The Integration of Efficacy and Safety Outcomes Identifies the Net Clinical Benefit of Targeted Agents in Upfront Therapy of Chronic Lymphocytic Leukemia: Results of Network Meta-Analysis

In the absence of head-to-head randomized trials, indirect comparisons of therapy with targeted agents (TAs) across trials may well be informative in the management of chronic lymphocytic leukemia (CLL). However, such published analyses have mostly described progression-free survival (PFS) and provided sparse data on overall survival (OS) or toxicity. We, therefore, conducted a network meta-analysis (NMA) of published upfront CLL TA studies which incorporated a variety of efficacy and safety outcomes, in an attempt to predict the net benefit of TAs. We searched MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) assessing the efficacy and safety of Bruton kinase inhibitors (BTKis) and venetoclax-based regimens in treatment-naïve CLL. Efficacy outcomes (PFS, OS, time to next treatment [TTNT], overall response rate [ORR], complete remission [CR], minimal residual disease [MRD]), safety, and toxicity were evaluated.

The surface under the cumulative ranking curve (SUCRA) was obtained for each treatment. The SUCRA provides a numeric representation (range from 0 to 100%), allowing for an overall ranking. The closer the SUCRA value to 100%, the higher the likelihood that therapy is in the top rank, whereas the closer to 0 the SUCRA value, the more likely treatment is in the bottom rank.

Nine RCTs met the criteria of low risk for bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Five were excluded because they lacked a common comparator arm (RESONATE2, ALLIANCE, ECOG-ACRIN, FLAIR, SEQUOIA). Four trials were suitable for network analysis (ILLUMINATE, ELEVATE-TN, CLL14, GLOW). Chlorambucil-obinutuzumab (CO) was the control arm across these studies (n=610). In all, these included 1547 patients and evaluated ibrutinib-obinutuzumab (IO) (ILLUMINATE; n=113), venetoclax-obinutuzumab (VO) (CLL14; n=216), acalabrutinib (A) monotherapy (ELEVATE-TN; n=179), A plus obinutuzumab (AO)(ELEVATE-TN; n=179) ibrutinib-venetoclax (IV)(GLOW; n=195). In this NMA, we used the longest published follow-up for each trial (GLOW 27.7 months, CLL14 52,4 months, ILLUMINATE 45 months, ELEVATE-TN 46.9 months). Patients with disrupted TP53 were excluded from the GLOW study and hence from our analysis.

AO had the highest probability of efficacy in terms of PFS (SUCRA,0.9923), OS (SUCRA, 0.9010), and ORR (SUCRA,0.8670). In contrast, venetoclax-based regimens had the highest likelihood of achieving a better quality clinical and MRD responses. IV ranked first in terms of CR (SUCRA 0.9208) and VO in terms of undetectable MRD (SUCRA,0.9020). In the analysis of TTNT, IO was preferable (SUCRA,0.9810)(Tab 1).

We developed a ranking chart for efficacy outcomes. The average (Av) SUCRA for PFS, OS, ORR, and CR was used to create an efficacy rankogram (k ranks ranged from 1 to 6). In the aggregate efficacy analysis, AO ranked first (Av SUCRA,0.8544) and CO last (Av SUCRA, 0.0575). The full Av SUCRA ranking order was AO, IV, VO, IO, A, CO (Av SUCRA, 0.8544, 0.5793,0.5747,0.4456,0.3864, 0.0575) (Fig 1).

When outcomes of toxicity were included, the ranking order changed. The average SUCRA values for toxicities (assessed by the common terminology criteria adverse events (CTCAE) as grade 3 and above, which included neutropenia, infections, diarrhoea, and atrial fibrillation facilitated the development of a safety rankogram in which reduced toxicity is associated with an increased SUCRA value. The toxicity SUCRA ranking selected A first. The full toxicity SUCRA ranking is as follows : A, CO, AO, IV VO and IO (Av SUCRA; 0.70160.6650,0.4390,0.4377, 0.4325 and 0.3242)(Fig 2).

A mixed efficacy-toxicity (E-T) rankogram was generated from the efficacy and toxicity Av SUCRA scores; this showed that AO ranked first followed by A, CO, IV, VO, and IO (ET-Av SUCRA: 0.6467, 0.5440,0.5247,0.5085,0.5035, 0.3850)(Fig 3).

This is the first NMA that can aid the selection of upfront therapy in CLL patients with intact TP53. In patients who are physically fit a model based solely upon efficacy may be able to inform treatment decisions.On the other hand , a model based exclusively on toxicity outcomes may guide therapy selection in unfit patients. If a combined efficacy/toxicity model is utilized , it identifies a preference for acalabrutinib-based regimens.