Multi-Institutional Assessment of Circulating Cell-Free DNA in Cerebrospinal Fluid Facilitates Central Nervous System...

Diagnosis of central nervous system (CNS) lymphoma has historically required CNS tissue biopsy, which often leads to delays in diagnosis and carries risk of neurological morbidity. MYD88 L265P is a prevalent recurrent mutation in CNS lymphoma that can be effectively detected by polymerase chain reaction (PCR) of cell-free DNA. We sought to determine whether detection of MYD88 L265P is a viable method for diagnosis of CNS lymphoma.

We developed and implemented a Clinical Laboratory Improvement Amendments-certified rapid PCR assay for the detection of circulating MYD88 L265P variant in cerebrospinal fluid. Testing was conducted across a multi-institutional prospective cohort, and diagnostic yield, clinical course, and treatment outcomes were analyzed.

Our assay was implemented in 184 patients from 19 hospitals over the course of 16 months. A positive result (N = 14 patients with clinical data) facilitated rapid initiation of CNS lymphoma-targeted treatment with clinical response. There was 100% diagnostic concordance with CNS tissue biopsy (N = 8) and multiple cases (N = 6) for whom treatment was initiated without the need for CNS tissue confirmation. Time to treatment was faster in patients who underwent cerebrospinal fluid analysis for MYD88 L265P without CNS biopsy ( P = .048).

These findings support the utilization of rapid PCR of cell-free DNA as a diagnostic method that may obviate tissue biopsy in the diagnosis of CNS lymphoma. Liquid biopsy to detect the MYD88 L265P variant is a rapid, feasible, and safe method for diagnosing CNS lymphoma.