I know a few patients who have shown further progression (without MRI activity) after having aHSCT therapy. Is this a case of "smouldering MS" and would further treatment would you consider?
Yes, a large number of pwMS who have AHSCT still go onto get worse. Particularly those with more advanced MS and this is due to smouldering disease. We don't have treatments yet outside of the holistic management of MS and my approach of marginal gains. However, we are doing trials to tackle this problem.
would astrocyte glia cells also fall under the category for potentially causing smouldering MS, next to microglia? In both categories aHCST wouldn't be approapriate...
In addition to the usage of PET for imaging microglia and astrocytes, I wonder which biomarker within CNF are to be found and which lab is already experienced in detecting the same. We all agree IgB bands are not specific enough and if smouldering MS can comprise of different pathological drivers we'd need to have different CNF biomarkers for the same. Following study goes in that direction. What is your advise?
It depends on the intensity of immunosuppression, in general the herpes viruses reactivate and you get peripheral CMV and EBV reactivation. HSV and VZV also reactivate but you can suppress these with prophylactic antivirals.
Dont if you konw but there is EBMT and they have Autoimmune Diseases Working Party every year the update their recomendatios for auto immune diseases (also ms)
Implications of immune monitoring for clinical practice: recommendations for infection prophylaxis and re-vaccination
This text as manny incorrect statements i am gonna pic just one
So you mention myeloablative regime
This is why you have to be revaccinated with all your childhood vaccines ~2 years after AHSCT to restore your immune responses to these common infections. Please note that not all BMT units demand revaccination; it depends on how ablative your HSCT is
So this study is the mosstttt intensive regime ever myeloablative and total body irradiation (8 Gy)
(TBI)
Guess what it did not clear previous vaccinations
Antibodies
Even though B cell and CD4 T cell counts were very low in the first 3 months posttransplant, median serum levels of total IgM, IgA, IgG, IgG2 as well as IgG specific for tetanus toxoid, H. influenzae, and S. pneumoniae remained normal (Fig. 4). ~
Just stating that some BLT units revaccinate their patients with childhood vaccines and yes it may not be necessary. However, plasma cells don't live forever and they are dead-end cells, i.e. post-mitotic and when they die they die. What is more important in terms of memory are memory T-cells and memory B-cells. The question is what happens to memory B-cells post-ablative AHSCT.
Yes, but I don't run a BMT unit. You need to tell the haematology community to produce a consensus and get them to change their protocols. I am only the messenger. Some units revaccinate and others don't. Our STAR-MS study is looking into vaccine immunity, but then we are non-myeloablative.
I understood his response to align with that? From what you've said it would have to be a highly ablative chemo to do this?
As to HSCT v alemtuzumab, depends on chemo used by HSCT. Perhaps it would be better to stop saying HSCT and call it x,y,z chemo instead?
STAR-MS sounds well worth doing. It strikes me that many potential participants may not even be diagnosed yet, yet alone reading MS blogs and news!
Re no autoimmunity post HSCT, fairly sure I've read that rituximab used routinely afterwards in clinics abroad 'to clear the last of the B cells'? So hardly a level playing field.
HSCT refers to harvesting and then reinfusing bone marrow / peripheral blood-derived stem cells. The non-myeloablative vs. ablative refers to the chemotherapy component and there are many different protocols. I will do a supplementary MS-Selfie Newsletter on this specific topic.
Thanks. What I was trying to say was that if the chemo is non ablative ie doesn't completely clear the body (all compartments inc CNS) of all immune cells, the reinfused stem cells aren't going to reboot anything just fastrack regrowth. Ie exactly as you describe v Prof Sharrack suggests a reboot which sounds a lot more attractive! Maybe it's a case of words and understanding...but a lot of pw more advanced MS are travelling abroad in hope of a reboot.
I am 40, female, I'm in the Republic of Ireland, I have had HARRMS for 7 years and am on my fifth DMT in that time. Copaxone, tecfidera, tysabri all failed. Lemtrada, whilst effective, cost me my thyroid gland and I started to relapse after it. I am now on ocrelizumab but am relapsing. My neurologist has referred me for AHSCT in London and I am provisionally accepted. I am having an MRI tomorrow morning to check for new lesions as I have new neurological symptoms. Will my referral only be accepted if I have new MRI activity? I have a 15 year old daughter and don't want any more children so the menopause aspect isn't such an issue for me, I'm more worried about how long I'd be away from home! I spent 18 weeks in hospital after a severe relapse and that was hard, even though I was in hospital in Ireland and it was pre-covid and could have visitors. The thing that puts me off is being away from my daughter and family for a long time.
