Neurological Sciences | 2021
Severe lymphopenia switching from Fingolimod to Siponimod
Abstract
Siponimod is authorized for the treatment of secondary progressive Multiple Sclerosis (SPMS) with disease activity evidenced by relapses or imaging features of active inflammation [1]. It is a sphingosine-1-phosphate (S1P) receptor modulator, selective for subtypes 1 and 5, which promote a marked and long-lasting internalization of the S1P1 receptor, with consequent reduction of lymphocytes recirculation from lymphatic tissue to the central nervous system. Siponimod is metabolized by the cytochrome P450 system (at first CYP2C9, followed by CYP3A4). Before starting treatment, patients should be genotyped for CYP2C9 in order to decide the titration schedule and maintenance dose, that is 2 mg/die, except for CYP2C9*1*3 or *2*3 genotype (in these cases, it is 1 mg/die), and contraindicated in CYP2C9*3*3 genotype [2]. We introduce the case of a SPMS patient who switched from Fingolimod to Siponimod, and 1 month later, he developed a severe lymphopenia that recovered very slowly after dose adjustment (Fig. 1). A 55-year-old man received a diagnosis of MS in 1999 and was treated with interferon beta1a (44 mcg × 3/week). Due to ongoing disease activity, the treatment was switched to Fingolimod in 2012. He had no disease activity and no adverse events in Fingolimod. During the whole treatment period, the lowest lymphocyte count was 530/mmc. After a transitional phase, because of a progressive worsening of neurologic function with disability accrual over time, in 2016, he was diagnosed with SPMS. In May 2019, he stopped Fingolimod to be enrolled in the Compassionate Use Program: “CBAF312A2001M.” The patient underwent the scheduled screening for Siponimod, including viral testing for HBV, HCV, HIV (except for antibodies to VZV because he was already positive before starting Fingolimod), and Quantiferon. Two months after Fingolimod discontinuation, the lymphocyte count was 1000/mmc. The patient genotype was CYP2C9*1*1; therefore, he started Siponimod 2 mg/ die in May 2020. After 1 month of Siponimod treatment, he developed a severe lymphopenia (200/mmc) that was confirmed 1 week later. Siponimod dosage was changed from 2 to 1 mg/die with persistent lymphopenia (200/mmc) 1 month later, confirmed after another week. For safety issues, we decided for an off-label administration schedule at 1 mg every other day. Four weeks later, the lymphocyte count was 500/mmc. The redistribution of lymphocytes to secondary lymphoid organs, due to the long-lasting internalization of the S1P1 receptor, produces the main pharmacodynamic effect of Siponimod: a dose-dependent reduction of the peripheral lymphocyte count, to 20–30% of baseline values, with a recovery of the normal range within 10 days after treatment discontinuation in 90% of the patients, and up to 3–4 weeks in a few patients [2]. In the EXPAND study, the grade 4 lymphopenia (< 200/mmc) occurred in only 1% of patients [3]. A dose-dependent decrease in total peripheral lymphocytes to 20–30% of the baseline can be observed also during Fingolimod treatment, with a recovery of the normal range about 1–2 months after treatment stop [4]. Although Siponimod-related reduction in total lymphocyte count is well-known [5], the peculiarity of our case is the unexpected different effect on lymphocyte count during Fingolimod and Siponimod treatment. In our patient, the lowest lymphocyte count was 530/mmc during Fingolimod and 200/mmc after only 1 month of Siponimod treatment, with a decrease in total peripheral lymphocytes to 20% of baseline. Even 1 month later, in every other day schedule, the lymphocyte count remained abnormal, but with a slow rise of lymphocyte count even without drug discontinuation (500/mmc). Considering the EXPAND study data on lymphopenia, we might have expected a faster recovery of lymphocyte count. * Simona Bonavita [email protected]