BCL2 and cBTK Inhibitors Show Superior Outcomes in CLL/SLL

Microscopic image of CLL cells - Generated with Google Gemini AI

Treatment sequences including covalent Bruton tyrosine kinase inhibitors (cBTKis) followed by B-cell lymphoma-2 (BCL2) inhibitors and anti-CD20 monoclonal antibodies (aCD20abs) are associated with better overall survival (OS) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In contrast, sequences involving chemoimmunotherapy (CIT) followed by cBTKi monotherapy or anti-CD20 antibodies resulted in worse OS.¹

These findings were presented during a presentation at the 2024 American Society of Hematology (ASH) Annual Meeting through analyzing the impact of real-world treatment sequences on OS in patients with CLL/SLL in the US.¹

Background and Objectives of the Trial

Over the past decade, treatment strategies for CLL/SLL have evolved, with a shift from traditional CIT to targeted therapies, including BTKis, BCL2 inhibitors, and aCD20abs. However, the sequencing of these therapies to optimize patient outcomes remains an area of debate, according to the poster presented at ASH. This is particularly true in the real-world setting, where multiple factors influence treatment decisions.

In this study, investigators utilized the Flatiron Health electronic health recordz–derived de-identified database to analyze treatment sequences in adult patients with CLL/SLL who started systemic therapy after 2016. The study compared OS associated with the most frequent treatment sequences across the first and second lines of therapy.

A total of 2354 patients met the eligibility criteria, which included having CLL/SLL, being 18 years or older at the index date, having received first-line treatment on or after January 1, 2016, and having received at least 2 lines of therapy. The study then focused on 1711 patients who received 1 of 16 of the most frequent treatment sequences, which included combinations of CIT, aCD20ab, cBTKi, and BCL2i.

The median age of patients in this cohort was 71 years (interquartile range, 63-78), and most were male (63%) and non-Hispanic White (73.6%). For those with available data, 10.8% of patients had a del(17p)/TP53 mutation, 62.2% had unmutated IGHV, 91.4% had an ECOG performance status of 0 or 1, and 62.6% were initially diagnosed with RAI stage 0/I.

The study identified several treatment sequences that were commonly used in the real world, including CIT followed by cBTKi monotherapy (20.5%), aCD20ab monotherapy followed by cBTKi monotherapy (11.7%), aCD20ab monotherapy followed by BCL2i + aCD20ab (10.2%), and cBTKi monotherapy followed by aCD20ab monotherapy (6.3%).

Findings and Clinical Implications

OS was analyzed by comparing various treatment sequences to the reference sequence of cBTKi monotherapy followed by BCL2i and aCD20ab, which was associated with the best OS outcomes.

Patients who received the following sequences had significantly worse OS: cBTKi monotherapy followed by aCD20ab monotherapy (adjusted hazard ratio [aHR], 2.47), aCD20ab monotherapy followed by CIT (aHR, 2.68), and CIT followed by CIT (aHR, 2.87). Sequences that included cBTKi monotherapy followed by BCL2i and aCD20ab were not significantly different in OS when adjusted for baseline factors and treatment history.

OS outcomes were similar to the reference group with sequences that did not involve BCL2i in the second line of therapy. The median OS for those given cBTKi monotherapy followed by aCD20ab monotherapy sequence was 63 months, while OS for most other sequences could not be estimated due to limited follow-up or patient drop-out.

“Optimizing treatment sequencing remains an important area of future research in this population,” study authors wrote in the poster.

REFERENCE:

1. Rhodes JM, Bhandari NR, Khanal M, et al. Overall survival associated with real-world treatment sequences in patients with CLL/SLL in the United States. Blood. 2024;144(suppl 1):5144. doi:10.1182/blood-2024-198104