I suspect if you have been accepted already it is because you have active disease.
The advantage of AHSCT is that the bone marrow function recovers quite quickly and most patients only spend 2-3 weeks in hospital before it is safe for them to be discharged. In the past we didn't use stem cells it would take 6-8 weeks and sometimes longer for bone marrow function to return to a level that didn't require support. i.e. platelet and blood transfusions and aggressive management of infections with isolation units etc.
I hope the original poster can access this treatment in UK, the protocol there requires x3 trips back and forward for an Irish visitor, and overall it is much quicker to go to Mexico or Russia from start to finish. But when it’s being paid for and if you’re receiving a slightly more intensive regime in London that might tip the scales.
To Dr G, I wanted to highlight how this is a clear case of the post code lottery in terms of access to health care. Living in NI I know numerous ppl from the south of Ireland who have managed to access this treatment in the UK as Europeans abroad. I know zero people from NI, under care of NI neurologists (thus UK residents) who have been able to access this treatment in London , when I last posed the question to my neurologist he said the answer was 0, in addition ppl from the Northern Ireland can not enrol on the Star Ms trial, how is this equitable
Yes, correct. This is what I find in the clinic; 4 out of 5 women of childbearing age so no thanks to AHSCT referral. However, men don't seem to mind. Also, sperm banking is much easier and quicker than egg banking, which may have something to do with it.
Thanks for these reflections on AHSCT. You wrote: "... more pwMS have a recurrence of their disease activity after non-myeloablative AHSCT, when compared to ablative-AHSCT". Is there any source for this observation? What I've read in papers is that both protocols can achieve NEDA at circa 70 % of RRMS patients for 5+ years.
Boffa et al. for the Italian BMT-MS study group. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. 2021 Jan 20:10.1212/WNL.0000000000011461. doi: 10.1212/WNL.0000000000011461.
Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.
Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.
Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.
Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.
Classification of evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.
Excellent overview of HSCT. I have PPMS am 45 and have thought about it but am too worried about dying and leaving 3 girls and my wife. From what I read it is less likely to work for me and it seems like I would be borderline to get it on the NHS. The only people I know who have had it it hasn't really worked for them. One thing I would consider if I won the lottery is going to Panama (https://www.cellmedicine.com/) and having allogeneic human umbilical cord stem cells/ autologous bone marrow stem cells. I know there is an argument that no chemo it doesn't work but I would be interested on your thoughts on this other way. It seems like with this way you ideally have to go back a few times which makes it prohibitive even if you did a one off mega splurge.
Where can one actually go to have myeloablative HSCT done? As far as I can tell all the private clinics offering it are doing non-myeloablative protocols. Is myeloablative available through the NHS?
Not sure. The BMTs unit treating MS in the NHS are not using ablative protocols. You could try one of the private units, for example, London Bridge, and speak to the haematologist.
Hello,
I know a few patients who have shown further progression (without MRI activity) after having aHSCT therapy. Is this a case of "smouldering MS" and would further treatment would you consider?
Yes, a large number of pwMS who have AHSCT still go onto get worse. Particularly those with more advanced MS and this is due to smouldering disease. We don't have treatments yet outside of the holistic management of MS and my approach of marginal gains. However, we are doing trials to tackle this problem.
would astrocyte glia cells also fall under the category for potentially causing smouldering MS, next to microglia? In both categories aHCST wouldn't be approapriate...
Yes. Astrocytes and microglia contribute to smouldering MS.
In addition to the usage of PET for imaging microglia and astrocytes, I wonder which biomarker within CNF are to be found and which lab is already experienced in detecting the same. We all agree IgB bands are not specific enough and if smouldering MS can comprise of different pathological drivers we'd need to have different CNF biomarkers for the same. Following study goes in that direction. What is your advise?
https://multiplesclerosisnewstoday.com/news-posts/2022/10/25/more-inflammation-biomarkers-found-csf-ppms-patients-study/
Thanks for the swift reply. What trials are these? Is it about the use of ATA188, for example https://multiplesclerosisnewstoday.com/ata188-multiple-sclerosis/ ?
