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

Rituximab in combination with fludarabine and cyclophosphamide (RFC) is currently the standard of care for medically fit patients with previously untreated chronic lymphocytic leukemia (CLL) [1‐3]. However, many patients with CLL are in their 70’s and beyond before they need to start treatment, and are likely to have a greater co-morbidity burden [4]. For this often medically unfit population, RFC is unsuitable, with data from several clinical studies suggesting that the regimen is associated with excessive toxicity (e.g., cytopenias and increased infection rates) relative to the remission rates achieved [5, 6]. Other therapeutic options are available for unfit patients with CLL and include chlorambucil (Clb) in combination with an anti-CD20 antibody such as rituximab (R-Clb), obinutuzumab (G-Clb) or ofatumumab (O-Clb), rituximab in combination with bendamustine (R-Benda), dose-reduced fludarabine with cyclophosphamide (FC), and a dose-modified RFC regimen (RFC-Lite) [2‐4, 7‐10]. Available data from randomized controlled trials (RCTs) suggest an improvement in efficacy with certain regimens in this setting. For example, significant improvements in progression-free survival (PFS) have been reported in unfit patients with CLL with R-Benda compared with R-Clb in the MaBLe study (median PFS 39.6 versus 29.9 months; hazard ratio [HR] 0.523; 95% confidence interval [CI] 0.339–0.806; P = 0.003) [10], and with G-Clb compared with the equivalent rituximab regimen in the CLL11 study (29.2 versus 15.4 months; HR 0.40; 95% CI 0.33–0.50; P < 0.001) [11]; however, with a limited number of head-to-head treatment comparisons available, the optimal treatment for unfit patients with CLL remains unclear.

Network meta-analysis (NMA) allows information from direct head-to-head studies to be combined with information from indirect treatment comparisons to enable estimation of the comparative efficacy of therapies and build a hierarchy of available treatments [12, 13]. Furthermore, the outputs of NMA-based comparative effectiveness research can be used in a full economic appraisal of competing interventions to assess the cost-effectiveness [14]. The usefulness of NMA has been demonstrated across a range of therapeutic interventions and disease areas including CLL [15‐20]. Naïve comparison of drug treatments based on data from different studies carries with it a risk of making incorrect conclusions; by assuming the constancy of relative treatment effects (odds ratios or HRs) to link studies, NMA minimizes this risk. We, therefore, conducted a systematic review and Bayesian NMA of data from all RCTs comparing at least two interventional treatments in patients presenting with ‘first-line’ CLL and/or who were not eligible to receive full-dose fludarabine (F) to determine the relative effects of treatments on PFS and overall survival (OS).

This NMA evaluating the relative efficacy of therapeutic interventions for the first-line treatment of unfit patients with CLL produced a number of key findings. Consistently, for both efficacy endpoints (PFS and OS) and all scenarios, our results suggest that therapy comprising a combination of the anti-CD20 monoclonal antibody obinutuzumab and chlorambucil (G-Clb) is likely to be superior to many other treatment options including Benda, R-Clb, O-Clb, Alm, F, and Clb in unfit patients with CLL. In addition, G-Clb showed a trend for greater efficacy over the regimens RFC-Lite and R-Benda in this setting. Our results for OS were generally consistent with the data on PFS, suggesting beneficial outcomes with G-Clb over other regimens, and were driven by the consistent trend in OS favoring G-Clb in the CLL-11 trial [11, 27, 32]. However, the OS data in our study were associated with greater uncertainty, and this was not unexpected given that the follow-up times for OS were relatively short. We also note that to the best of our knowledge, PFS has not yet been validated as a surrogate endpoint for OS in the first-line treatment of unfit patients with CLL within a meta-analytic framework [33].

Our NMA of PFS (additional analysis) also supported the findings of the Knauf study suggesting that Benda is a more potent chemotherapy, leading to ‘deeper’ remission than the traditional agent Clb in unfit patients [29]. Given this finding, it was of interest to note a trend favoring the combination of obinutuzumab with Clb over rituximab combined with Benda, as shown by the HR estimate for PFS (0.81 CrI 0.49, 1.33).

