HSCT appears more effective than current MS drugs

Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, Mancardi GL. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis.Neurology. 2017 Apr 28. pii: 10.1212/WNL.0000000000003987. doi: 10.1212/WNL.0000000000003987. [Epub ahead of print]

OBJECTIVE:To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS).
METHODS:We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression.
RESULTS: Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%-3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%-24.5%) and 23.3% (95% CI 16.3%-31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%-92%) and at 5 years was 67% (range 59%-70%).
CONCLUSIONS: The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.

If you want more definitive evidence that MS is immune-mediasted this is it. They have looked at all the studies and done a meta analysis of HSCT transplants from 1995-2016.

The NEDA (No Evident Disease Activity) rates of ablative haematopoeitic stem cells are high and higher than any of the current MS drugs. Importantly the people being put forward are more likely to be highly aggressive than the norm.

It is not surprising as you are taking a sledge hammer to the immune system. Removing it and replacing it and disease becomes silenced in many people. However, it fails in a significant proportion, is this because of brain activity not touched by the treatment or was the treatment started to late. This likewise justifies the pharma approach of attacking the immune system and so anyone that thinks these treatments do nothing are deluding themselves….(Bruv:-).

Likewise these studies are not blinded and so you can’t definatively say that a drug woulddn’t have worked as well, can yo do a head to head of ablative verses drug or ablative verses non-ablative HSCT.

However, likewise it should also be evident that this is not a cure for many and disease continues to progress. I would suggst this represents the damage accumulated burning along. Importantly, if you remove the immune system you are at risk from serious infection and the death rate of the studies was 2% (mean somewhere between about 1.5-3.5% with high confidence). So up to three deaths in a hundred people taking the treatment. However this is skewed because this was higher in the earlier studies, so the figure can be used to make the proceedure more alarming.

A James Lind Alliance question of the MS Society is can early aggressive treatment stop disease and the ultimate aggressive treatment would be to perform HSCT as the first treatement straight from diagnosis. Would you be willing to risk this treatment? It is clear many Neurologists wouldn’t, but should it be their choice?

Why do I say this, if a neurologist would not be willing to use alemtuzumab early they are unlikely to go for HSCT.

Casanova B, Jarque I, Gascón F, Hernández-Boluda JC, Pérez-Miralles F, de la Rubia J, Alcalá C, Sanz J, Mallada J, Cervelló A, Navarré A, Carcelén-Gadea M, Boscá I, Gil-Perotin S, Solano C, Sanz MA, Coret F.Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.
Neurol Sci. 2017. doi: 10.1007/s10072-017-2933-6. [Epub ahead of print]

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

This is another HSCT study published after the review will have been done.  Again this suggests the earlier you start the more likely the procedure will suceed and is more suitable for RRMS.

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  • Some irony in the fact that many (no idea how many, but know of a couple) choose this option once at the 'what have I got to lose' point.
    Googled the clinic in Mexico where Caroline Wyatt went, they sound busy.

    • What's the alternative? Have a lifetime supply of Ocrelizumab, every 6 months? The data on living long term (indefinitively) without b cells is thin – even with rituximab.

      Strong quick dangerous hit v. simmering ongoing suppression.

      My partner made the choice too. Not because she had nothing to lose (far out, there was so much to lose).

      She just wanted to lessen her risk for secondary autoimmunity (as associated with lemtrada) and she didn't want to spend a lifetime on tysabri.

      All the clinics are busy. HSCT patients in India are dying (2 I think within a space of a month). Ah well, I suppose times are moving.

  • The problem is that with the risk of death in HSTC it's only offered to pwMS when this person is already full of damage, sequelae, or when he/she has already become SPMS…

    • Cinara, that's no longer the case in the context of clinical trials (though they still require dmt failure or five, which takes time).

      In non clinical settings, you pay and they will treat almost anyone whose body is likely to withstand…

  • If EBV controlled memory B-cells are Team G's current hypothesis for being the black swan in causing/controlling MS, then how does HSCT with chemotherapy, or any current MS therapy for that matter, fit in treatment of MS?

