Considering Third-Line Loncastuximab Tesirine Plus Rituximab in Follicular Lymphoma

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, combined with rituximab, shows promising and substantial activity as a third-line option for relapsed/refractory (R/R) follicular lymphoma. Initial data from a small, single-center Phase 2 trial demonstrated a high overall response rate of 97% and a complete response rate of 77% in high-risk patients, translating to an impressive 12-month progression-free survival (PFS) of 94.6%.

However, the data are constrained to this small study, necessitating larger, multi-center, and ideally comparative trials to robustly confirm its efficacy and warrant a preferred regimen status. The National Comprehensive Cancer Network (NCCN) currently lists loncastuximab tesirine plus rituximab as a Category 2B "Other Recommended Regimen" for third-line follicular lymphoma, reflecting consensus on its appropriateness despite the limited evidence base.

In terms of safety and mechanism, loncastuximab tesirine plus rituximab offers a targeted, chemotherapy-free approach by combining a CD19-directed toxin (loncastuximab tesirine) with a CD20-directed antibody (rituximab). Its safety profile is considered manageable, with common adverse events including neutropenia, elevated liver enzymes, and rash. This profile compares favorably to toxicities such as cytokine release syndrome and neurotoxicity that are associated with chimeric antigen receptor (CAR) T-cell therapy, another highly effective, established third-line option.

The main strategic consideration for loncastuximab tesirine plus rituximab, as with all CD19-directed treatments, is its impact on treatment sequencing. The concern is that using loncastuximab tesirine may lead to a loss or modulation of CD19 expression on lymphoma cells. Since CAR T-cell therapies for follicular lymphoma also rely on the CD19 target, any prior therapy that reduces this expression could negatively impact the future use or effectiveness of CAR T cells, requiring physicians to carefully choose the optimal sequence of these novel agents.