Through the use of pre-defined ‘co-morbidity’ inclusion criteria combined with expert review, we were able to restrict our analysis to unfit patients with CLL who were likely to meet the unfit definition as described in the CLL11 trial [27]. However, information on CLL patient ‘fitness’/CIRS is not always reported in the literature, making it difficult to evaluate a study population’s level of fitness/co-morbidity; moreover, there is no well-defined surrogate marker for fitness status/co-morbidity. To address this, we used five pre-defined co-morbidity criteria (median CIRS >6, median CrCL ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm) to approximate the level of patient fitness/co-morbidity indirectly in each study. Because of the potential heterogeneity of the identified papers, a manual review of the full text of the identified papers was conducted, and the final selection of papers was approved by experts. This final selection led to the exclusion of the following studies from the main analysis: Cam307 (study inclusion criteria included adequate renal and liver function and median age was 59–60 years) [30], Calgb_9011 (F dose appeared to be the full dose, 20 or 25 mg/m² intravenously days 1–5 every 28 days) [31], and Knauf (a high percentage of patients in both the Benda [70%] and Clb [65%] arms had a WHO performance score of 0 and a median age of approximately 65 years, therefore, it was unlikely that the patients included were not eligible for full-dose F) [29]. It is also important to note that the three excluded studies were conducted at a time when Clb (rather than RFC) was the standard of care even in fit patients, since at that time, no treatment had shown an OS benefit over Clb. Also, these studies were not designed to explicitly enroll unfit patients, their median age was substantially lower than the remaining five studies, and chemotherapy alone is not currently considered a relevant treatment option (even in unfit CLL).

An important advantage of NMA over naïve inter-trial comparisons is that the calculations are based on relative treatment effects (in terms of HRs) rather than absolute effects. Thereby, NMA circumvents the potential incomparability of two studies due to differences in the distributions of measured and/or unmeasured prognostic factors. For example, a naïve comparison of the R-Benda arm in MaBLe (median PFS 39.6 months) [10] with the G-Clb arm in CLL11 (median PFS 29.2 months) [11] would have led to the opposite conclusion of better performance of R-Benda versus G-Clb. This naïve comparison compares efficacy on an ‘absolute’ scale and ignores the fact that the common comparator R-Clb in these two studies showed substantial discrepancy in terms of median PFS (29.9 months in MaBLe and 15.4 months in the CLL11 study, respectively). The prognostic differences that lead to this study bias between MaBLe and CLL11 may be manifold with differences in methodology of data generation and data read-out as the main drivers. We note that our NMA does not account for potential effect modifiers, which are defined as patient or study characteristics that influence the two treatment arms to a different extent and, therefore, alter the relative treatment effect. A speculative effect modifier could be the difference in the cumulative dose of Clb in MaBLe and CLL11. However, we do not believe that this solely explains the discrepancies seen in median PFS between the two R-Clb arms from MaBLe and CLL11, since there is evidence which points against ‘Clb dosing’ as an effect modifier of PFS [27, 34, 35]. Admittedly, there is still some debate around the role of Clb dosing on PFS.

The results of our NMA should ideally be validated in independent studies, and our findings should be interpreted taking into account a number of limitations. First, a limited number of studies were eligible for inclusion in the analysis. Many of the comparisons were informed by a single trial (e.g., CLL11 was the only trial to compare G-Clb and R-Clb). This limited the statistical assessment of heterogeneity and inconsistency and also precluded the performance of more sophisticated analyses, for example, meta-regression to adjust for potential effect modifiers. Our selection strategy (five criteria and expert opinion) also aimed at increasing the homogeneity of the trials in the network. Nonetheless, the levels of unfitness still varied among the selected trials, which could ultimately have influenced our NMA. Second, the follow-up times for OS (and to a lesser extent PFS) were relatively short; longer follow-up would likely have impacted on the effect size, especially the CrIs. Third, in two trials, assumptions were required to calculate lnHR and SD, and these estimates may have differed from the estimate of HR using whole Kaplan–Meier curves.

Our results are comparable with the findings reported by Ladyzynski et al. [16] in their recent NMA of first-line treatment for CLL. Using a Bayesian NMA, they compared the effectiveness of available therapies in terms of PFS and OS in patients with treatment-naïve symptomatic CLL and in subgroups of younger/fit and older/unfit patients (median age ≥69 years). Of the five treatments evaluated in older/unfit patients (Clb, F, O-Clb, G-Clb, and R-Clb), G-Clb was associated with longer projected mean PFS versus all other comparators (60 months versus 16–30 months) and had the highest potential of increasing OS (90 months versus 44–59 months). Also, corresponding median hazard rates for G-Clb were the lowest of all the analyzed treatment options (PFS <0.05 over 120 months; OS <0.01 during the initial 65 months of survival). Of note, this analysis differed from our own NMA in a number of respects: it stipulated stricter study eligibility criteria (all included RCTs were required to provide a survival curve); an overall analysis (no restriction on fitness); and separate analyses for fit and unfit were performed, whereas our focus was on the unfit setting only; older/unfit was defined as median age ≥69 years or median CIRS ≥8, whereas we used five criteria; and the MaBLe study was not included.