    Do they just deplete future stores of EBV memory B-cells but not any of the current EBV driven B-cells and therefore does not address the problem that could cause MS relapses and progression?

    I thought MD that you would be "over the moon" and bragging when a recent Australian trial showed CD8 specific T cells induced to attack EBV controlled memory B-cells given by infusion showed improvements in progressive MS. Is this the cure/treatment of both RRMS and progressive MS, if your team's hypothesis holds true? All of the other drugs and HSCT are not addressing the underlying problem, EBV induced memory B-cells.

    Is this why HSCT only treats a minority of the MS population (early RRMS <10 years or aggressive RRMS MS patients) and still shows progression of the disease in many? Is it because it is not addressing the real problem of treating these EBV driven memory B-cells? Do any current medications, HSCT or current DMDs, actually treat EBV driven memory cells? Aren't the rest of the DMDs just "putting out fires" downstream of the cause of MS and hence only partially stopping relapses and progression of the disease?

    • EBV does control memory cells but it is also the reservoir for EBV, as EBV is inside the B cells. Deplete the B memory and you deplete the reservoir. HSCT is going to deplete memory B cells too. It gets rid of them all, except those left in the CNS.

      EBV is ProfG's baby and so he may answer that bit I am still getting my head round it.

      As to being over the moon..smptomatic improvement was reported. I will wait until more people are done before I start jumping for joy and I would not start mentioning the C word. Did the T cells get rid of the virus. We need to see publication. Maybe ProfG or NDG were there.

      I think progression is probably progressing not because of the EBV but because a neurodegenerative process has been triggered and this is unresponsive to immuno-modulation (it could be B cells in the CNS though) I suspect they are not touched by HSCT but I don't know.

    • Thanks for your views MD, much appreciated that you take the time for all of us. When I talk about EBV controlled memory B-cells, I meant in the brain, not in periphery. Chemotherapies can deplete most peripheral B-cells, but cannot deplete current memory B-cells in follicles in the brain, as far as I know, because chemotherapy cannot cross BBB. This is why chemotherapy fails inevitably in treating most forms of brain cancer. This is probably why, according to Dr. G's hypothesis, that all current treatments,including chemotherapy, fail to address these EBV induced memory B-cells in the brain and therefore fail to completely stop relapses and progression.

      Do any current therapies address the current EBV-induced memory B-cells other than this small trial of CD8 induced T-cells that attack EBV induced memory B-cells in the brain? Do current B-cell therapies stop the transformation of B-cells into EBV-induced memory B-cells in the brain and is this why they work at all?

    • Do current therapies….No
      cladribine could do this but not cleaqr if enough gets in. I guess the memory cells traffic in

  • My husband had HSCT in Moscow and is definitely doing better ❤️ It was so worth a chance. They've been doing this for MS in Moscow since 1994 with great results. He began taking CIDP patients in 2014.

  • My 30 yr old daughter has been advised by her neurologist to have HSCT having failed on Lemtrada (four new lesions, inflammation and total body numbness within four months of the first infusion). She is reluctant to have it at this stage due to the infertility which comes with it. Does anyone know if it is possible to have HSCT without loss of fertility?

    • Re: "Does anyone know if it is possible to have HSCT without loss of fertility?"

      Most BMT units offer egg harvesting and banking. In addition, not everyone who has HSCT is left infertile. Our haematologists quote a figure of ~40%. But in general any woman who has HSCT should be willing to sacrifice their fertility; this is the downside of this treatment that is seldom discussed.

      Other options for treating early alemtuzumab failures is anti-CD20 therapy (rituximab / ocrelizumab) or daclizumab. Please note these are general comments and don't necessarily apply to any specific individual patient.

  • Absolutely I would "risk" this treatment. As someone who had this done in Italy, I was on the cusp of SPMS, 12 years diagnosed and it may already be too late. I think at the first sign of CIS, it should be done on RRMS patients. Period. The risk of being permanently disabled is guaranteed, affecting job prospects, relationships, QOL…etc. I'd rather have cancer that has a shot at being cured. I wish neurologists understood how this really affects MS patients and how it destroys your life.

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