Cyclophosphamide kills immune cells dead

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Most immunologists are well versed in the use of cyclophosphamide for all sorts of non-MS related inflammatory disorders; it is for all intents and purposes a ‘Domestos’. It’s dirt cheap – one 500mg vial costs £9.66 on the NHS, and is often only used as induction therapy with a few doses at time. It’s ‘Domestos’ action comes from its apoptosis (or cell death) action.

Immune Depletion, Immune Modulation, and Immunosuppression in MS: A Review.  - ppt download

It is generally sold as T-cell immunomodulatory drug, but it affects all cell types. And, it also has good CNS bioavailability (i.e. it gets into the brain). However, the evidence for it’s efficacy in MS has always been mixed.

Cyclophosphamide treatment regimen = 1g IV for 6 months, followed by 1g every two months until completion of at least 9g of total dose.

This latest open-label study of cyclophosphamide shows that not only the annualized relapse rate (see figure below), but the progression index (defined as current EDSS score divided by years since their clinical diagnosis) also reduced: 14% at 12months, 19% after 24 months, and 30% after 36 months (see figure below) – note that 13 of the total 16 in this study had SPMS. Moreover, the more highly active the disease, the better it worked.

Figure: Annualized relapse rate (defined as the total
number of relapses divided by the total person-time at risk
of relapse)
Figure: Progression index change

Others have also reported on the benefits of using high dose cyclophosphamide (200mg/kg over 4 days or 50mg/kg for 4 days; a myeloablative regimen) with long-term reduction in disability levels.

Therefore in areas where there is no access to the latest DMTs, cyclophosphamide has a role for use in MS.

Abstract

Neurol Sci. 2021 Jan 16. doi: 10.1007/s10072-021-05052-1. Online ahead of print.

Cyclophosphamide treatment in active multiple sclerosis

Enrique Gómez-Figueroa Efrain Gutierrez-LanzAlonso Alvarado-Bolaños  Adriana Casallas-VanegasChristian Garcia-Estrada Indhira Zabala-Angeles Arturo Cadena-Fernandez Rivas-Alonso Veronica Treviño-Frenk IreneJosé Flores-Rivera

Objective: Cyclophosphamide (CYC) is an alkylating agent with immunosuppressive effect by inhibiting DNA synthesis and producing apoptosis used in many autoimmune diseases, including multiple sclerosis (MS). Here, we analyze the efficacy of CYC treatment in relapsing-remitting (RRMS) and active secondary progressive MS (SPMS) in our center with a monthly scheme.

Methods: Patients with MS treated with CYC and a follow up of at least 36 months were eligible for inclusion. All participants had received a standard CYC regimen. The EDSS score mean annualized relapse rate (ARR) and progression index (PI) were measured as efficacy outcomes at 12, 24, and 36 months. Outcomes were also analyzed comparing disease course and activity.

Results: A total of 16 patients were included (50% male, 18.75% RRMS and 81.25% SPMS). EDSS remained stable along the follow-up period, with 62.5% improving or maintaining the same EDSS score at 12 months. PI decreased 14% and 21% at 12 and 24-36 months of follow-up, respectively. ARR decreased 20% after 12 months, 19% after 24 months, and 30.23% after 36 months. Median differences in ARR were higher in patients with high relapse activity (0.60 vs 0.07, p = 0.001) and malignant course (0.60 vs 0.17, p = 0.027). PI also differed with higher mean differences in patients with high relapse activity (0.70 vs 0.03, p = 0.016) and malignant course (1.17 vs 0.03, p = 0.003).

Conclusions: CYC continues to be a valid therapeutic option, especially in regions with limited access to high-efficiency therapies particularly in patients with high relapsing activity and malignant course.

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Neuro Doc Gnanapavan

2 comments

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  • You have to be cruel.to be kind and.dose is key dribs and drabsof low doses over a long time is side effect central and not enough efficacy short courses of high.doses are.what works in animals.
    However animals fur doesn’t.fall out untike.people. it on kills dividing cells and is a better B cell killer than a T cell killer.
    Again another example of how the wrong trial design kills MS drugs

    • Interesting that you say that, I use a regimen of 15mg/kg (in a 72kg male this is 1.08g) every two weeks for three pulses, followed by every three weeks for next 3-6 pulses. In most inflammatory disorders this buys me two years. There is lymphopaenia after the three pulses on average.

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