What are your thoughts on Mesenchymal stem cell therapy to treat MS? Is the research ongoing or going nowhere?
We need more data in relation to the effectiveness of mesenchymal stem cell therapy; studies to date are small and may have some biases.
What happens to viruses that are already living in your bloodstream after AHSCT? Herpes, chickenpox, JCV, EBV, etc.
It depends on the intensity of immunosuppression, in general the herpes viruses reactivate and you get peripheral CMV and EBV reactivation. HSV and VZV also reactivate but you can suppress these with prophylactic antivirals.
Dont if you konw but there is EBMT and they have Autoimmune Diseases Working Party every year the update their recomendatios for auto immune diseases (also ms)
Implications of immune monitoring for clinical practice: recommendations for infection prophylaxis and re-vaccination
https://www.nature.com/articles/bmt2014251
Most of the peoples are maven just like you
You may know some of them
Paolo muraro
J A Snowden
R Saccardi
M Kazmi
Arnold atkins
Dominique farge
etc
This text as manny incorrect statements i am gonna pic just one
So you mention myeloablative regime
This is why you have to be revaccinated with all your childhood vaccines ~2 years after AHSCT to restore your immune responses to these common infections. Please note that not all BMT units demand revaccination; it depends on how ablative your HSCT is
So this study is the mosstttt intensive regime ever myeloablative and total body irradiation (8 Gy)
(TBI)
Guess what it did not clear previous vaccinations
Antibodies
Even though B cell and CD4 T cell counts were very low in the first 3 months posttransplant, median serum levels of total IgM, IgA, IgG, IgG2 as well as IgG specific for tetanus toxoid, H. influenzae, and S. pneumoniae remained normal (Fig. 4). ~
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956741/
Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases)
Just stating that some BLT units revaccinate their patients with childhood vaccines and yes it may not be necessary. However, plasma cells don't live forever and they are dead-end cells, i.e. post-mitotic and when they die they die. What is more important in terms of memory are memory T-cells and memory B-cells. The question is what happens to memory B-cells post-ablative AHSCT.
They are back after 2 year in that full on myeloablative study and disease did seem to come back ...Data iis in that study
Yes, but I don't run a BMT unit. You need to tell the haematology community to produce a consensus and get them to change their protocols. I am only the messenger. Some units revaccinate and others don't. Our STAR-MS study is looking into vaccine immunity, but then we are non-myeloablative.
Thank you for this topical newsletter. I think what attracts people to try HSCT is the 'reboot of faulty immune system' idea?
When the MS Trust interviewed Prof Basil Sharrack recently
https://mstrust.org.uk/news/ask-expert-stem-cell-transplantation
I understood his response to align with that? From what you've said it would have to be a highly ablative chemo to do this?
As to HSCT v alemtuzumab, depends on chemo used by HSCT. Perhaps it would be better to stop saying HSCT and call it x,y,z chemo instead?
STAR-MS sounds well worth doing. It strikes me that many potential participants may not even be diagnosed yet, yet alone reading MS blogs and news!
Re no autoimmunity post HSCT, fairly sure I've read that rituximab used routinely afterwards in clinics abroad 'to clear the last of the B cells'? So hardly a level playing field.
HSCT refers to harvesting and then reinfusing bone marrow / peripheral blood-derived stem cells. The non-myeloablative vs. ablative refers to the chemotherapy component and there are many different protocols. I will do a supplementary MS-Selfie Newsletter on this specific topic.
Thanks. What I was trying to say was that if the chemo is non ablative ie doesn't completely clear the body (all compartments inc CNS) of all immune cells, the reinfused stem cells aren't going to reboot anything just fastrack regrowth. Ie exactly as you describe v Prof Sharrack suggests a reboot which sounds a lot more attractive! Maybe it's a case of words and understanding...but a lot of pw more advanced MS are travelling abroad in hope of a reboot.
