Mitoxantrone as rescue therapy in worsening relapsing–remitting MS patients receiving IFN-β

Correale, Jorge; Rush, Carolina; Amengual, Alejandra; Goicochea, María Teresa

doi:10.1016/j.jneuroim.2005.02.003

Cited by 30 publications

(19 citation statements)

References 43 publications

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“…Our use of GA as a followup treatment to mitoxantrone was prompted by disappointing experience with interferon beta utilised in a small number of similar patients whose disease had stabilised on mitoxantrone, with relapse activity recurring on Interferon 6-12 months after withdrawal of mitoxantrone. Similar treatment experience has been recently reported by Correale et al where in 10 patients with very active RRMS, whose disease had stabilised on mitoxantrone, relapse activity recurred in 6 of the 10 patients within 18 months of withdrawal of mitoxantrone despite subsequent treatment with interferon beta [5].…”

Section: Discussionsupporting

confidence: 75%

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

et al. 2006

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Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

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Section: Discussionsupporting

confidence: 75%

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

et al. 2006

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“…18 The ELISPOT detection kits for IL-4, IL-6, IL-10, IL-17, and IFN-γ were purchased from R&D Systems, and the kits for TNF and IL-12 from Abcam.…”

Section: Quantification Of Secreted Cytokinesmentioning

confidence: 99%

Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis

Negrotto¹,

Farez²,

Correale³

2016

JAMA Neurol

Self Cite

143

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IMPORTANCE Metabolic syndrome (MetS) is thought to influence several autoimmune diseases, including multiple sclerosis (MS). Anti-inflammatory effects of treatments used for MetS, such as metformin hydrochloride and pioglitazone hydrochloride, have been demonstrated, although clinical evidence supporting use of these treatments in MS is lacking.OBJECTIVES To determine whether metformin and/or pioglitazone are associated with a reduction in disease activity as measured by brain magnetic resonance imaging in patients with MS and MetS and to evaluate the potential mechanisms underlying this anti-inflammatory effect. DESIGN, SETTING, AND PARTICIPANTSA prospective cohort study was conducted from March 1, 2012, to December 30, 2014, at a private MS referral center among 50 obese patients with MS who also developed MetS. Twenty patients received metformin hydrochloride, 850 to 1500 mg/d, and 10 patients received pioglitazone hydrochloride, 15 to 30 mg/d; 20 untreated patients served as controls. Groups were comparable in terms of sex, age, body mass index, Expanded Disability Status Scale score, disease duration, annual relapse rate, and treatment status. Patients were followed up for a mean (SD) of 26.7 (2.7) months (range, 24-33 months). MAIN OUTCOMES AND MEASURESMagnetic resonance imaging of the brain was performed at 6-month intervals, and the presence of new or enlarging T2 lesions or gadolinium-enhancing lesions was registered. Serum leptin and adiponectin levels were measured. The production of cytokines by peripheral blood mononuclear cells was assayed, as were regulatory T-cell numbers and function. RESULTSOf 50 patients, after 6 months of treatment, 20 patients with MS who were treated with metformin and 10 who received pioglitazone showed a significant decrease in the number of new or enlarging T2 lesions (metformin, 2.5 at study entry to 0.5 at month 24; pioglitazone, 2.3 at study entry to 0.6 at month 24), as well as of gadolinium-enhancing lesions (metformin, 1.8 at study entry to 0.1 at month 24; pioglitazone, 2.2 at study entry to 0.3 at month 24). Compared with controls, both treatments led to a decrease in mean (SD) leptin levels (metformin, 5.5 [2.4] vs 10.5 [3.4] ng/mL, P < .001; pioglitazone, 4.1 [0.8] vs 11.0 [2.6] ng/mL, P < .001) and increase in mean (SD) adiponectin serum levels (metformin, 15.4 [5.5] vs 4.5 [2.4] μg/mL, P < .001; pioglitazone, 12.6 [3.6] vs 4.8 [0.6] μg/mL, P < .001). Mean (SD) number of myelin basic protein peptide-specific cells secreting interferon γ and interleukin (IL)-17 were significantly reduced in patients receiving metformin compared with controls (interferon γ, 30.3 [11.5] vs 82.8 [18.8], P < .001; 212.4 [85.5] vs 553.8 [125.9], P < .001). Patients treated with pioglitazone showed significant decreases in the mean (SD) number of myelin basic protein peptide-specific cells secreting IL-6 and tumor necrosis factor compared with controls (IL-6, 361.6 [80.5] vs 1130.7 [149.21], P < .001; tumor necrosis factor, 189.9 [53.4] vs 341.0 [106.0], P < .001). Both metformin and...

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“…Monotherapy use of Mito or Cy [15,[19][20][21][22][23][24] or either used in combination with immunomodulatory agents [25][26][27] has considerably increased over the last years. Despite the risk of dramatic adverse events, like severe acute or delayed heart failure [28] and acute myeloid leukaemia [20][21][22][23][24][25][26][27][28][29][30], Mito has become, after approval by the FDA and EMEA, a first-line rescue therapy for RRMS patients who do not respond to IMA and for rapidly deteriorating SPMS [31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the risk of dramatic adverse events, like severe acute or delayed heart failure [28] and acute myeloid leukaemia [20][21][22][23][24][25][26][27][28][29][30], Mito has become, after approval by the FDA and EMEA, a first-line rescue therapy for RRMS patients who do not respond to IMA and for rapidly deteriorating SPMS [31][32][33][34]. Cy, although used in many MS Centres in Europe and the US [35], is not approved for MS and can be used in Italy only when informed consent is obtained.…”

Section: Discussionmentioning

confidence: 99%

Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis

et al. 2006

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Fifty secondary progressive multiple sclerosis (SPMS) patients who had lost one or more EDSS points in the prior two years were selected to receive either cyclophosphamide (25 patients, 13 females, 12 males, F/M = 1.08; mean age: 42.4 years; mean disease duration: 13.3 years; mean EDSS at study entry: 5.7) or mitoxantrone (25 patients, 14 females, 11 males, F/M = 1.27; mean age: 38.2 years; mean disease duration: 11.5 years; mean EDSS at study entry: 5.5). SPMS patients were treated for two years with clinical evaluation (relapse rate, disability progression) every three months and radiological imaging (conventional magnetic resonance imaging) before therapy initiation and at the end of the first and second years of therapy. Safety profile and costs of the two therapeutic protocols were also analysed. In terms of clinical and radiological measures the drugs exerted a quite identical effect on both, and produced a significant reduction in both relapse rate (mitoxantrone Mito): p = 0.001, cyclophosphamide (Cy): p = 0.003) and disability progression (Mito: p = 0.01; Cy: p = 0.01). Subgroups of mitoxantrone- and cyclophosphamide-responding patients were identified (14/25 and 17/25, respectively) and were characterized by a significantly shorter duration of the secondary progressive phase of the disease. In these subgroups, the improvement in the EDSS score at the end of therapy was highly significant (p<0.0001 for Mito, p = 0.0004 for Cy). The safety profiles of both drugs were acceptable; however, the Cy-based therapy protocol was significantly less expensive. We conclude that Cy should be considered as a therapeutic option in rapidly deteriorating SPMS patients.

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Mitoxantrone as rescue therapy in worsening relapsing–remitting MS patients receiving IFN-β

Cited by 30 publications

References 43 publications

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis

Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis

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