Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies

Eli Hatchwell; Edward B Smith 3rd; Shapour Jalilzadeh; Christopher D Bruno; Yassine Taoufik; Houria Hendel-Chavez; Roland Liblau; David Brassat; Guillaume Martin-Blondel; Heinz Wiendl; Nicholas Schwab; Irene Cortese; Maria Chiara Monaco; Luisa Imberti; Ruggero Capra; Jorge R Oksenberg; Jacques Gasnault; Bruno Stankoff; Todd A Richmond; David M Rancour; Igor J Koralnik; Barbara A Hanson; Eugene O Major; Christina R Chow; Peggy S Eis

doi:10.3389/fneur.2022.1016377

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies

Front Neurol. 2022 Dec 14:13:1016377. doi: 10.3389/fneur.2022.1016377. eCollection 2022.

Authors

Eli Hatchwell¹, Edward B Smith 3rd², Shapour Jalilzadeh¹, Christopher D Bruno³, Yassine Taoufik⁴, Houria Hendel-Chavez⁴, Roland Liblau^{5

6}, David Brassat^{5

6}, Guillaume Martin-Blondel^{5

7}, Heinz Wiendl⁸, Nicholas Schwab⁸, Irene Cortese⁹, Maria Chiara Monaco¹⁰, Luisa Imberti¹¹, Ruggero Capra¹², Jorge R Oksenberg¹³, Jacques Gasnault¹⁴, Bruno Stankoff¹⁵, Todd A Richmond¹⁶, David M Rancour¹⁷, Igor J Koralnik¹⁸, Barbara A Hanson¹⁸, Eugene O Major¹⁹, Christina R Chow³, Peggy S Eis²

Affiliations

¹ Population Bio UK, Inc., Oxfordshire, United Kingdom.
² Population Bio, Inc., New York, NY, United States.
³ Emerald Lake Safety LLC, Newport Beach, CA, United States.
⁴ Department of Hematology and Immunology, Hôpitaux Universitaires Paris-Saclay and INSERM 1186, Institut Gustave Roussy, Villejuif, France.
⁵ Infinity, Université Toulouse, CNRS, INSERM, UPS, Toulouse, France.
⁶ Department of Immunology, CHU Toulouse, Hôpital Purpan, Toulouse, France.
⁷ Department of Infectious and Tropical Diseases, Toulouse University Hospital Center, Toulouse, France.
⁸ Department of Neurology With Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
⁹ Experimental Immunotherapeutics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
¹⁰ Viral Immunology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
¹¹ Centro di Ricerca Emato-Oncologica AIL (CREA) and Diagnostic Department, ASST Spedali Civili of Brescia, Brescia, Italy.
¹² Lombardia Multiple Sclerosis Network, Brescia, Italy.
¹³ Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
¹⁴ Department of Internal Medicine, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.
¹⁵ Department of Neurology, Hôpital Saint-Antoine, Paris, France.
¹⁶ Richmond Bioinformatics Consulting, Seattle, WA, United States.
¹⁷ Lytic Solutions, LLC, Madison, WI, United States.
¹⁸ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
¹⁹ Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.

Abstract

Background: Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.g., leukemias, lymphomas, and multiple myeloma), autoimmune disorders (e.g., psoriasis, rheumatoid arthritis, and systemic lupus erythematosus), and organ transplants. In some patients, iatrogenic (i.e., drug-induced) PML occurs as a serious adverse event from exposure to immunosuppressant therapies used to treat their disease (e.g., hematological malignancies and multiple sclerosis). While JCV infection and immunosuppression are necessary, they are not sufficient to cause PML.

Methods: We hypothesized that patients may also have a genetic susceptibility from the presence of rare deleterious genetic variants in immune-relevant genes (e.g., those that cause inborn errors of immunity). In our prior genetic study of 184 PML cases, we discovered 19 candidate PML risk variants. In the current study of another 152 cases, we validated 4 of 19 variants in both population controls (gnomAD 3.1) and matched controls (JCV+ multiple sclerosis patients on a PML-linked drug ≥ 2 years).

Results: The four variants, found in immune system genes with strong biological links, are: C8B, 1-57409459-C-A, rs139498867; LY9 (alias SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; STXBP2, 19-7712287-G-C, rs35490401. Carriers of any one of these variants are shown to be at high risk of PML when drug-exposed PML cases are compared to drug-exposed matched controls: P value = 3.50E-06, OR = 8.7 [3.7-20.6]. Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B^*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Conclusion: For the first time, a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug in order to decrease the incidence of PML and enable safer use of highly effective therapies used to treat their underlying disease.

Keywords: JC virus; PML; immunodeficiency; multiple sclerosis; natalizumab; pharmacovigilance; progressive multifocal leukoencephalopathy; serious adverse event.

Copyright © 2022 Hatchwell, Smith, Jalilzadeh, Bruno, Taoufik, Hendel-Chavez, Liblau, Brassat, Martin-Blondel, Wiendl, Schwab, Cortese, Monaco, Imberti, Capra, Oksenberg, Gasnault, Stankoff, Richmond, Rancour, Koralnik, Hanson, Major, Chow and Eis.