Effects on Melanoma Cell Lines Suggest No Significant Risk of Melanoma Under Cladribine Treatment
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BRIEF REPORT
Effects on Melanoma Cell Lines Suggest No Significant Risk of Melanoma Under Cladribine Treatment Christine Lebrun-Frenay
. Ilona Berestjuk . Mikael Cohen .
Sophie Tartare-Deckert
Received: May 31, 2020 Ó The Author(s) 2020
ABSTRACT Cladribine is an oral synthetic purine analog that depletes lymphocytes and induces a dosedependent reduction of T and B cells. It was approved for the therapy of highly active relapsing-remitting multiple sclerosis. Given cladribine’s mechanism of action, an increased risk of malignancies was suspected from the number of cancers that occurred in the 3.5 mg/ kg-treated arm (CLARITY study). We showed that cladribine inhibits cell proliferation on three melanoma cell lines tested, irrespectively of their mutational oncogenic status and invasive/metastatic potential. Aggregated safety data demonstrated that the risk of melanoma is not confirmed.
Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12662237. M. Cohen ˆ te d’Azur, URRIS UR2CA, Nice, France Universite´ Co M. Cohen Centre de Ressources et de Compe´tence Scle´rose En ˆ pital Pasteur2, Nice, Plaques, CHU de Nice, Ho France C. Lebrun-Frenay (&) I. Berestjuk S. Tartare-Deckert ˆ te d’Azur, INSERM, C3M, Nice, France Universite´ Co e-mail: [email protected]
Keywords: Cladribine; Immunosuppressors; Melanoma; Multiple sclerosis Key Summary Points There is literature relating immunosuppressive drugs used for autoimmune diseases to the risk of cancer Clinical studies have raised some doubts about cladribine being responsible for an increased risk of melanoma in multiple sclerosis patients Our study demonstrates that at either low or high cladribine concentrations, there is no proliferation or differentiation of melanocytes These results could affect future clinical practice for neurologists using cladribine for their MS patients and could influence monitoring Data from registries are mandatory to confirm our in vitro study
INTRODUCTION Cladribine (2-chloro-20 -deoxyadenosine, 2-CDA) is a synthetic purine nucleoside analog
Neurol Ther
cytotoxic to lymphocytes and, to a lesser degree, monocytes and hematopoietic cells. As a result, cladribine induces a dose-dependent reduction of T and B cells lasting months to years. The 96-week, placebo-controlled CLARITY study showed that treatment with oral cladribine is clinically and radiologically effective in patients with relapsing-remitting multiple sclerosis (MS) [1]. However, US and European regulatory authorities expressed concerns about the risk-benefit profile of the drug, and the sponsor initially decided not to continue its further development in MS. Patients included in the phase 3 randomized ORACLE MS trial from October 2008 to 2010 receiving either cladribine 5.25 mg/kg cumulative dose, cladribine 3.5 mg/Kg cumulative dose or placebo were offered participation in an extension period [2]. Three cases of cancer occurred in patients treated with 3.5 mg/kg cladribine (one cutaneous melanoma, one pancreati
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