Use of LOncastuximab Tesirine in patients with RElapsed/Refractory Diffuse Large B-Cell LYmphoma (DLBCL) or High Grade B-Cell Lymphoma (HGBCL) who have progressive disease after CAR T-cell treatment - LORELY

CAR (Chimeric Antigen Receptor) therapy targeting the cluster of differentiation 19 (CD19) is a promising treatment for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Two autologous CAR-T cell therapies directed against CD19 (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel) have been tested for the treatment of these patients, showing significant overall responses with long-term follow-up data. Moreover, the approval of a third CAR-T cell therapy (lisocabtagene maraleucel) is expected soon. 

However, approximately 60% of patients do not respond to CAR-T therapy or relapse and are left without treatment options, representing a critical unmet medical need with poor outcomes. 

Loncastuximab tesirine is an antibody-drug conjugate (ADC) consisting of an anti-CD19 antibody and pyrrolobenzodiazepine (PBD) dimers. Recently published phase 2 data reported an ORR of 48.3% with loncastuximab tesirine monotherapy in a heavily pretreated population of chemo-refractory DLBCL patients, with an acceptable safety profile and independent of CD19 expression levels. Notably, encouraging responses were also observed in high-grade lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit), which is typically associated with a very poor prognosis. 

Additionally, a subgroup analysis of the study showed an ORR of 46% for loncastuximab tesirine when administered after CAR-T therapy failure, which is comparable to the result observed in patients who had not received CAR-T therapy. 

Based on these findings, we hypothesize that loncastuximab tesirine has the potential to induce remission in patients who have failed CAR-T therapy and could be used as a bridge to allogeneic transplant or other consolidation therapies. A repeat biopsy is recommended before initiating treatment with loncastuximab to perform biomarker analyses.