Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Abstract

Aim:A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic lymphocytic leukemia patients, as comparative evidence is scarce. Materials & methods: Relative treatment effects of progression-free survival, overall survival and safety outcomes were estimated via network meta-analysis based on data identified via systematic literature review. Results: Ibrutinib was superior in all pairwise comparisons for progressionfree survival (probability to be better [P] range: overall population: 69-100%; fludarabine-ineligible population: 69-100%) and overall survival (P range: overall: 89-100%; fludarabine-ineligible: 91-100%) and had the highest probability of being best for all outcomes. Conclusion: Ibrutinib provides superior benefit in survival and safety compared with other front-line treatments of chronic lymphocytic leukemia. Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in western countries and occurs mainly in older people. Overall, 4.2 per 100,000 population per year develop the condition, a figure that rises to over 30 per 100,000 per year among those aged over 80 years [1]. The overall 5-year survival rate for people with CLL is 83%, although survival varies widely according to disease stage [2]. Treatment for CLL has evolved rapidly over the past two decades, with the addition of CD20-targeted antibodies, B-cell lymphoma-2 (BCL-2)-targeted treatment and B-cell receptor-targeted treatment resulting in improved outcomes [3][4].As indicated by both the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network [1,5], there are various management options for CLL, and treatment choices must account for key patient and disease characteristics known to affect therapeutic outcomes. These include patient age [6], fitness/comorbidities [7] and molecular cytogenetics [6,8]. Generally, for fit patients with advanced, symptomatic disease, the so-called 'full-dose fludarabine-based' regimen of fludarabine + cyclophosphamide + rituximab (FCR) is recommended [1]. However, for elderly patients and/or those with significant comorbidities, FCR is associated with significant risk of myelosuppression and severe infection [9]. Options are further limited if these individuals also have cytogenetic characteristics associated with poor outcomes from current treatments (such as 17p or 11q deletion, or absence of IgVH mutation). For these patients, ESMO and National Comprehensive Cancer Network guidelines recommend ibrutinib monotherapy [1,5,9].Given the range of CLL treatment options for people with differing levels of fitness, and the dearth of head-tohead clinical trials comparing front-line treatments, there remains considerable uncertainty regarding the optimal regimen for each patient group. The objectives of the presented systematic literature review (SLR) and network meta-analyses (NMAs) were therefore to determine the relative efficacy and safety of intervention...

Single‐agent ibrutinib versus chemoimmunotherapy regimens for treatment‐naïve patients with chronic lymphocytic leukemia: A cross‐trial comparison of phase 3 studies

“…These findings are consistent with the results of a previously conducted network meta‐analysis of 15 randomized controlled trials in the first‐line CLL setting, including ibrutinib data from the primary analysis of the RESONATE‐2 study (median follow‐up 18.4 months) . Results of the network meta‐analysis demonstrated a benefit in PFS, as well as OS, with ibrutinib over CIT in overall and fludarabine‐ineligible populations, with particular efficacy demonstrated in subgroups with del(11q) or unmutated IGHV statu s .…”

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

“…10,[26][27][28] A recent network meta-analysis of randomized clinical trials showed superior benefit in survival and safety with ibrutinib compared with other first-line treatments for CLL. 29 According to the network metaanalysis of safety outcomes, ibrutinib was associated with the lowest risk of treatment discontinuations and discontinuations due to AEs vs comparators in the overall first-line population and the fludarabine-ineligible population. 29 Of note, higher discontinuation due to toxicity has been reported with ibrutinib outside of the clinical study setting.…”

“…29 According to the network metaanalysis of safety outcomes, ibrutinib was associated with the lowest risk of treatment discontinuations and discontinuations due to AEs vs comparators in the overall first-line population and the fludarabine-ineligible population. 29 Of note, higher discontinuation due to toxicity has been reported with ibrutinib outside of the clinical study setting. 30 Such variations in discontinuation rates between "real-world" and clinical studies are likely due to differences in patient and study characteristics.…”

Unusual cause of light chain cast nephropathy

“…This clear benefit in overall survival and long-term safety outcomes was also described in a network meta-analysis 17. Ibrutinib has the lowest risk of treatment discontinuations owing to less frequent adverse events 17. In addition, ibrutinib-treated patients may have their bone marrow function restored 18.…”

“…The randomised phase 3 studies (RESONATE-2 trial) provides an extensive clinical evidence supporting the superiority of monotherapy ibrutinib in newly diagnosed older patients with CLL compared with chlorambucil, which is a standard first-line cytotoxic chemotherapy 16. This clear benefit in overall survival and long-term safety outcomes was also described in a network meta-analysis 17. Ibrutinib has the lowest risk of treatment discontinuations owing to less frequent adverse events 17.…”