Comparative effectiveness of IV cyclophosphamide therapy versus no- or siponimod-treatment in delaying disability accrual in Secondary Progressive Multiple Sclerosis.
SYNOPSIS AND RESULTS
Effectiveness of available disease-modifying treatments (DMTs) on disability progression in multiple sclerosis (MS) is marginal, hence therapeutic options for secondary progressive (SP) MS are still limited;[1] siponimod is indeed the only DMT approved specifically for SPMS in Europe.[2] The lack of effective DMTs is probably due to the contribution of chronic inflammatory lesions, compartmentalized within the central nervous system (CNS), to axonal injury and disability progression in SPMS.[3-4] This type of lesions seems to be poorly affected by most available DMTs, likely due to their minimal bioavailability within the CNS compartment [5] and to their limited effect on myeloid and microglial cells, which are increasingly recognized as active players in this process.[6] Capability of crossing a brain- blood barrier (BBB), fully repaired after the acute phase of the lesions, and activity on the myeloid and lymphoid compartments are likely pre-requisites for acting on 4 compartmentalized inflammation. Cyclophosphamide (CY), an alkylating agent with immunosuppressive effects and high BBB penetration, approved in Italy for the treatment of autoimmune neurological disorders (ex law 648), has shown efficacy on disability in SPMS, but data are mainly observational and of low quality, excepted for few trials conducted with heterogeneous administration protocols, thus requiring further investigation for this promising medication.[7-16] In previous comparative studies in SPMS, CY showed a similar effectiveness on disability progression with a better safety profile compared with mitoxantrone [17], a nice comparator as the latter was robustly superior to placebo on disability outcomes in worsening relapsing-remitting and SPMS.[18] In addition, in two recent studies on SPMS, autologous hematopoietic stem cell transplantation (which includes CY in the immune-suppressive protocol) showed a superior effectiveness on disability outcomes compared to standard DMTs/no treatment [19], but similar effect compared to CY.[20] Effectiveness of CY in SPMS could be appropriately evaluated comparing long term disability outcomes of SPMS patients treated with CY to untreated -natural history- or Siponimod -current standard therapy- treated SPMS controls. The main aim of this retrospective observational study is to compare the effectiveness of IV pulses of CY with (i) no- or (ii) siponimod-treatment in delaying disability progression in SPMS, assessed through worsening-free survival (W-FS) and progression-free survival (P-FS). Key secondary endpoints will be EDSS score time course, prevalence of disability improvement, relapse-free survival (R-FS), cumulative proportion of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Safety outcomes will include mortality for any cause (primary) and incidence of neoplasms (secondary).
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
Comparative effectiveness of IV cyclophosphamide therapy versus no- or siponimod-treatment in delaying disability accrual in Secondary Progressive Multiple Sclerosis.
Effectiveness of available disease-modifying treatments (DMTs) on disability progression in multiple sclerosis (MS) is marginal, hence therapeutic options for secondary progressive (SP) MS are still limited;[1] siponimod is indeed the only DMT approved specifically for SPMS in Europe.[2] The lack of effective DMTs is probably due to the contribution of chronic inflammatory lesions, compartmentalized within the central nervous system (CNS), to axonal injury and disability progression in SPMS.[3-4] This type of lesions seems to be poorly affected by most available DMTs, likely due to their minimal bioavailability within the CNS compartment [5] and to their limited effect on myeloid and microglial cells, which are increasingly recognized as active players in this process.[6] Capability of crossing a brain- blood barrier (BBB), fully repaired after the acute phase of the lesions, and activity on the myeloid and lymphoid compartments are likely pre-requisites for acting on 4
compartmentalized inflammation. Cyclophosphamide (CY), an alkylating agent with immunosuppressive effects and high BBB penetration, approved in Italy for the treatment of autoimmune neurological disorders (ex law 648), has shown efficacy on disability in SPMS, but data are mainly observational and of low quality, excepted for few trials conducted with heterogeneous administration protocols, thus requiring further investigation for this promising medication.[7-16] In previous comparative studies in SPMS, CY showed a similar effectiveness on disability progression with a better safety profile compared with mitoxantrone [17], a nice comparator as the latter was robustly superior to placebo on disability outcomes in worsening relapsing-remitting and SPMS.[18] In addition, in two recent studies on SPMS, autologous hematopoietic stem cell transplantation (which includes
CY in the immune-suppressive protocol) showed a superior effectiveness on disability outcomes compared to standard DMTs/no treatment [19], but similar effect compared to CY.[20] Effectiveness of CY in SPMS could be appropriately evaluated comparing long term
disability outcomes of SPMS patients treated with CY to untreated -natural history- or Siponimod -current standard therapy- treated SPMS controls.
The main aim of this retrospective observational study is to compare the effectiveness of IV pulses of CY with (i) no- or (ii) siponimod-treatment in delaying disability progression in SPMS, assessed through worsening-free survival (W-FS) and progression-free survival (P-FS). Key secondary endpoints will be EDSS score time course, prevalence of disability improvement, relapse-free survival (R-FS), cumulative proportion of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA). Safety outcomes will include mortality for any cause (primary) and incidence of neoplasms (secondary).
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