1. Introduction
Chronic lymphocytic leukemia (CLL) is the most common B-cell malignancy in adults of the Western world. An annual incidence of two to six per 100,000 people has been reported, with a median age of 72 years at initial diagnosis [
1]. The clinical course of CLL is heterogeneous. Most patients are diagnosed with early stage, indolent disease. However, in some high-risk patients, particularly those with gene mutations, such as the 17p deletion, unmutated IGHV (Immunoglobulin heavy variable region), and 11q deletion, the disease may develop rapidly. These patients require further treatment for disease progression [
2].
Chemoimmunotherapy, known as the FCR regimen (Fludarabine, Cyclophosphamide. and Rituximab), now prolongs the overall survival (OS) of CLL patients and as such is the recommended first-line treatment for patients without the 17p deletion [
3]. However, CLL remains incurable and eventually relapses or becomes refractory to first-line treatment. Many of the patients are elderly, with toxicity and comorbidities resulting from aggressive chemoimmunotherapy. As a result, treating these patients is a challenge.
Traditional therapy for relapsed or refractory chronic lymphocytic leukemia (R/R CLL) has included alkylating agents, such as bendamustine, and anti-CD20 monoclonal antibodies, such as rituximab and ofatumumab. A commonly used regimen has been bendamustine in combination with rituximab or single-agent ofatumumab or single-agent rituximab. Recently, a range of novel targeted agents, including ibrutinib, venetoclax, idelalisib, and duvelisib, have provided greater survival with a modest toxicity profile. These new treatments were established by pivotal randomized controlled trials (RCTs) in patients with R/R CLL [
4,
5,
6,
7,
8,
9,
10,
11]. Ibrutinib is a once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, which inhibits B-cell receptor signaling [
12]. Venetoclax is an orally administered potent and selective BH3 mimetic that targets the BCL-2 (B-Cell Leukemia/Lymphoma 2 Gene) inhibitor, exhibiting significant apoptotic activity [
13]. Idelalisib is an orally bioavailable selective small-molecule inhibitor of phosphatidylinositol 3-kinase δ (PI3Kδ) [
14]. Duvelisib is an oral dual inhibitor of PI3K-δ,γ [
15].
The results of clinical trials evaluating progression-free survival (PFS) and OS of small-molecule inhibitors, with or without other anti-leukemic drugs, have been reported. The outcomes of most of these treatments have been evaluated by–comparisons to previous traditional regimens, either bendamustine combined with rituximab or ofatumumab or rituximab monotherapy. However, no study has presented a head-to-head comparison of the efficacy of these new small-molecule inhibitors in treating R/R CLL patients. We conducted this network meta-analysis to assess the relative efficacy of each drug with the aim of providing treatment recommendations to physicians in daily clinical practice.
4. Discussion
This systematic review and NMA compares the efficacy of several new novel targeted agents for the treatment of CLL. Our results show that Ibr and VR are the most efficacious agents with respect to PFS and OS in patients with R/R CLL. According to our NMA, treatment with each of the novel targeted agents resulted in greater PFS than did traditional R, Ofa, or BR regimens. Ibr and VR were ranked as the best treatment options based on PFS analysis. We also conducted subgroup analysis in patients without del(17p) mutation. On account of the HELIOS trial populations excluded patients carrying del(17p), differences between the patient populations should be considered to produce more accurate results. In the analysis of OS, both Ibr and VR prolonged the elapsed time from trial randomization to death. Thus, both Ibr and VR treatment result in greater PFS and OS, supporting the recommendations made by the NCCN identifying Ibr and VR as the preferred agents for patients with R/R CLL, especially those with del(17p) [
34].
Our results are consistent with a recent analysis that indirectly compared four treatments: ibrutinib, idelalisib plus ofatumumab, ofatumumab and physician’s choice. A strong and consistent trend of superior results for ibrutinib treatment was observed. The analysis demonstrated that ibrutinib treatment resulted in a higher ORR and longer PFS and OS as compared to idelalisib plus ofatumumab, ofatumumab monotherapy, and conventional chemotherapy. However, VR was not included in this study.
Our study used HR as the measure of survival and OS as the secondary endpoint. The network included the results of more recent trials and the individualized indirect comparison reported by Hillmen et al. [
25] synthesized into one single network for R/R CLL. Using a frequentist model NMA, it was possible to combine evidence from seven phase III RCTs, including nine different treatments, into one NMA. Therefore, the present results provide important information for clinical physicians to use in making treatment decisions for patients with R/R CLL.
Our NMA results indicate that Ibr monotherapy is more beneficial than Ibr combination therapy for treating patients with R/R CLL. Similarly, Burger et al. [
35] reported no improvement in treatment outcomes offered by the addition of rituximab to the ibrutinib regimen in treatment-naïve (
n = 27) or R/R CLL (
n = 181) patients. The addition of rituximab did not improve the ORR (Ibr, 92.3%; Ibr + R, 92.3%) or the two-year PFS (Ibr, 95%; Ibr + R, 92.5%). Furthermore, the individualized indirect comparison by Hillmen et al. [
25] suggested the superiority of single-agent ibrutinib to ibrutinib plus BR for PFS and OS in patients with R/R CLL, showing that the benefit of ibrutinib plus BR mainly reflected the effect of ibrutinib. According to currently available evidence, the addition of conventional agents (bendamustine, rituximab) did not improve the efficacy but increased greater toxicities. However, there is no proper study directly compared ibrutinib with ibrutinib plus BR. On the basis of current evidence, Ibr monotherapy should remain the standard of care.
