Evaluating the effectiveness of Rituximab in rElapsiNg Multiple Sclerosis patiEnts previously treated with hiGhly-Active Disease modifying thErapies (RENEGADE).
SYNOPSIS AND RESULTS
Introduction: Active Multiple Sclerosis (MS) management requires the use of high-efficacy disease-modifying therapies (DMTs) such as fingolimod (FTY), natalizumab (NTZ), cladribine (CLD) or alemtuzumab (ALM) in order to reduce relapse activity, disability accrual and irreversible brain atrophy [1]. However, some patients are needed to suspend these treatments because of safety reasons (i.e progressive multifocal leukoencephalopathy [PML] risk), pregnancy, poor tolerability, and poor efficacy. In such patients, evidences about the appropriate therapeutic strategies are limited. Moreover, the suspension of highly active treatments may increase the risk of MS relapses and MRI activity [2-9]. :6&:%L#$/,&;B !B6B#&0% &G!*3&#'' 6& #9 :: & 1 &. :6&:%L#$/,&;B !B6B#&0% &G!*3&#'' 6& #9 :: & 1 &. :6&:%L#$/,&;B !B6B#&0% &G!*3&#'' 6& #9 :: & 1 &. :6&:%L#$/,&;B !B6B#&0% &G!*3&#'' 6& #9 :: & 1 &. Numerous reports have demonstrated that rituximab (RTX) induces e a dramatic reduction of the inflammatory activity of relapsing MS (RMS) [10]. However, to date, current treatment algorithms for relapsing MS (RMS) include RTX as a third-line therapy. Particularly, in Italy, RTX is licensed for the off-label use in RMS patients [11]. In addition, little information is currently available concerning the efficacy and safety of RTX as escape strategy in case of discontinuation of highly active DMTs. Objective: to evaluate the effectiveness and safety of RTX in RMS patients who discontinued highly active treatments (FTY, NTZ, ALM and CLD) because of inefficacy or poor tolerability. Inclusion Criteria: age >18 years; diagnosis of RMS in accordance with the revised McDonald criteria (2010) [12]; previous treatment with highly-active DMTs (NTZ; FTY, ALM and CLD) for at least 6 months; at least one course of RTX of 2000 mg (1000 mg at day 1 and at day 14); at least 6 months of follow-up from treatment with RTX; availability of clinical (relapse and EDSS evaluations) and MRI data. Exclusion Criteria: diagnosis of primary progressive MS; diagnosis of neuromyelitis optica; treatment with RTX for other concomitant medical conditions; lack of follow-up data. Methods: this multicenter retrospective study of prospectively collected data will evaluate effectiveness and safety of RTX in patients previously treated with highly-active DMTs. In order to evaluate disability progression, EDSS evaluations will be compared at pre-baseline (within 6iou6 months from the suspension of the highly-active DMTs), at baseline (±3 months from the RTX initiation;), at 6±3 months (T6), at 12±3 months (T12), at 18±3 months (T18) and at 24±3 months (T24) after RTX initiation. The confirmed EDSS worsening (CEW), defined as either a ≥1-point or ≥2-points increase in EDSS score from baseline that was confirmed at 12 and 24 months of treatment will be calculated [13]. Moreover, disability progression index (PI), defined as disability grade divided by the duration of the disease will be evaluated [14]. We will also collect the annualized relapse rate (ARR) during the second line treatment period, at baseline, at 12 and 24 months after RTX initiation. The presence of brain and/or spine contrast-enhanced lesions (CELs) and the increased number of brain and/or spine T2 lesions compared to the previous MRI will be evaluated. NEDA-3 will be also calculated at each time points. All adverse events (AEs) after RTX initiation mentioned in the medical record will be registered and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Outcomes: (1) proportion of patients free from relapses at T6, T12, T18 and T24 during RTX treatment; (2) ARR at T12 and T24; (3) proportion of patients free from disability progression at T6, T12, T18 and T24; (4) proportion of patients free from new T2 and/or CELs on brain MRI at T6, T12, T18 and T24 during RTX treatment; (5) proportion of patients with NEDA defined as the absence of relapses, disability progression, and new T2 lesions and /or CELs on brain and spine MRI at T12 and T24 during RTX treatment; (6) frequency of adverse events and their grade.
