Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukemia

Therapeutic options for chronic lymphocytic leukemia (CLL) patients have expanded over recent years as efficacious novel agents (NA) have received licensing approval, initially in relapsed, refractory (R/R) disease. Ibrutinib is a Bruton tyrosine kinase (BTK) inhibitor (BTKi) targeting Bcell receptor (BCR) pathway signaling. It has potent activity in relapsed disease as monotherapy with significant benefit compared to ofatumumab and combined with bendamustine-rituximab (BR) versus BR. Idelalisib also targets the BCR pathway by inhibiting the delta isoform of phosphoinositide 3-kinase (PI3Ki). It is licensed in combination with rituximab following improved progression-free survival (PFS) compared to rituximab in heavily pre-treated patients. However, toxicity concerns now limit its use in R/R CLL, and the randomized ASCEND trial has shown PFS superiority for the second generation BTKi acalabrutinib versus idelalisib-rituximab (hazard ratio [HR] 0.29; P<0.0001). Moreover, a large retrospective series has previously compared ibrutinib and idelalisib-rituximab as first NA (NA1) and found a similar, indirect PFS advantage for ibrutinib. Venetoclax is a potent, oral small-molecule BCL2 inhibitor (BCL2i) licensed as monotherapy ± rituximab in R/R CLL. Venetoclax is increasingly utilized at first relapse in combination with rituximab for a 2-year fixed duration. However, to date, no prospective trials have directly compared ibrutinib with venetoclax as NA1 in R/R CLL. It remains a key unanswered question as to which of these two NA optimizes the balance of safety and efficacy when used as the NA1 in R/R CLL. To address this, we report a large, international study to establish the efficacy of ibrutinib and venetoclax ± anti-CD20 as NA1 in R/R CLL. To our knowledge, this is the largest series comparing these two approaches as NA1. To address this question, a single NA database was created from prior international, collaborative, multicenter retrospective analyses examining each NA to describe and compare the characteristics and outcomes of CLL patients treated with ibrutinib or venetoclax ± anti-CD20 as the NA1 between 2015-2019. To be eligible for comparison, patients could not have been treated with a targeted agent in the front-line setting and had to receive ibrutinib or venetoclax as NA1 no later than line 5. Twenty centers participated in this study from academic and community sites. To define the study cohort for the primary analysis, medical chart reviews were performed to identify all consecutive patients with CLL at each institution who received ibrutinib or venetoclax as NA1 in the R/R setting including only patients in routine clinical practice. To verify that cohorts were similar, baseline characteristics were collected prior to NA exposure. Using a standardized case report form, investigators collected data on preNA demographics, disease/prognostic characteristics (including del(17)p, complex karyotype [CK] defined: ≥3 aberrations, IGHV status, and TP53 mutation), clinical and genetic characteristics, number and type of prior therapies. Toxicity data regarding dose interruptions, reductions, NA discontinuation, and reasons for discontinuation were collected. Other primary endpoints were overall response rate (ORR) and PFS for the NA1. Investigators were requested to classify responses by International Workshop on CLL (iwCLL) criteria as complete remission (CR), partial remission (PR) (including PR with lymphocytosis), stable disease (SD), and progressive disease (PD). PFS was defined as the time from NA1 to last follow-up, progression of CLL or death. Overall survival (OS) was defined as the time from NA1 to death from any cause. PFS and OS were estimated by the Kaplan-Meier method. All other comparisons were descriptive. Comparisons were made using Cox regression or log-rank tests. Statistical analyses were performed using STATA 10.1. Follow-up was censored at most recent visit or death. A total of 433 patients received a NA1: 385 ibrutinib; 48 venetoclax ± anti-CD20 (80% monotherapy). Data for PFS were available for 417 patients. Median follow-up was 14 months (ibrutinib) and 13.5 months (venetoclax), respectively. Each group had a median of two prior lines (range 1-4 for each). Median age of each cohort (ibrutinib: 69 years; venetoclax: 65 years) were similar, as were the proportion with adverse features such as del(17p) (Table 1). Overall response rate and CR were: ibrutinib (71% and 12%, respectively) and venetoclax (96% and 56%, respectively). Venetoclax-treated patients had a statistically significantly higher CR rate versus ibrutinib (P<0.001). Figure 1A shows PFS of all patients stratified according to NA1. Using ibrutinib as the comparator (HR, 1.0), PFS HR for venetoclax was 0.29 (95%Cl: 0.10-0.92; P=0.036) (Figure 1A). Using ibrutinib as the comparator for OS, HR was 1.2 (95%Cl: 0.47-3.1; P=0.70) for the venetoclax-treated cohort (Figure 1B). When considering del(17p), del(11q), CK and IGHV status, we could not identify a subgroup that benefited in terms of PFS when comparing each NA1 (data not shown). Considering the whole cohort, only those with a CK (HR, 1.99 [1.1-3.80]; P=0.04) had a statistically significant inferior PFS. Dose interruptions were recorded in 33% ibrutinib and 32% venetoclax-treated patients (Table 2). Dose reduc-