Novel CD5 Biomarker Effective for Identifying DLBCL Subtypes Sensitive to BTK Inhibitor Therapy

Justin Kline, MD, Department of Medicine, Section of Hematology/Oncology, University of Chicago, Illinois, discussed a novel CD5 gene expression signature (CD5sig) that is a useful biomarker to identify diffuse large B-cell lymphoma (DLBCL) subtypes vulnerable to BTK inhibitor therapies, and which complements current biomarker approaches.
 

Transcript:

I'm Justin Kline and I'm a lymphoma specialist and director of the lymphoma program at the University of Chicago Hospital. This project is centered around developing precision therapy for [patients with] diffuse large B-cell lymphoma (DLBCL). There has recently been a genetic or genomic classifier called LymphGen, which has been applied to large numbers of DLBCL cases, and in certain genomic subsets of DLBCL within that classifier, have been associated with response or improved response to specific targeted therapies. 

The one we were interested in our project was sensitivity or responsiveness to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. Although some retrospective work out of the [National Cancer Institute] (NCI) indicated that 2 very specific LymphGen DLBCL clusters were retrospectively associated with good response to the combination of [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone] (R-CHOP) plus ibrutinib in the randomized phase 3 PHOENIX trial.

The use of the LymphGen classification system in clinical settings is challenging. What we set out to do was to identify a more readily usable biomarker that might predict response to, say, R- CHOP plus a BTK inhibitor. We centered on CD5; CD5 as a cell surface marker on the surface of B cells and T-cells. It reflects active signaling through the B-cell receptor, which is a feature of DLBCLs that were shown to be genetically susceptible to BTK inhibition with ibrutinib in the PHOENIX study. CD5 is also expressed on other lymphomas sensitive to BTK inhibition such as [chronic lymphocytic leukemia) (CLL) and mantle cell lymphoma (MCL). 

We performed CD5 immunohistochemistry (IHC) on a large DLBCL cohort of about 400 cases and identified about 6% as CD5 immunohistochemistry or IHC positive among the non-germinal center DLBLCs or activated B-cell like DLBCLs. We found about 12% CD5 IHC positivity and these CD5 positive DLBCLs were associated with inferior outcomes to R-CHOP therapy, as has been suggested by prior studies looking at their transcriptional phenotype because we also had available RNA sequencing and whole exome sequencing data for many of these samples.

These CD5 IHC positive DLBCLs were associated with evidence of enhanced B-cell receptor signaling. A number of them harbored mutations in genes known to confer chronically active B-cell receptor signaling such as CD79b and MYD88, although certainly not all of them carry those mutations. We wanted to validate the CD5 immunohistochemistry in sort of a prospective clinical trial like PHOENIX, for example, but lacked the tissue to do so. Alan, who was the first author on the study, developed a gene signature where he called it the CD5 signature (CD5sig) and that was derived from the 60 most differentially expressed genes between CD5 IHC positive and IHC negative DLBCLs. 

He validated that the CD5 gene signature recapitulated many biological features of the IHC positive DLBCLs and then applied the CD5 signature to [patients with] DLBCL that were enrolled onto the PHOENIX trial and showed that CD5 signature positive DLBCLs were associated with significant benefit from the addition of ibrutinib to R-CHOP in younger patients, patients less than 60, not only amongst those that could be classified by LymphGen, say as MCD or those that carry MYD88 or CD79b mutations, but also in LymphGen unclassifiable DLBCLs.These are DLBCLs that you can't bin into one of the known 7 genetic clusters identified by LymphGen. What Alan did with his signature was identify DLBCLs with a genetic and non-genetic basis for enhanced BCL receptor signaling, and therefore benefit from the BTK inhibitor—in this case, ibrutinib. 

Source:

Cooper A, Tumuluru S, Kissick K, et al. CD5 gene signature identifies diffuse large b-cell lymphomas sensitive to brutonʼs tyrosine kinase inhibition. J Clin Oncol. Published online December 11, 2023. doi: 10.1200/JCO.23.01574