Optimizing Treatment Sequences Remains Key in CLL/SLL

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The treatment sequence of chemoimmunotherapy or an anti-CD20 monoclonal antibody monotherapy followed by chemoimmunotherapy and the sequence of covalent BTK inhibitor monotherapy followed by covalent BTK inhibitor monotherapy were both associated with worse overall survival (OS) outcomes vs covalent BTK inhibitor monotherapy followed by a BCL2 inhibitor plus anti-CD20 monoclonal antibody in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). An examination of real-world treatment sequences in the US featuring these therapies and more in CLL/SLL was presented at the 2024 ASH Annual Meeting.¹

Investigators wrote in the poster that optimizing CLL/SLL treatment sequencing remains an important area of research as no significant decreases in outcomes between certain targeted-therapy sequences vs the reference sequence were observed.

Findings and Clinical Implications

OS was analyzed by comparing various treatment sequences to the reference sequence of covalent BTK inhibitor monotherapy followed by a BCL2 inhibitor and an anti-CD20 monoclonal antibody. Patients who received the following sequences had a significantly worse OS vs the reference sequence: covalent BTK inhibitor monotherapy followed by anti-CD20 monoclonal antibody monotherapy (adjusted HR, 2.47), anti-CD20 monoclonal antibody monotherapy followed by chemoimmunotherapy (adjusted HR, 2.68), and chemoimmunotherapy followed by chemoimmunotherapy (adjusted HR, 2.87). Investigators noted that all other key treatment sequences vs the reference sequence were not significantly different in model 1 and model 2 for OS or were only significantly different in model 1.

Although the unadjusted OS for most key sequences examined could not be estimated, data revealed that the median OS for those given covalent BTK inhibitor monotherapy followed by anti-CD20 monoclonal antibody monotherapy was 63 months whereas it was 81 months for those who received a BCL2 inhibitor after covalent BTK inhibitor monotherapy. For patients who received chemoimmunotherapy followed by chemoimmunotherapy, the unadjusted median OS was 72 months. Those who received an anti-CD20 monoclonal antibody monotherapy first experienced an unadjusted median OS of 82 months when the second therapy was a covalent BTK inhibitor monotherapy and an unadjusted median OS of 93 months when the second therapy was chemoimmunotherapy.

Background and Objectives of the Trial

Over the past decade, treatment strategies for CLL/SLL have evolved, with a shift from traditional chemoimmunotherapy to targeted therapies, including BTK inhibitors, BCL2 inhibitors, and anti-CD20 monoclonal antibodies. 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 chemoimmunotherapy, anti-CD20 monoclonal antibodies, covalent BTK inhibitors, and BCL2 inhibitors.

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 chemoimmunotherapy followed by covalent BTK inhibitor monotherapy (20.5%), anti-CD20 monoclonal antibody monotherapy followed by covalent BTK inhibitor monotherapy (11.7%), anti-CD20 monoclonal antibody monotherapy followed by a BCL2 inhibitor plus anti-CD20 monoclonal antibody (10.2%), and covalent BTK inhibitor monotherapy followed by anti-CD20 monoclonal antibody monotherapy (6.3%).

Reference

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