The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants

by Selleckchem | Mar 28 2023

Background: Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies.

Objectives: We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes.

Material and methods: The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology.

Results: In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib.

Conclusions: Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

Comments：

The study aimed to evaluate the efficacy of ibrutinib, a BTK inhibitor, in treating relapsed/refractory (r/r) primary and secondary central nervous system lymphoma (CNSL) patients and to investigate whether genomic variants affect treatment outcomes. The results showed that ibrutinib-based therapy was effective and relatively safe for treating r/r CNSL. Patients with less genomic complexity, especially with regard to tumor mutation burden (TMB), responded better to ibrutinib therapy. The study also identified specific gene mutations that were associated with a positive response to ibrutinib.

Key findings:

The overall response rate of ibrutinib-based therapy in 12 r/r primary CNSL patients was 75%, with a median overall survival (OS) not reached and progression-free survival (PFS) of 4 months.
Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months.
Infections were common during ibrutinib therapy (42.86%).
Patients with gene mutations in PIM1, MYD88, and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded well to ibrutinib therapy.
Patients with simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months.
Patients with complex genomic features, especially those with extremely high TMB (58.39/Mb), responded poorly to ibrutinib therapy.
Conclusion:

The study suggests that ibrutinib-based therapy is effective and relatively safe for treating r/r CNSL patients, and patients with less genomic complexity, especially with regard to TMB, may benefit more from ibrutinib regimens. The study also identified specific gene mutations that were associated with a positive response to ibrutinib, which may have implications for patient selection in future clinical trials.