I am 40, female, I'm in the Republic of Ireland, I have had HARRMS for 7 years and am on my fifth DMT in that time. Copaxone, tecfidera, tysabri all failed. Lemtrada, whilst effective, cost me my thyroid gland and I started to relapse after it. I am now on ocrelizumab but am relapsing. My neurologist has referred me for AHSCT in London and I am provisionally accepted. I am having an MRI tomorrow morning to check for new lesions as I have new neurological symptoms. Will my referral only be accepted if I have new MRI activity? I have a 15 year old daughter and don't want any more children so the menopause aspect isn't such an issue for me, I'm more worried about how long I'd be away from home! I spent 18 weeks in hospital after a severe relapse and that was hard, even though I was in hospital in Ireland and it was pre-covid and could have visitors. The thing that puts me off is being away from my daughter and family for a long time.
I suspect if you have been accepted already it is because you have active disease.
The advantage of AHSCT is that the bone marrow function recovers quite quickly and most patients only spend 2-3 weeks in hospital before it is safe for them to be discharged. In the past we didn't use stem cells it would take 6-8 weeks and sometimes longer for bone marrow function to return to a level that didn't require support. i.e. platelet and blood transfusions and aggressive management of infections with isolation units etc.
I hope the original poster can access this treatment in UK, the protocol there requires x3 trips back and forward for an Irish visitor, and overall it is much quicker to go to Mexico or Russia from start to finish. But when it’s being paid for and if you’re receiving a slightly more intensive regime in London that might tip the scales.
To Dr G, I wanted to highlight how this is a clear case of the post code lottery in terms of access to health care. Living in NI I know numerous ppl from the south of Ireland who have managed to access this treatment in the UK as Europeans abroad. I know zero people from NI, under care of NI neurologists (thus UK residents) who have been able to access this treatment in London , when I last posed the question to my neurologist he said the answer was 0, in addition ppl from the Northern Ireland can not enrol on the Star Ms trial, how is this equitable
Refreshingly honest
I had no idea the infertility risk was so high. This means HSCT will never become mainstream and is likely to remain a rescue treatment.
Women with MS also don't like the idea of premature menopause even though it is treatable with HRT.
Yes, correct. This is what I find in the clinic; 4 out of 5 women of childbearing age so no thanks to AHSCT referral. However, men don't seem to mind. Also, sperm banking is much easier and quicker than egg banking, which may have something to do with it.
Thanks for these reflections on AHSCT. You wrote: "... more pwMS have a recurrence of their disease activity after non-myeloablative AHSCT, when compared to ablative-AHSCT". Is there any source for this observation? What I've read in papers is that both protocols can achieve NEDA at circa 70 % of RRMS patients for 5+ years.
Boffa et al. for the Italian BMT-MS study group. Long-Term Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis. Neurology. 2021 Jan 20:10.1212/WNL.0000000000011461. doi: 10.1212/WNL.0000000000011461.
Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients.
Methods: To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required.
Results: 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.
Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.
Classification of evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.
Median baseline EDSS was 6
Majority of patients had progressive ms
Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years
You know better than me that any chance of success should occur very early on in
Hit hard and early its what you allways say?
Excellent overview of HSCT. I have PPMS am 45 and have thought about it but am too worried about dying and leaving 3 girls and my wife. From what I read it is less likely to work for me and it seems like I would be borderline to get it on the NHS. The only people I know who have had it it hasn't really worked for them. One thing I would consider if I won the lottery is going to Panama (https://www.cellmedicine.com/) and having allogeneic human umbilical cord stem cells/ autologous bone marrow stem cells. I know there is an argument that no chemo it doesn't work but I would be interested on your thoughts on this other way. It seems like with this way you ideally have to go back a few times which makes it prohibitive even if you did a one off mega splurge.
With no immunosuppression, anything allogenic without HLA matching will result in the cells being rejected.
I thought as much
Sizomus, STAT-2, Octopus, etc ...
Where can one actually go to have myeloablative HSCT done? As far as I can tell all the private clinics offering it are doing non-myeloablative protocols. Is myeloablative available through the NHS?
Not sure. The BMTs unit treating MS in the NHS are not using ablative protocols. You could try one of the private units, for example, London Bridge, and speak to the haematologist.
they do it in Mexico as medical tourism for about 53k US.