Progression despite transplantion of stem cells

Curro’ D, Vuolo L, Gualandi F, Bacigalupo A, Roccatagliata L, Capello E, Uccelli A, Saccardi R, Sormani MP, Mancardi G.
Low intensity lympho-ablative regimen followed by autologous haematopoietic stem cell transplantation in severe forms of multiple sclerosis: A MRI-based clinical study.
Mult Scler. 2015 Jan 12. pii: 1352458514564484. [Epub ahead of print] BACKGROUND:Autologous hematopoietic stem cell transplantation (HSCT) has been successfully used to treat aggressive forms of multiple sclerosis (MS) that are unresponsive to approved therapies. In the last years, in view of the risk of mortality related to the procedure, the utilization of low-intensity conditioning regimens has been considered.
OBJECTIVE:To report magnetic resonance imaging (MRI) and clinical data in a small cohort of patients treated with a low-intensity lympho-ablative regimen, followed by HSCT.
METHODS:Seven patients affected by relapsing-remitting MS (RRMS) underwent HSCT, with cyclophosphamide 120 mg/kg in 2 days as the conditioning regimen; and were then followed with serial MRI evaluations until 36 months, with clinical evaluations until 60 months.
RESULTS: The mean number of gadolinium (Gd)-enhancing lesions significantly decreased after treatment, but a complete suppression of inflammatory activity was not obtained. No deaths occurred, but every patient developed adverse events, although not severe. After 5 years of follow-up, two patients remained stable, one patient markedly improved and four patients had a mild progression of the disease. Only one patient experienced a relapse after treatment.
CONCLUSION: A low-intensity conditioning regimen with HSCT has a profound effect on MRI inflammation and relapses, but is not able to completely abrogate MRI activity and disease progression of aggressive RRMS.

We have shown that a high dose of cyclophosphamide can shut down relapsing EAE. In this study it helps clear out the old immune response. But using a less aggressive treatment then it doesn’t get rid of all activity and disease can carry-on. Is this better than some thing like Alemtuzumab?

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  • High dose Cyclophosphamide treatment alone is called "revimmune" in the US. Cytoxan is just a brand name for cyclophosphamide…

    Re the study above, it has to be viewed in the context that the chemo dose is roughly half of what is used in most non-myelo protocols (120mg/kg over 2 days vs 200mg/kg over 4 days), and also the majority of non-myelo protocols are not single agent (i.e. they use ATG, Rituximab or Alemtuzumab in combination) to further ablate the immune system. In the Phase II MIST trial (200mg/kg Cyclophophamide + either rATG or Alemtuzumab), at 3 years 81% of patients had improved by one EDSS point or more, 0% had EDSS progression, and 76% were relapse free. Which is roughly on par with Dr Nash's recently published results in the myeloablative HALT-MS trial.

  • If the "more is better" when it comes to lymphoablation, and we no Alemtuzumab is (probably) not strong enough to stop ALL disease activity (including subclinical), does this not suggest that those being treated with Alemtuzumab should be treated more regularly (regardless of MRI activity) – i.e. every year ongoing?

  • HSCT seems like the most effective treatment available today but a lot needs to be learned regarding the durability of the response and how much conditioning is required to shut down MS activity .. we will learn very useful lessons when both HALT-MS and MIST trials are concluded as HALT MS is intense chemotherapy while MIST is reduced intensity

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