Comprehensive Genomic Profiling Demonstrates Differences in Primary CNS Lymphoma and Systemic Diffuse Large B Cell Lymphoma and Reveals Biomarkers Indicating Potential Benefit from Immune Checkpoint Inhibitors

BACKGROUND: B-Cell Primary CNS Lymphoma (PCL) is Diffuse Large B-cell Lymphoma (DLBCL) confined to the CNS. Less than 50% of PCL patients achieve complete remission with current therapies. Comprehensive genomic profiling (CGP) may suggest treatment modalities including use of immune checkpoint inhibitors (ICPI).

DESIGN: 35 cases of B-cell PCL and 455 cases of DLBCL were evaluated by CGP of 406 genes via DNAseq for all classes of genomic alterations and 265 genes via RNAseq for rearrangements (FoundationOne Heme^®). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. Microsatellite instability status was determined by a customized algorithm.

RESULTS: The PCL cohort was 49% male and 51% female, aged 21-84 y (median age 67), while the DLBCL cohort was 64% male and 36% female, aged 14-88 y (median age 63). Genomic alterations with significant differences between PCL and DLBCL included MYD88 (42.9% vs 15.6%), CD79B (25.7% vs 6.6%), ETV6 (25.7% vs 3.1%), PRDM1 (22.9% vs 5.1%), PIM1 (17.1% vs 6.6%), CXCR4 (14.3% vs 4.4%), TP53 (20.0% vs 38.8%), and CREBBP (0.0% vs 30.8%) (p<0.05 by two-tailed Fisher Exact Test).

Median TMB was similar (median 9.2 vs 10 mutations/mb) and the percent of TMB-high cases (>20 mutations/mb) were not statistically different (26% vs 20%). Three PCL cases were PD-L1 ( CD274 ) and PD-L2 (PDCD1LG2) amplified with TMBs of 64, 10, and 6 mutations/Mb and one PCL case had a CD274-MLANA fusion. All PCL cases were microsatellite stable.

De novo resistance to the BTK inhibitor Ibrutinib has been reported in a patient with PCL and a mutation in the coiled-coiled domain of CARD11 (Grommes et al ). In this PCL cohort, 3 patients (8.6%) had mutations in CARD11 , all located in the coiled-coiled domain, suggesting potential de novo resistance to BTK inhibition in these patients.

CONCLUSIONS: CGP of PCLs reveals biomarkers predictive of immunotherapy efficacy including TMB-high (26%) and CD274 amplification or rearrangements (11%). TMB-high and CD274 amplification are both linked to immunotherapy response. These results could be used to refer patients to clinical trials such as NCT02779101 employing ICPI treatment in PCL. Additionally, CGP detects potential de novo resistance to BTK inhibition. This is the first series of PCL to report mutational burden and demonstrate a significantly increased frequency of ETV6 , CXCR4 and PIM1 genomic alterations compared to DLBCL. Given the limitations of standard of care for PCL, CGP can potentially identify new therapeutic approaches in this rare form of lymphoma.