALBI 2, and ALBI 3, respectively. ALBI grade was associated with a 3-fold increase in bleeding risk (3.1% in ALBI 1 vs 10.2% in ALBI 2/3, p=0.008). Among 192 patients with pre-treatment EGD, G2 and G3 varices were associated with an increased risk of bleeding, whereas G1 varices had a similar risk as no varices. Patients with ALBI 1 achieved a longer median OS (not reached; 95% CI, 24.9– 33.7), than ALBI 2 (9.7 months; 95% CI, 7.0– 12.3) or ALBI 3 (5.6 months; 95% CI, 0.1– 12.0). ALBI outperformed the CP score for predicting 6-month OS with an AUC 0.79 of ALBI versus 0.71 for the CP score (p=0.01).Conclusion: A Higher ALBI grade was associated with an increased risk of gastrointestinal bleeding after receiving A+B, and outperformed the CP score in predicting worse survival.Keywords: hepatocellular carcinoma, ALBI, bleeding risk, systemic treatment