A Systematic Review and Network Meta-Analysis to Evaluate the Comparative Efficacy of Interventions for Unfit Patients with Chronic Lymphocytic Leukemia

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

Conclusion: G-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.

Funding: F. Hoffmann-La Roche Ltd.

Keywords: Bendamustine; Chlorambucil; Chronic lymphocytic leukemia; Co-morbidities; First-line; Fludarabine; Hematology; Network meta-analysis; Obinutuzumab; Oncology; Rituximab; Treatment-naïve.

Fig. 1

Network of trials and treatments selected using the five ‘fludarabine-ineligibility’ criteria a PFS and b OS. The main analysis excluded the three studies highlighted in red (expert recommendation). The additional analysis is based on the whole network. Alm alemtuzumab, Benda bendamustine, Clb chlorambucil, F fludarabine, G-Clb obinutuzumab + chlorambucil, O-Clb ofatumumab + chlorambucil, OS overall survival, PFS progression-free survival, R-Benda rituximab + bendamustine, R-Clb rituximab + chlorambucil, RFC rituximab + fludarabine + cyclophosphamide

Fig. 2

Main analysis (Knauf, Cam307, and Calgb_9011 excluded): effect of interventional treatments on a PFS and b OS using a FE model. Forest plots show relative effect of each treatment on PFS and OS as compared with the reference combination treatment G-Clb. Median HRs and CrIs are shown. Clb chlorambucil, CrI credible interval, F fludarabine, FE fixed effects, G-Clb obinutuzumab + chlorambucil, HR hazard ratio, O-Clb ofatumumab + chlorambucil, OS overall survival, PFS progression-free survival, R-Benda rituximab + bendamustine, R-Clb rituximab + chlorambucil, RFC rituximab + fludarabine + cyclophosphamide

Fig. 3

Additional analysis (Knauf, Cam307, and Calgb_9011 included): effect of interventional treatments on a PFS and b OS using a FE model. Forest plots show relative effect of each treatment on PFS and OS as compared with the reference combination treatment G-Clb. Median HRs and CrIs are shown. Alm alemtuzumab, Benda bendamustine, Clb chlorambucil, CrI credible interval, F fludarabine, FE fixed effects, G-Clb obinutuzumab + chlorambucil, HR hazard ratio, O-Clb ofatumumab + chlorambucil, OS overall survival, PFS progression-free survival, R-Benda rituximab + bendamustine, R-Clb rituximab + chlorambucil, RFC rituximab + fludarabine + cyclophosphamide