While all of the studies included in our NMA were clinical trials, they were conducted in selected populations and in different locations. To gain insight into practice patterns, real-world evidence should be taken into consideration. Ibrutinib demonstrates long-term efficacy and tolerability not only in these trials but also in actual practice. In a 30-month follow-up real-world cohort study reported by Winqvist et al. [
36], ibrutinib treatment resulted in an ORR of 84%, PFS of 52% and OS of 63% at a median follow-up of 30 months. The study cohort included 95 patients with a median age of 69 years (del(17p)/TP53 mutation, 63%, the median number of previous therapies, 3). Another five-year study of single-agent Ibr treatment for patients with R/R CLL was reported by Brien et al. [
37]. This study included 101 R/R CLL patients with a median age of 68 years; del(17p), 34%; median number of previous therapies, four; and median follow-up time of 39 months. The ORR was 86% and the median PFS was 52 months. Thus, these real-world studies of single-agent ibrutinib treatment show a durable response in patients with R/R CLL, supporting our NMA results showing that mono-Ibrutinib therapy is the most favourable option for reducing both the risk of disease progression and death in R/R CLL patients.
While our results indicate that Ibr is the first choice of novel targeted agents. The results of the MURANO trial [
10] of venetoclax and rituximab may challenge this conclusion. Evidence from real-world studies of venetoclax remains quite sparse. A prospective study by Mato et al. [
38] investigated the efficacy of novel targeted agents in 683 CLL patients with no previous kinase inhibitor (idelalisib or ibrutinib) treatment. The median number of previous therapies was two, and approximately one-third of the patients had high-risk genetic features identified as del17p, del11q, or complex karyotype. With a median follow-up of 17 months, R/R CLL patients receiving Ibr-based therapy experienced a significantly greater PFS as compared to idelalisib-based therapy (HR, 2.8; CI, 1.9–4.1;
P < 0.001). Subsequent regimens after initial kinase inhibitor failure were classified as kinase inhibitor-based therapy (ORR: 58.5%), venetoclax (ORR: 73.6%) and chemoimmunotherapy combinations (ORR: 49.9%). The authors concluded that Ibr is superior to idelalisib for treating patients with R/R CLL. The efficacy of venetoclax was established in patients in whom previous kinase inhibitor treatment (idelalisib or ibrutinib) failed. Another real-world retrospective cohort analysis [
39] of patients with CLL (98% R/R) demonstrated that venetoclax has a similar ORR (72.1%) to that previously reported in a clinical trial [
40]. In addition, as the authors concluded, venetoclax was effective in patients who had previous ibrutinib therapy and carried mutations known to confer resistance to ibrutinib.
In current real-world practice, ibrutinib monotherapy is effective and provides better survival outcomes than other treatments, suggesting its use as the standard of care for R/R CLL patients. Although real-world experience with VR is limited, venetoclax monotherapy demonstrated promising efficacy and a high response rate. However, optimization of novel targeted agents is required for their further evaluation.
This study has several limitations. First, because of the limited number of studies included in our NMA, the connections within our network are sparse. The treatment comparisons were therefore estimated by either direct or indirect evidence. Consequently, it is not feasible to evaluate inconsistencies in treatment effects between direct and indirect comparisons [
41]. Furthermore, our fixed effect models may underestimate the uncertainty of treatment effects. Second, to provide missing links between treatments in our integrated network, we combined the data from an individualized, indirect comparison of the RESONATE [
5] and HELIOS [
6] trials reported by Hillmen [
25]. In this indirect comparison, the author used patient-level data from both studies. The biases in cross-trial comparisons had already been adjusted, including treatment and clinically relevant prognostic variables as covariates (age, gender, Rai staging, ECOG score, del11q status, refractory status, number of prior lines of therapy, bulky disease, IgVH status). However, including such data in an NMA may increase the risk of producing a biased effect estimate and influence the results. Third, adverse-event profiles are not accounted for in our NMA. Ibrutinib displayed a manageable safety profile in the results of previous RCTs [
3,
8]. However, insight from real-world practice, adverse event profiles and treatment discontinuation were emphasized.
Toxicity was the most common reason for ibrutinib discontinuation in CLL patients, approaching 50% [
42]. Atrial fibrillation, infectious complications, and cytopenias were the most commonly described adverse events in patients treated with ibrutinib [
43]. In addition, an uncommon but potentially life-threatening complication, tumor lysis syndrome, has been recently reported in venetoclax administration [
44]. However, a comparison of safety issues or reasons for treatment discontinuation was not included in our NMA because of insufficient data.
Despite these limitations, our NMA provides insight into the rank order of treatment efficacy according to the presently available evidence. This information may help doctors to select the most appropriate treatment for each individual patient, in the absence of direct head-to-head comparison trials. The findings of this NMA suggest that ibrutinib monotherapy and venetoclax rituximab (VR) are most likely to become the most effective treatments with respect to long-term PFS and OS for patients with R/R CLL.