Cyclophophamide is an anti-cancer drug that is not approved for MS but is used sometimes off-label. This inhibits relapses, as shown in this paper, but not quite as good as abalative HSCT stem cell therapy (This is where you get rid of the immune cells and replace the immune response using bone marrow stem cells). This inhibits relapses well, but with regard to progression they are as good or as bad as each other. They then say “progressive-MS disability progression becomes more based on non-inflammatory neurodegeneration than on inflammation. I agree with the sentiment but I believe the comments are probably not correct. Inflammation drives relapses by the immune system entering the brain and spinal cord, but I think that neurodegeneration is also driven by inflammation. However, this is a different type of inflammation that may not response to drugs that inhit relapse. You prevent relapses by depleting the lymphocyte out side of the CNS. To inhibit progression you have to affect inflammation inside the CNS. Cyclophophamide can get into the brain as can elements of the BEAM but thet will only inhibit dividing cells and many of the immune cells in the brain in MS are not dividing. Whilst there will be some inflammation that may respond to a CNS penetrant immunomodulator, the inflammation involved in progressive MS is probably due to the glial cells and macrophages and not lymphocytes.
However, this study suggests the effort of trying to treat progressive MS with HSCT costing thousands may be lttle better than use of cyclophosphamide costing a few dollars. However, it makes the case of why treatment of relapsing MS offer greater benefit potential than progressive MS.
Mariottini A, Bulgarini G, Forci B, Innocenti C, Mealli F, Mattei A, Ceccarelli C, Repice AM, Barilaro A, Mechi C, Saccardi R, Massacesi L. Autologous hematopoietic stem cell transplantation vs low-dose immunosuppression in secondary-progressive multiple sclerosis. Eur J Neurol. 2022 Feb 11. doi: 10.1111/ene.15280.
Background: Effectiveness of autologous haematopoietic stem-cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP-) MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment.
Methods: Retrospective monocentric 1:2 matched study in SP-MS patients treated with BEAM-AHSCT (cases) or IV pulses of Cy (controls) at a single Academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity-score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), disability progression (P-FS) and NEDA-2.
Results: 93 SP-MS were included: 31 AHSCT, 62 Cy. Mean follow-up: 99 months in the AHSCT and 91 months in the Cy groups. relapse-free survival was higher in AHSCT compared to Cy patients: at year 5, 100% vs 52% respectively (p<0.0001). Progression free surviva did not differ between the groups (at year 5: 70% in AHSCT and 81% in Cy, p=0.572), nor did no evidence of disease activity (lesions and relapses) (p=0.379). Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred.
Conclusion: This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Despite the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes more based on non-inflammatory neurodegeneration than on inflammation.
COI: multple but not relevant
Disclaimer: The views are those of the author and not institution.
For any HSCT zealot please don’t shoot the messenger and we are aware of potential benefits of HSCT and use it in our clinical practise
For the last few years I have listened / interacted with many people who have had hsct myeloablative and non, I would say I could count on one hand the number of ppl who have had genuine great results… for the rest it’s a mixed bag of what to me reads like PIRA, but for the zealots is explained as you’re stressed, you’re tired, you’re sick, you’re getting sick, it’s you’re menstrual cycle, it’s the cold damp weather, it’s the heat…
＞I would say I could count on one hand the number of ppl who have had genuine great results
But the number of people who have great results with progressive MS on simvastatin or without any treatment is zero… A small chance, even with risks, is better than no chance when you have a disease as bad as progressive MS.
MD1,
Thanks for this post.
“To inhibit progression you have to affect inflammation inside the CNS. Cyclophophamide can get into the brain as can elements of the BEAM but thet will only inhibit dividing cells and many of the immune cells in the brain in MS are not dividing. Whilst there will be some inflammation that may respond to a CNS penetrant immunomodulator, the inflammation involved in progressive MS is probably due to the glial cells and macrophages and not lymphocytes.”
The recognition that CNS inflammation causing progression is different to the inflammation which causes relapses is probably the biggest advance since research of this disease began. The problem is that pharma are still milking the goose which lays the golden egg for as long as they can ie they want MSers on the expensive drugs which tackle the inflammation which causes relapses. I see some hope in the future – maybe BTK inhibitors, anti-virals, current drugs which can better penetrate the CNS (?DODO trial), perhaps drugs targeting plasma cells in the CNS (?SIZOMUS trial). It’s a pity that pharma didn’t invest in drugs to target the inflammation / processes driving progression, but money talks unfortunately. Are there any other CNS diseases where glial cells and macrophages are the real culprits? It’s a pity that MS researchers couldn’t hook up with the researchers of these diseases and come up with solutions which address neuro-degeneration/ progression.
