A number of CD19-targeted medicines, such as chimeric antigen receptor T-cell therapy (CAR-T), antibody-drug conjugates (ADCs), monoclonal antibodies, and bispecific drugs, have been approved for the treatment of B-cell malignancies and are clinically validated targets. The best order in which to administer these therapies had not been determined. It was recommended for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after receiving ≥2 systemic therapies. Loncastuximab tesirine (loncastuximab tesirine-lypl; Lonca) is an ADC that consists of an anti-CD19 antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. A response to Lonca was not precludeable by prior CAR-T therapy, and responses were also seen in patients who received CAR-T therapy after Lonca. For a study, researchers sought to ascertain how CD19 expression affected reactions in patients using Lonca.

Immunohistochemistry (IHC)-based CD19 expression was assessed in a cohort of patients who participated in the LOTIS-2 clinical trial using tissue samples that were available after their final anti-cancer systemic medication and before Lonca. The LE-CD19 antibody (DAKO) was used for IHC, and the BenchMark ULTRA platform (Ventana) was used to assess expression. By using semi-quantitative grading of the H-Score and the proportion of tumor cells that are positive, CD19 expression was evaluated (semiquantitative assessment of the percentage of CD19 positive cells and staining intensity). The response to Lonca was predicted using quantitative systems pharmacology (QSP) modeling, and patient-specific covariate hypotheses were tested. 

The group comprised patients (n = 59) who had undergone any previous systemic treatments, including patients (n = 9) who had CAR-T as their final treatment before a biopsy. Patients with all levels of CD19 expression, including those with extremely low or undetectable CD19 expression at baseline & extremely low H-Scores, responded to Lonca. Patients were expected to experience a clinical response to Lonca based on the QSP modeling, even with CD19 tumor cell-surface concentrations as low as 1,000 molecules/cell.

R/R DLBCL patients with extremely low IHC-measured CD19 tumor expression showed a response to Lonca. According to QSP modeling, CD19 surface density enhances the ability to predict response to Lonca, but CD19 expression level by IHC does not. Estimated tumor cell surface densities in responding patients were as low as 1,000 molecules/cell, which is often below the threshold for IHC detection. The results showed that Lonca, even in individuals anticipated to have a low level of CD19 expression, is a viable therapeutic choice for patients with R/R DLBCL following ≥2 lines of therapy. Future studies addressing the sequencing of CD19-targeted agents can build on the findings.

Reference: ash.confex.com/ash/2022/webprogram/Paper159626.html