I post to manage expectations and counteract fake news.
There is a group of pro-HSCTers going around and saying HSCT is a cure for MS even in MSers with more advanced disease, i.e. it halts and reverses their disability. This is simply not correct and we have no published, peer-reviewed, data to support their position.
The meta-analysis below from Paulo Muraro and colleagues clearly shows that in MSers with SPMS and PPMS having HSCT the ‘majority of study subjects’ continue to progress. This is why most bone marrow transplant units generally don’t treat progressive MS. Even Richard Burt one of the main proponents of treating MS with HSCT stopped transplanting MSers with progressive MS when his BMT unit was still active.
The figure below from the Muraro paper confirms the above; over 60% of the SPMSers and 100% of the PPMSers worsened compared to about 45% of the RRMSers. Why? I suspect it is due to smouldering MS.
HSCT is simply a very potent IRT (immune reconstitution therapy) and is effective at switching off relapses and new focal MRI activity. We have no data to suggest that it impacts on smouldering MS. In fact, we have evidence to the contrary, that the chemotherapy used to deplete the immune system is neurotoxic and some patients actually develop worsening disability as a result of ‘chemo brain’ or acute neurotoxicity associated with the induction protocol. In the Canadian study, which uses myeloablative chemotherapy, treated patients lost more than 2% of their brain volume in year 1. Believe me, this is serious brain volume loss way above what you expect MS to do and is indicative of neurotoxicity. The reason why relapsing MSers cope with the HSCT conditioning is because of reserve and progressive MSers do not, because their MS has already consumed their reserve capacity.
Many years ago we showed that MSers undergoing BMT/HSCT release very high levels of neurofilaments as part of the induction protocol and the levels of neurofilaments released predicted worsening disability. In other words, the chemotherapy caused acute neurotoxicity and resulted in disability worsening. This is one of the reasons why the Rotterdam BMT unit, and many other units, stopped treating progressive MSers. However, if you go to a fee-for-service BMT unit they will treat all-comers. Why? It is called a business and money talks. Don’t be gullible.
What about the anecdotal cases of HSCT curing progressive MS? I can’t say I have seen a single case. All the patients in my practice with progressive MS who have gone abroad to have HSCT have continued to worsen on their return. I am aware of a case of a colleague of mine who had a patient who was in a wheelchair who had HSCT abroad who miraculously got up and walked after having HSCT. My colleague informed me that he had diagnosed this patient as having somatization disorder, a very common MS mimic, that is a psychiatric condition. I am, therefore, sceptical about miraculous anecdotes and I would urge you to be careful before you base your decisions to have HSCT based on anecdotes. What we as an MS community needs is published data on the risks and benefits of HSCT in advanced MS to base our decisions on.
Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. doi: 10.1001/jamaneurol.2016.5867.
IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.
OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.
DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.
EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.
MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.
RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85. doi: 10.1016/S0140-6736(16)30169-6.
BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.
METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.
FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.
INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.
Petzold et al. Evidence for acute neurotoxicity after chemotherapy. Ann Neurol. 2010 Dec;68(6):806-15. doi: 10.1002/ana.22169.
OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients’ quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.
METHODS: This prospective study included patients with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMS patients matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).
RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT patients and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL patients or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).
INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.