The results of a second NMA evaluating US Food and Drug Administration/European Medicines Agency-approved treatment options for previously untreated patients with CLL ranked RFC highest in terms of efficacy, while all single agents (with the exception of Alm) occupied the worst ranks [19]. Unlike our NMA, the authors imposed no restrictions in terms of physical fitness or age of the study participants, and full-dose F studies were also included. Furthermore, the analysis did not include important recent trials, for example, CLL11 (G-Clb), MaBLe (R-Benda), and Complement 1 (O-Clb). In an earlier study, Cheng et al. [36] also used similar NMA methodology to analyze treatments that had not been directly compared in terms of PFS in previously untreated patients with CLL. The findings suggested that RFC achieved relatively longer PFS compared with FC, F, Alm, and Clb (76 months versus 23–60 months); however, the data were limited to younger patients (59–65 years) with good performance status and early-stage disease [36]. In a multiple-treatment meta-analysis using direct and indirect data based on all available head-to-head RCTs, Terasawa et al. [37] concluded that there was insufficient evidence on OS to recommend a specific first-line treatment for CLL and that any observed PFS differences may have been attributable to the relatively young uncomplicated patient populations.

Our NMA suggests that G-Clb is an effective treatment for unfit patients with CLL, with suggestion of superiority over R-Benda and RFC-Lite, accepting the limitations discussed elsewhere in this manuscript. Previously, the MaBLe study showed that using Benda instead of Clb as the backbone of immunochemotherapy for unfit patients with CLL improves efficacy [10]. In addition, the ongoing GREEN study (NCT01905943) has reported preliminary safety and efficacy data for obinutuzumab in combination with bendamustine (G-Benda), also in the patient subset of unfit CLL [38]. A potential future therapeutic intervention for unfit patients with CLL that was not considered in our NMA is ibrutinib, a first-in-class oral inhibitor of Bruton’s tyrosine kinase which is a key mediator of B-cell signaling [39, 40]. Ibrutinib was recently licensed for the treatment of adult patients with previously untreated CLL, including those aged ≥65 years. In a final analysis of the phase III RESONATE-2 trial, ibrutinib was reported to significantly improve PFS and OS compared with Clb in previously untreated patients with CLL (n = 269; PFS median not reached versus 18.9 months, HR 0.16, 95% CI 0.09–0.28, P < 0.0001; OS median not reached for either arm, HR 0.16, 95% CI 0.05–0.56, P = 0.0010). Patients were aged ≥65 years, approximately 30% had a CIRS score >6, and the median European Cooperative Oncology Group status was 0, thus the majority of patients were closer to the populations in the CLL8 and CLL10 trials than to the population in CLL11 [40]. In addition, Ibrutinib is also under evaluation in the unfit setting in combination with G-Benda (CLL2-BIG trial, Clinical Trials.gov identifier, NCT02345863) [41]. Pyruvate dehydrogenase kinase (PDK) inhibitors [42] and other inhibitors of the B-cell receptor (BCR) pathway [43] are also in development for the treatment of CLL. However, PDK inhibitor development is still at a very early stage, and following initial promising efficacy results for idelalisib, studies of first-line use have been halted due to severe immune-mediated toxicities, and further safety data are now required [44]. We are not aware of any information regarding the availability and affordability of these compounds in the patient population considered for this NMA.

The goal of the current study was to inform on the efficacy of commercially available drugs for the treatment of unfit patients with CLL. Although economic factors play a key role in shaping healthcare decision-making, the consideration of drug costs and treatment outcomes was beyond the scope of the current study. For this reason, information on the cost-effectiveness of the different treatment options for unfit patients with CLL requires careful evaluation in subsequent publications and/or health technology assessment submissions. Furthermore, while considerations of effectiveness may be applicable across different healthcare systems, considerations of costs and values are more likely to be healthcare system-specific. Therefore, a cost-effectiveness guideline may be less transferable across countries than one based on clinical effectiveness [45].

Results from our NMA demonstrate a clear preference in terms of PFS for G-Clb versus R-Clb, O-Clb, fludarabine and chlorambucil, and a trend for better efficacy versus R-Benda and RFC-Lite. A higher degree of uncertainty was associated with the OS results, but the findings were generally consistent with PFS data. Together, these data support the conclusion that G-Clb is an effective first-line treatment for unfit patients with CLL and is likely to show superior efficacy compared with other treatment options.