- Early clinical trials in autologous haematopoietic stem cell transplant (AHSCT) involved aggressive chemotherapy regimens, but this has evolved in recent years to involve chemotherapy regimens that are safer and better tolerated but still effective.
- This study followed over 500 people in a single centre for up to 5 years post-AHSCT treatment to help provide better-informed judgement on the risks and role of AHSCT, as well as assist clinicians with the selection of people who will benefit most from AHSCT.
- Findings from the study revealed that participants with inflammatory relapsing remitting MS (RRMS) were significantly more responsive to AHSCT than participants with neurodegenerative secondary progressive MS (SPMS).
Clinical trials in AHSCT
AHSCT is an immune-suppressing chemotherapy treatment combined with reinfusion of blood stem cells, with the aim of rebuilding the immune system without MS. Whilst AHSCT may be able to stabilise or improve disability in some people with MS, MS is a disease with a varied outcome affecting each individual differently and therefore this treatment is not suitable for all people, nor all types of MS.
Clinical trials in AHSCT started in the 1990s and enrolled participants with relapsing remitting MS as well as secondary progressive MS. The type of chemotherapy that was administered was aggressive, which was originally developed for cancer. These studies showed that this intense chemotherapy regimen was effective in stopping relapses, new lesions and improving quality of life, but did not improve neurological symptoms or stop disease progression in people with secondary progressive MS. Brain atrophy (shrinking of the brain) also continued for at least two years post-treatment in people with secondary progressive MS.
As a result, AHSCT clinical trials moved to mainly enrolling participants with relapsing remitting MS as well as using a less aggressive chemotherapy regimen to try and reduce some of the chemotherapy-related side effects. These trials showed that there was sustained reversal of neurological disability after AHSCT in people with relapsing remitting MS. However, these trials only involved small numbers of participants. Also, treatment by AHSCT wasn’t being compared to standard disease modifying therapies (DMTs). This comparison didn’t happen until 2019 when the results of an international clinical trial, called the MIST clinical trial, was published, comparing the effect of AHSCT and standard DMTs on MS progression in 110 people with very active relapsing remitting MS over a period of up to five years. This study showed on average that participants treated with AHSCT had improvement in disability and fewer relapses compared to participants on the standard DMTs. There were also no deaths.
What did this new study look at?
The areas of unmet need in understanding the role of AHSCT in MS care are firstly, consistent follow-up of large numbers of people with relapsing remitting MS who have undergone AHSCT and secondly, understanding whether AHSCT benefits those with newly diagnosed secondary progressive MS who still experience active inflammation (“active” SPMS). Published in the Journal of Neurology, this study reported the results of a single-centre real-world experience of AHSCT in 507 participants with MS (414 RRMS, 93 “active” SPMS) who had undergone the procedure between 2003 and 2019. On average, the participants had received four DMTs prior to receiving AHSCT treatment.
Complications associated with AHSCT
One of the major risks of AHSCT has been death (mortality) related to the procedure. However, transplant-related mortality (TRM) rates of AHSCT have dropped to about 1% now compared to 3% a decade ago. In this study, there was one death due to a hospital-acquired legionella pneumonia post-procedure, making the TRM 0.19%. The overall survival was 98.8% due to five non-treatment-related deaths, which all occurred more than one year after the procedure.
The main infections that participants developed during and after the transplant period were bacterial and viral, causing common infections such as urinary tract, sinus, gut or upper respiratory tract infections, which resolved with treatment.
Secondary autoimmune diseases
There is a slight risk of developing secondary autoimmune diseases after AHSCT. In this study, two new autoimmune diseases occurred after AHSCT treatment – these were the bleeding disorder idiopathic thrombocytopenic purpura (ITP) and inflammation of the thyroid gland (thyroiditis). However, these were thought to be related to the drug alemtuzumab, which was originally used in the chemotherapy regimen and is known to cause these side effects. Since alemtuzumab has been changed to other agents, the occurrence of these secondary autoimmune diseases has reduced.
Neurological outcomes of AHSCT
After the AHSCT procedure, no further DMTs were given, unless there was a clinical relapse. The proportion of patients that remained relapse-free five years after AHSCT treatment was 80.1% for relapsing remitting MS and 98.1% for secondary progressive MS. It is not unexpected that a higher proportion of people with secondary progressive MS are relapse-free, as they are less likely to relapse than people with relapsing remitting MS. The proportion of patients that did not experience disease progression, defined as a sustained worsening in the expanded disability status scale (EDSS), four years after AHSCT treatment was 95% for relapsing remitting MS and 66% for secondary progressive MS. This is also not unexpected as people with secondary progressive MS are at an increased risk of progression.
People with relapsing remitting MS showed significant improvement in disability as measured by the EDSS, with an average pre-AHSCT EDSS of 3.87 and an average 5-year post-AHSCT EDSS of 2.19. For secondary progressive MS, the EDSS improved significantly only at 1-year post-AHSCT, but not afterwards – the average pre-AHSCT EDSS for people with secondary progressive MS was 5.18, which improved to 4.85 after one year. Once again, this would be expected with secondary progressive MS.
These differences between relapsing remitting MS and secondary progressive MS may be a result of the different disease processes, with relapsing remitting MS being more inflammatory and secondary progressive MS being predominantly neurodegenerative.
What can be concluded from this study?
The study shows that overall, AHSCT is an effective one-time therapy for people with very active relapsing remitting MS who are not responding to standard DMTs. In particular, people with relapsing remitting MS who have undergone AHSCT treatment experienced reversal of disability by greater than 1.0 EDSS. While there are some risks, including infection, secondary autoimmunity and death, these have significantly improved over the years due to improved patient selection, the choice of conditioning regimen (moving towards less aggressive regimens) and the increasing experience of transplant centres.
For more information on AHSCT, please visit the MS Australia AHSCT information page here.