title: A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia.
abstract: Rituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in 'unfit' (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.
  
  
  
  For inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.
  
  
  
  In unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).
  
  
  
  G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.
  
  
  
  F. Hoffmann-La Roche Ltd.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. nicolas.staedler@roche.com.
authors.forename: Nicolas
authors.identifier: 0000-0001-8212-7459
authors.initials: N
authors.lastname: Städler
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Aijing
authors.initials: A
authors.lastname: Shang
authors.affiliation: Hematology Department, University Hospital Vall d'Hebron, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Bosch
authors.affiliation: Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Briggs
authors.affiliation: Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Goede
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Aurelien
authors.initials: A
authors.lastname: Berthier
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Renaudin
authors.affiliation: UPMC GRC11-GRECHY, AP-HP Hôpital Pitié Salpêtrière, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblond
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015897:Comorbidity; D000075202:Contraindications; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000453:epidemiology; D054539:Medication Therapy Management; D018579:Patient Selection; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Bendamustine; Chlorambucil; Chronic lymphocytic leukemia; Co-morbidities; First-line; Fludarabine; Hematology; Network meta-analysis; Obinutuzumab; Oncology; Rituximab; Treatment-naïve