ICML 2023 | Identification of genomic biomarkers of disease progression & survival in primary CNS lymphoma

So this is a study we performed which addresses the question of the unmet need for highly reliable biomarkers that can identify those patients that are likely to progress during chemotherapy in primary CNS lymphoma, which is a highly aggressive subtype of non-Hodgkin’s lymphoma. While there’s been a lot of progress in improving survival in this disease, there’s a liability that many patients face during the first six months. Approximately 20 to 30% of patients progress during induction chemotherapy. And these patients really have a poor prognosis. So we asked the question, can we identify through next-generation sequencing genomic changes that are indicative of that clinical phenotype? And indeed we achieve this. We have identified three genomic alterations at three loci that seem to account for approximately 87% of the progression events in a cohort of 65 patients with a discovery and validation set largely conducted at the University of California, San Francisco, with the standard methotrexate-based induction regimen that’s used nationally and in some places worldwide. But the clinical problem is universal to all methotrexate-based induction regimens. The loci that we identified include genomic changes at the p arm of chromosome six, which encompasses most of the major histocompatibility antigen presentation genes. And we found through our next-generation sequencing platform two genomic alterations which are most significant in identifying high-risk patients, homozygous deletions involving the MHC II of which is relatively rare. But we also, through our technology, identified a genotype called uniparental disomy or copy number neutral loss of heterozygosity involving 6p, which we found the breakpoint initiates at generally at p21.1 the initiation of the MHC II genes. We validated the significance of this by showing that most of the cases with 6p copy number neutral LOH or homozygous deletion at 6p have a low expression of HLA-DR, which is a key antigen presentation molecule that has been validated as a significant independent adverse prognostic factor when it’s expressed at low levels in systemic, diffuse large B-cell lymphoma. And so we’ve shown that those patients that unfortunately have this genotype are particularly vulnerable to progression during the first six months of therapy. In addition, we found two tumor suppressor genes which are commonly co-mutated with 6p copy neutral LOH, but also half the time mutated independent of the 6p alteration, and these are BTG1 and ETV6. These are two tumor suppressor genes that are part of the well described MCD phenotype of diffuse large B-cell lymphoma, which has been established through work from the Staudt lab at the National Cancer Institute to be associated with poor prognosis in systemic DLBCL. We found reproducibly that patients with BTG1 mutations or ETV6 mutations or those in combination also have a have a poor risk generally, oftentimes progress during the first six months, but a subset of these patients actually progressed after consolidation therapy between two and four years of therapy. So we believe this is actually the first identification of genomic biomarkers that could be useful for risk stratification and development of special therapeutics for this high-risk subgroup of patients. The next steps are validation and further cohorts and further clinical translation.