Clinical Outcomes Among Real-World Patients with Chronic Lymphocytic Leukemia (CLL) Initiating First-Line Ibrutinib or Chemoimmunotherapy (CIT) Stratified By Risk Status: Results from a US Retrospective Chart Review Study

Background: Patients with high-risk (HR) CLL, characterized by cytogenetic/molecular abnormalities, are associated with poor prognosis. Although small molecular inhibitor (SMI) therapies have repeatedly demonstrated improved outcomes in patients with HR CLL compared to CIT in the clinical trial setting, CIT use remains common in real-world (RW) practice. There is limited RW evidence of clinical outcomes in HR and non-HR CLL patients based on first-line (1L) treatment. This study describes treatment patterns and time to next treatment (TTNT) in HR and non-HR patients with CLL receiving ibrutinib (IBR) or CIT as 1L therapy.

Methods: At 40 US clinical practices (68% community; 32% academic), medical records were abstracted for adult HR and non-HR CLL patients who initiated 1L single-agent IBR or CIT (index date) between 14Feb2014 – 31Dec2016. HR was defined as having one or more of the following prior to 1L initiation: del(17p), del(11q), TP53 mutation, unmutated IGHV, or complex karyotype (≥ 3 chromosomal abnormalities). Non-HR was defined as testing-confirmed absence of above abnormalities. Baseline characteristics were compared by Chi-square, t- / Mann Whitney U tests; TTNT was assessed by Kaplan-Meier (KM) and cox-proportional hazards regression analyses for: (a) IBR HR vs CIT HR, (b) CIT HR vs CIT non-HR, and (c) IBR HR vs IBR non-HR. Log-rank tests were used to assess statistical significance in TTNT comparison. Inverse probability treatment weighting (IPTW) was conducted to balance the baseline characteristics between the IBR HR and CIT HR groups. IPTW was not conducted in HR vs non-HR comparisons as baseline differences may reflect the inherent differences associated with risk status.

Results: A total of 516 CLL patients were included in this analysis: 271 HR (IBR: 175; CIT: 96 [49.0% BR, 29.2% FCR, 17.7% G-Clb]) and 245 non-HR (IBR: 82; CIT: 163 [54.0% BR, 34.4% FCR, 9.8% G-Clb]). Baseline demographics and clinical characteristics were balanced within each pair of comparison groups. For both the weighted IBR and CIT HR groups, mean age was ~66 years with ~40% female, >50% Rai Stage 3-4, >85% ECOG 0-1, ~54% del(17p), ~30% del(11q), ~29% TP53mut, and ~33% unmutated IGHV. Median (range) duration of 1L therapy was 28.6 (1.0-58.1) vs 5.5 (0.5-38.4) months, and median (range) follow-up duration was 33.3 (1.4-58.5) vs 35.3 (1.3-59.5) months, for weighted IBR and CIT HR groups, respectively.

KM analysis showed that weighted IBR HR patients had significantly longer median TTNT (Figure 1 and Table 1) and were 54% less likely to start a new treatment compared to CIT HR patients (Hazard Ratio [95% CI]: 0.46 [0.34-0.62]; p<0.01). For the CIT HR vs CIT non-HR comparison, CIT HR patients had significantly shorter median TTNT (Figure 2 and Table 1) and were 2.43 times more likely to start a new treatment (Hazard Ratio [95% CI]: 2.43 [1.58–3.47]; p<0.01). No significant differences were noted in TTNT between IBR HR and IBR non-HR groups (Figure 3 and Table 1; median TTNT not reached; Hazard Ratio [95% CI]: 2.2 [0.96-4.96]; p=0.06).

During the available follow-up, more weighted IBR HR patients had only one line of treatment compared to weighted CIT HR patients (74.7% vs 47.2%), more CIT non-HR patients had only one line of treatment compared to CIT HR patients (69.9% vs 45.8%), and more IBR non-HR had only one line of treatment compared to IBR HR patients (91.5% vs 81.7%). Majority of patients received SMI therapy in 2L. Most common 2L agents were single-agent IBR in the CIT groups (HR: 86.5%; non-HR: 83.7%) and venetoclax (VEN) in the IBR groups, either as monotherapy (HR: 37.5%; non-HR: 28.6%) or in combination with rituximab (HR: 28.1%; non-HR: 28.6%).

Conclusions: To the best of our knowledge, this is the largest RW study to date comparing clinical outcomes in HR CLL patients on 1L IBR vs CIT. HR CLL patients treated with single-agent IBR had significantly longer TTNT than those treated with CIT, despite similar demographics and clinical characteristics. This RW study also demonstrated that IBR therapy provided sustained clinical benefit regardless of risk status and supports the use of IBR in 1L setting, with VEN being the most common 2L agent among those who required next line of therapy post-IBR. Finally, this study highlighted the need of cytogenetic/molecular testing before CIT treatment, consistent with clinical treatment guidelines.