Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma.
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ABSTRACT:
SUBMITTER: Wirsching HG
PROVIDER: S-EPMC8234854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract 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 novel treatment modalities including use of immune checkpoint inhibitors (ICPI). DESIGN: 24 cases of B-cell PCL and 432 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq for all classes of genomic alterations and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. RESULTS The PCL cohort was 50% male and 50% female, aged 21 to 84 with a median age of 66, while the DLBCL cohort was 64% male and 36% female, aged 14 to 88 with a median age of 63. Genomic alterations with significant differences between PCL and DLBCL included MYD88 (50.0% vs 17.6%), ETV6 (38% vs 2.3%), PIM1 (25.0% vs 7.6%), PRDM1 (25.0% vs 5.8%), CXCR4 (16.7% vs 2.5%), TP53 (16.7% vs 40.3%), and CREBBP (0.0% vs 21.5%) (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 (33% vs 19%). Two PCL cases were PD-L1 (CD274) amplified with TMBs of 64 and 10 mutations/mb. CONCLUSIONS CGP of PCLs reveals biomarkers predictive of ICPI efficacy including TMB-high (33%) and CD274 amplification (8%). These results could be used to refer patients to clinical trials such as NCT02779101 employing ICPI treatment in PCL. This is the first series of PCL to report mutational burden and demonstrate a significantly increased frequency of ETV6, CXCR4 and PIM1 genomic alterations in comparison to DLBCL. Given the limitations of standard of care for PCL, CGP can potentially identify new therapeutic approaches in this rare form of lymphoma.
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Project description:The age of personalized medicine continues to evolve within clinical oncology with the arsenal available to clinicians in a variety of malignancies expanding at an exponential rate. The development and advancement of molecular treatment modalities, including targeted therapy and immune checkpoint blockade, continue to flourish. Treatment with targeted therapy (BRAF, MEK, and other small molecule inhibitors) can be associated with swift disease control and high response rates, but limited durability when used as monotherapy. Conversely, treatment with immune checkpoint blockade monotherapy regimens (anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1/programmed cell death protein 1 ligand) tends to have lower response rates than that observed with BRAF-targeted therapy, although these treatments may offer long-term durable disease control. With the advent of these forms of therapy, there was interest early on in empirically combining targeted therapy with immune checkpoint blockade with the hopes of preserving high response rates and adding durability; however, there is now strong scientific rationale for combining these forms of therapy-and early evidence of synergy in preclinical models of melanoma. Clinical trials combining these strategies are ongoing, and mature data regarding response rates and durability are not yet available. Synergy may ultimately be apparent; however, it has also become clear that complexities exist regarding toxicity when combining these therapies. Nonetheless, this increased appreciation of the complex interplay between oncogenic mutations and antitumor immunity has opened up tremendous opportunities for studying targeted agents and immunotherapy in combination, which extends far beyond melanoma to other solid tumors and also to hematologic malignancies.
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Project description:Background: This systematic review and meta-analysis aims to provide comparative and quantitative data about immune checkpoint inhibitor (IMM) and targeted therapy (TAR) in this work. Methods: A literature search was performed with PubMed, Embase, PMC database, and Web of Science databases to identify relevant studies. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) for overall response rate (ORR) were estimated. Results: Eighteen manuscripts were ultimately utilized for indirect comparisons. In general, both TAR and IMM can prolong the PFS either by monotherapy, combination therapy with chemotherapy or adjuvant therapy. BRAF inhibitor monotherapy showed superiority over anti-CTLA-4 in OS (HR: 1.28, 95%CI: 0.93-1.75) and best ORR (OR: 12.57, 95%CI: 6.63-23.82), as well as longer PFS (HR: 1.63, 95%CI: 1.00-2.67) and higher best ORR (OR: 3.29, 95%CI: 1.94-5.55) compared with anti-PD-1. However, MEK inhibitor monotherapy showed no priority. When combined with chemotherapy, anti-CTLA-4 showed marginally advantages over MEK inhibitor in OS (HR: 0.68, 95%CI: 0.44-1.03), however no advantage in PFS (HR: 1.12, 95%CI: 0.76-1.64), or ORR (OR: 1.78, 95%CI: 0.70-4.49). For post-operational melanoma patient, adjuvant TAR and adjuvant IMM showed no difference in OS (HR: 1.14, 95%CI: 0.82-1.58) or PFS (HR: 1.20, 95%CI: 0.79-1.83). Moreover, the high-rate adverse events and underlying diseases should be considered during the application of those agents. Conclusions: For the unresectable late-stage melanoma, IMM may be a better choice for the combined treatment with chemotherapy. If the chemotherapy is not tolerable for patients, BRAFi involved TAR can be considered.
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Project description:BackgroundPrimary central nervous system lymphoma (PCNSL) is rare and there is limited genomic and immunological information available. Incidental clinical and radiographic responses have been reported in PCNSL patients treated with immune checkpoint inhibitors.Materials and methodsTo genetically characterize and ascertain if the majority of PCNSL patients may potentially benefit from immune checkpoint inhibitors, we profiled 48 subjects with PCNSL from 2013 to 2018 with (1) next-generation sequencing to detect mutations, gene amplifications, and microsatellite instability (MSI); (2) RNA sequencing to detect gene fusions; and (3) immunohistochemistry to ascertain PD-1 and PD-L1 expression. Tumor mutational burden (TMB) was calculated using somatic nonsynonymous missense mutations.ResultsHigh PD-L1 expression (>5% staining) was seen in 18 patients (37.5%), and intermediate expression (1-5% staining) was noted in 14 patients (29.2%). Sixteen patients (33.3%) lacked PD-L1 expression. PD-1 expression (>1 cell/high-power field) was seen in 12/14 tumors (85.7%), uncorrelated with PD-L1 expression. TMB of greater than or equal to 5 mutations per megabase (mt/Mb) occurred in 41/42 tumors, with 19% (n = 8) exhibiting high TMB (≥17 mt/Mb), 71.4% (n = 30) exhibiting intermediate TMB (7-16 mt/Mb), and 9.5% (n = 4) exhibiting low TMB (≤6 mt/Mb). No samples had MSI. Twenty-six genes showed mutations, most frequently in MYD88 (34/42, 81%), CD79B (23/42, 55%), and PIM1 (23/42, 55%). Among 7 cases tested with RNA sequencing, an ETV6-IGH fusion was found. Overall, 18/48 samples expressed high PD-L1 and 38/42 samples expressed intermediate to high TMB.ConclusionsBased on TMB biomarker expression, over 90% of PCNSL patients may benefit from the use of immune checkpoint inhibitors.
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