Fondazione Italiana Sclerosi Multipla – FISM – Ente del Terzo Settore/ETS e, in forma abbreviata, FISM ETS. Iscrizione al RUNTS Rep. N° 89695 - Fondazione con Riconoscimento di Personalità Giuridica - C.F. 95051730109
Evaluating the effectiveness of Rituximab in rElapsiNg Multiple Sclerosis patiEnts previously treated with hiGhly-Active Disease modifying thErapies (RENEGADE).
Introduction: Active Multiple Sclerosis (MS) management requires the use of high-efficacy disease-modifying therapies (DMTs) such as fingolimod (FTY), natalizumab (NTZ), cladribine (CLD) or alemtuzumab (ALM) in order to reduce relapse activity, disability accrual and irreversible brain atrophy [1]. However, some patients are needed to suspend these treatments because of safety reasons (i.e progressive multifocal leukoencephalopathy [PML] risk), pregnancy, poor tolerability, and poor efficacy. In such patients, evidences about the appropriate therapeutic strategies are limited. Moreover, the suspension of highly active treatments may increase the risk of MS relapses and MRI activity [2-9].
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Numerous reports have demonstrated that rituximab (RTX) induces e a dramatic reduction of the inflammatory activity of relapsing MS (RMS) [10]. However, to date, current treatment algorithms for relapsing MS (RMS) include RTX as a third-line therapy. Particularly, in Italy, RTX is licensed for the off-label use in RMS patients [11]. In addition, little information is currently available concerning the efficacy and safety of RTX as escape strategy in case of discontinuation of highly active DMTs.
Objective: to evaluate the effectiveness and safety of RTX in RMS patients who discontinued highly active treatments (FTY, NTZ, ALM and CLD) because of inefficacy or poor tolerability.
Inclusion Criteria: age >18 years; diagnosis of RMS in accordance with the revised McDonald criteria (2010) [12]; previous treatment with highly-active DMTs (NTZ; FTY, ALM and CLD) for at least 6 months; at least one course of RTX of 2000 mg (1000 mg at day 1 and at day 14); at least 6 months of follow-up from treatment with RTX; availability of clinical (relapse and EDSS evaluations) and MRI data.
Exclusion Criteria: diagnosis of primary progressive MS; diagnosis of neuromyelitis optica; treatment with RTX for other concomitant medical conditions; lack of follow-up data.
Methods: this multicenter retrospective study of prospectively collected data will evaluate effectiveness and safety of RTX in patients previously treated with highly-active DMTs. In order to evaluate disability progression, EDSS evaluations will be compared at pre-baseline (within 6iou6 months from the suspension of the highly-active DMTs), at baseline (±3 months from the RTX initiation;), at 6±3 months (T6), at 12±3 months (T12), at 18±3 months (T18) and at 24±3 months (T24) after RTX initiation. The confirmed EDSS worsening (CEW), defined as either a ≥1-point or ≥2-points increase in EDSS score from baseline that was confirmed at 12 and 24 months of treatment will be calculated [13]. Moreover, disability progression index (PI), defined as disability grade divided by the duration of the disease will be evaluated [14].
We will also collect the annualized relapse rate (ARR) during the second line treatment period, at baseline, at 12 and 24 months after RTX initiation.
The presence of brain and/or spine contrast-enhanced lesions (CELs) and the increased number of brain and/or spine T2 lesions compared to the previous MRI will be evaluated. NEDA-3 will be also calculated at each time points. All adverse events (AEs) after RTX initiation mentioned in the medical record will be registered and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Outcomes: (1) proportion of patients free from relapses at T6, T12, T18 and T24 during RTX treatment; (2) ARR at T12 and T24; (3) proportion of patients free from disability progression at T6, T12, T18 and T24; (4) proportion of patients free from new T2 and/or CELs on brain MRI at T6, T12, T18 and T24 during RTX treatment; (5) proportion of patients with NEDA defined as the absence of relapses, disability progression, and new T2 lesions and /or CELs on brain and spine MRI at T12 and T24 during RTX treatment; (6) frequency of adverse events and their grade.
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