Can you milk a goose?
They get milk out of an almond!
You’re a frustrated English teacher MD2. In between Bargain Hunt and The Chase, you could try having a go at Wordle.
I’m too busy milking the applause Sidney.
They will but I suspect we have to wait for the patents to run out then the golden goose becomes the goose. Then the DMT become the cheap drug and the new neuroprotective becomes the expensive on
I fear the Sizomus trial won’t be too succussful seeing Asian OCB-negative pwms also progress away, maybe at a slower pace. Would the cost of wiping out plasma cells be too much if it doesn’t stop progression? I do hope the study help us to understand the neurodegen process more.
Dont know if its the same group but they had this study also
105 – Autologous hematopoietic stem cell transplantation reduces disability progression in patients with secondary progressive multiple sclerosis: results from the Italian MS Register
https://ectrims2021.abstractserver.com/program/#/details/presentations/861
Another same group
Impact of autologous haematopoietic stem cell
transplantation on disability and brain atrophy
in secondary progressive multiple sclerosis
Results: In total, 26 SP-MS patients with moderate-severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5-10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22).
https://pubmed.ncbi.nlm.nih.gov/32008439/
Results: Data from 79 SPMS patients who underwent AHSCT and 2361 matched control patients with SPMS treated with other DMT were included in the study. The final matched cohort consisted of 69 patients treated with AHSCT and 217 treated with other DMT. The mean follow-up of the matched cohort was 5.2 years. Mean (95% CI) EDSS change over 10 years was -0.013 (-0.087, 0.061) EDSS points per year in the AHSCT cohort and +0.157 (0.117, 0.196) in the “other DMT” group (p for time*treatment group interaction<0.001). The time to CDP was significantly longer in AHSCT patients as compared to “other DMT” group (HR= 0.50; 95% CI: 0.31, 0.81; p=0.005). The rate of CDI was significantly higher in AHSCT patients as compared with the “other DMT” group (HR = 4.21; 95% CI: 2.42-7.33; p<0.001) as well as the prevalence of sustained improvement over time (p<0.001).
I feel like the discourse on HSCT online and in media is overly positive. It’s frequently spoken of as a ”cure”, while, from what I’ve seen, this is not necessarily the case. I think there should be shed more light on the fact that HSCT is not necessarily this utopian thing of ”just take these drugs and you’ll be fine”. Tell you the truth, I believe that the fact that HSCT is one of the most invasive and intense medical procedures you can expose the human body too also deserves more attention. It’s not a pleasant ride, and to many patients with MS, I think opting for the (relatively) safe high-efficacy RRMS-treatments like natalizumab, cladribine (and, once the vaccine-related issues and role of covid-19 in the post-pandemic era are solved) also the anti-cd20 will be more appealing. And also the hopethat remyelinating and neuroprotective agents might soon emerge.
Im about to go in to barts for the second half of my hsct and this makes great reading for managing expectations.
Good luck Dan. I hope the outcome is what you are hoping for.
Thank you 😊
A big factor in this is that a lot of those people that did aHSCT actually faild on any other DMT…basically,lot of tham did it too late. Statistics should take care about this and evaluate the effects of age, edss score prior hsct, history od other DMTs etc…i beleive that was mantionated in this blog several times – if you want to do it, do it as soon as you can – flip the pyramid.
I beleive that there is also some oposition from the people who are simply afraid to do it, which is quite understandable , but looking at all data , it seems like the best existing option with all its risk
I doubt many went on aHSCT failed on “any” DMTs. And if the reason why the procedure is superior is because it wipes out immune then late or early shouldn’t have too much of a difference.
It will make a difference because the longer you wait, the longer you allow smouldering processes to establish themselves in the CNS. Once those are established you can’t affect the disease course with immunosuppression anymore. It’s just like RA: treat early with effective anti-inflammatories and you can halt damage, wait too long and lymphoid follicles develop and you can no longer prevent further deterioration.