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Non-Hodgkin Lymphoma
Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas
Sabela Bobillo,1* Marta Crespo,1* Laura Escudero,2* Regina Mayor,2 Priyanka Raheja,1 Cecilia Carpio,1 Carlota Rubio-Perez,2
Bárbara Tazón-Vega,1Carlos Palacio,1 Júlia Carabia,1 Isabel Jiménez,1
Juan. C. Nieto,1 Julia Montoro,1 Francisco Martínez-Ricarte,3 Josep Castellví,4 Marc Simó,5 Lluis Puigdefàbregas,1 Pau Abrisqueta,1 Francesc Bosch1#
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):513-521
and Joan Seoane2,6#
1Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Universitat Autònoma de Barcelona, Department of Medicine; 2Translational Research Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital (HUVH), Universitat Autònoma de Barcelona; 3Department of Neurosurgery, Universitat Autònoma de Barcelona, Hospital Vall d'Hebron; 4Department of Pathology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona; 5Department of Nuclear Medicine, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona and 6Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain and CIBERONC
*SB, MC and LE contributed equally as co-first authors. #FB and JS contributed equally as co-senior authors.
ABSTRACT
The levels of cell free circulating tumor DNA (ctDNA) in plasma cor- relate with treatment response and outcome in systemic lym- phomas. Notably, in brain tumors, the levels of ctDNA in the cere- brospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 sys- temic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic muta- tions of the primary tumor, then variant-specific droplet digital polymerase chain reaction was designed for each mutation. At time of enrollment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2 out of 6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in one patient with CNS lym- phoma in complete remission and in one patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed, indicating that CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in two cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though no tumoral cells were observed by flow cytometry (FC), indicating that CSF ctDNA detected residual disease better than FC. In conclusion, CSF ctDNA can detect CNS lesions better than plas- ma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas.
Introduction
Central nervous system (CNS) involvement in B-cell malignancies is associated with dismal prognosis, especially in the relapse setting.1 Primary central nervous sys- tem lymphoma (PCNSL) is defined by the presence of CNS lymphoma in the absence of systemic disease.2 Conversely, secondary involvement of the CNS (SCNSL) is characterized by CNS infiltration with concomitant or previous history of systemic lymphoma.3 The diagnosis of CNS lymphoma is commonly based on cra-
Correspondence:
JOAN SEOANE
jseoane@vhio.net
FRANCESC BOSCH
fbosch@vhio.net
Received: October 22, 2019. Accepted: February 18, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.241208
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