Symposium | First-line BTK inhibitors for CLL: Current and future perspectives

During the Lymphoma Hub virtual symposium on October 23, 2024, entitled Customizing first-line Bruton‘s tyrosine kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL), Paolo Ghia, Università Vita-Salute San Raffaele, RCCS Ospedale San Raffaele, Milano, IT, delivered a presentation on the current and future perspectives of BTK inhibitors in first-line (1L) CLL.

Ghia provided an overview of three generations of BTK inhibitors for the 1L treatment of CLL in the US and Europe, including their regulatory status. He emphasized the advantages of fixed-duration therapy, such as minimal side effects, a reduced risk of clonal evolution and resistance, lower financial costs, the possibility of retreatment, and improved quality of life. Additionally, he highlighted the importance of combining venetoclax, a B-cell lymphoma (BCL)-2 inhibitor, with BTK inhibitors and anti-CD20 monoclonal antibodies to achieve deep and lasting responses.

Ghia shared the latest data from clinical trials of fixed-duration BTK inhibitors as doublet and triplet combination therapies in 1L CLL, and presented key outcomes from the CAPTIVATE, GLOW, CLL13/GAIA, NCT03580928, and AMPLIFY trials (Figure 1). He then discussed the importance of measurable residual disease (MRD)-guided fixed-duration approaches in the 1L CLL treatment paradigm (Figure 2), using clinical data from the BoVen and FLAIR trials, and talked about how MRD-guided treatment allows tailored therapy duration based on the MRD status.

Finally, Ghia considered future trials of emerging doublet and triplet combinations of BTK inhibitors, including the CLL16, CLL17, MAJIC, and RESOLVE trials, with new oral therapies and next-generation anti-CD20 antibodies as promising options for patients with high-risk disease features.

1L, first line; 2L, second line; CI, confidence interval; CIT, chemoimmunotherapy; CK, complex karyotype; Clb, chlorambucil; CLL, chronic lymphocytic leukemia; CR, complete response; CRi, CR with incomplete bone marrow recovery; HR, hazard ratio; Ibr, ibrutinib; IGHV, immunoglobulin heavy chain variable region; mIGHV, mutated IGHV; MRD, measurable residual disease; Ob, obinutuzumab; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R, rituximab; uIGHV, unmutated IGHV, uMRD, undetectable MRD; Ven, venetoclax.
*Data from Wierda¹, Moreno et al.²,  Eichhorst et al.³_, and Davids et al.⁴

MRD, measurable residual disease; OS, overall survival; PFS, progression-free survival; uMRD, undetectable MRD.
*Adapted from Seymour, et al.⁵

 

Key learnings

The use of new oral, targeted therapies and next-generation anti-CD20 monoclonal antibodies has significantly improved outcomes for treatment-naïve patients with CLL.

Doublet and triplet combination regimens have shown encouraging outcomes, leading to fixed-duration regimens becoming potential alternatives to continuous therapy. Even in patients with high-risk disease features, BTK inhibitor/BCL2 inhibitor combinations exhibit improved responses with deep and durable disease control.

MRD-guided treatment represents a promising approach for managing CLL, offering the capability for more effective and less toxic therapy.

This independent educational activity was supported by an educational grant from Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. All content was developed independently by SES in collaboration with the faculty. The funder was allowed no influence on the content of this activity.