Cell-free DNA-Based Analysis for Diagnosis, Monitoring and Optimization of Therapy for Patients with Primary Central Nervous System Lymphomas

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Project Summary Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma that involves the central nervous system (CNS) without systemic disease. Approximately 1400 cases of PCNSL are diagnosed in the United States annually, classically occurring between the ages of 45 and 65, but the incidence is rising in older patients who represent a population in need of effective therapies with limited adverse effect profiles[1, 2]. Standard frontline therapy consists of high-dose methotrexate (HD-MTX) with autologous stem cell transplant as consolidation therapy. However, these regimens are not tolerated by all patients due to significant neurotoxicity[3]. Even then, about a third of patients are refractory to first-line treatment, and up to 60% of the patients will eventually relapse[4]. Prognosis for patients who are refractory to or relapse after initial therapy is poor, with median survival of only about 1-year failure of upfront therapy[5]. Due to poor long term outcomes, there is a desperate need for improved diagnostic and therapeutic modalities. A considerable hurdle in conducting clinical trials to improve outcomes is the lack of available biomarkers that can be used reliably to diagnose and monitor disease. As such, the diagnosis of PCNSL frequently requires neurosurgical biopsies that are invasive and associated with risk of infection, bleeding and neurological injury. Many patients initially undergo a lumbar puncture (LP) for cerebrospinal fluid (CSF) that is analyzed by cytology and flow cytometry. These approaches, however, lack sensitivity, require large quantities (> 10 mL) of CSF, and are non-diagnostic in many cases. Contrast-enhanced MRI, the gold-standard test of disease monitoring, furthermore, cannot detect early recurrence or minimal residual disease (MRD) leading to an inability to detect chemo-resistance, complete remission, or recurrence. There exists an unmet need not only for better treatment options for patients with PCNSL, but also for biological biomarkers to aid in diagnosis and monitoring of therapeutic response. Such biomarkers would be of incredible importance in planning and executing future clinical trials in PCNSL and related diseases. Recently, several targeted therapies, including Bruton tyrosine kinase inhibitors (e.g., ibrutinib) as well as immunomodulatory agents (e.g., lenalidomide) have shown to dramatically decrease recurrence rate [6-9]. The molecular basis for treatment resistance to these novel targeted agents in PCNSL is largely unknown, uncharacterized and a critical area of translational research. Safe-SeqS and Real-SeqS, technologies that provide an opportunity to detect and quantify tumor DNA in CSF (CSF-tDNA), provide an opportunity to better characterize CNS disease. In this proposal, we aim to develop robust Safe-SeqS and Real-SeqS assays for detection of tumor-derived circulating free DNA (cf-tDNA) which will improve our ability to diagnose and genotype PCNSL, to longitudinally monitor disease status, and to perform whole-exome sequencing (WES) to identify molecular characteristics that can identify patients for targeted therapies based on genomic signatures of response. The knowledge gained from the completion of the proposed Aims would enable the development of cf-tDNA as the first biomarker in PNCSL, a much needed advance for a devastating malignancy.