Earlier, I asked you for questions to take to Moscow for the HSCT conference for autoimmune diseases on November 22-24, 2019. This resulted in eleven clearly formulated and important questions. Based on conversations with Ellen Kramer, insights from the presentations and answers to questions I asked the presenters, I will try to answer these questions as well as possible below.
The EBMT discourages the use of HSCT for people with MS who do not have an “active” disease1. In a recent blog post, BartsMS also discourages the use of HSCT for progressive MS. Yet they treat many SPMS & PPMS patients who do not meet this condition, in fee-for-service BMT units around the world. Incredible success rates are reported by these units for this group of patients, how is that possible, and why is the treatment not recommended by most experts?
Perhaps this was the most discussed topic of the congress. The question came back during the panel discussion at the end of the first day, in which several experts were present.
The answer from the vast majority of experts was:
“From our experience, based on animal studies and clinical study results, we conclude that aHSCT is not effective for people with long-term progressive MS, for whom no active MS inflammations are visible on the MRI scan and for whom no acute clinical relapses occur. “
Patients present contradicted this idea. Prof. Dr Fedorenko, who was also a member of the panel, said that in his centre they do not treat every person with progressive MS and that for those they do treat, the goal of treatment was to stop disease progression.
In my later conversation with Prof. Dr Fedorenko, he told me that the HSCT treatment in itself is only part of the treatment. According to him, a positive attitude to life, a lifestyle with healthy food, no smoking and a lot of physical exercise is an essential part of the treatment.
How do you measure the success / effectiveness of an HSCT treatment in MS-patients that do not have MRI-activity or clinical relapses? In untreated patients, EDSS progresses very slowly at higher scores. Even if there would be a well-matched control group of progressive MS patients, finding a statistically significant difference between an untreated and treated group would be difficult and would likely require many years of follow-up.
When fee-for-service BMT units report success, how is this measured, especially for progressive MS patients without clinical relapses or active MS inflammation visible on MRI?
There is no clear-cut answer to this question. This partly explains the differences in reported effectiveness. Most scientific results are based on clinical progression after HSCT, defined as a permanent decrease in EDSS score of at least one point. EDSS scores above 5.5 are solely influenced by the patient’s walking function. Dr Fedorenko bases his effectiveness measurement largely on voluntary, standardized online questionnaires. Although the voluntary nature of completing these questionnaires and subjectivity might influence the findings, important things such as fatigue, daily functioning, quality of life, etc. are included in this measure of success.
These so-called PROMs (patient-reported outcome measures) were the subject of a presentation by Prof. Dr Tatiana Ionova from Saint Petersburg. For any future studies, it is certainly valuable to include these results.
Could the HSCT treatment make the MS / neurodegeneration worse? There have been some reports of chemotherapy caused acute neurotoxicity.
On top of the known short-term and long-term risks of HSCT treatment, (such as the risk of death shortly after treatment due to infections –Treatment-Related Mortality, TRM-, the increased risk of developing a second autoimmune disease or developing cancer), the chemotherapy used in HSCT worsens the breakdown of nerve cells (neurodegeneration). This can be especially worrisome in older patients with progressive forms of MS, so warned Prof. Burt.
For this group of patients, progression is not caused by inflammatory activity, but mainly by neurodegeneration (a process also called PIRA, or Progression Independent of RelApses).
Professor Burt cited this as an additional reason not to treat MS patients with progressive MS with HSCT.
Both in Russia and in Mexico no ATG is used in their treatment protocol. The rest of the centres do this, and the EBMT also recommends its use2. What is the motivation for this choice and does it have a possible impact on the long-term effectiveness of the treatment?
This question also keeps the experts busy. There is still uncertainty about the most optimal treatment protocol. No studies have been done to directly compare the different protocols. Based on the experiences of the different centres, it appears that there is currently no measurable difference between protocols. However, it is acknowledged that data is missing to make comprehensive, long-term comparisons.
Prof. Dr Burt, who used a protocol with cyclophosphamide and ATG in his MIST study, openly said that he might consider using Rituximab instead of ATG if he had to start again. Rituximab is better tolerated and it appears that fever caused by ATG in the isolation period predicts poorer treatment effectiveness.
Experts warned that this consideration is entirely based on experiences and opinions, and to be sure a thorough and long-term comparative study would need to be done. As this will not happen in the short term, the attending practitioners were urged to share their results with the community by reporting them to the EBMT register (a standardized database in which, among other things, HSCT results are collected). This database is accessible to researchers, so that future analysis studies can hopefully provide more clarity about this subject.
Is there a reason to prefer a more intense chemo-protocol (e.g. BEAM)? A number of European centres keep using BEAM, while in new trials always a cyclophosphamide + ATG treatment is given. Some people profess to the idea that it is more effective with progressive MS to use heavier chemotherapy.
To a large extent, the same applies here as for question 4. To be sure, a thorough, long-term clinical study must be done. However, a couple of European centres that carry out the treatment with the BEAM protocol have been reporting to the EBMT register for a long time. More information about the difference in treatment is therefore known, although there are hardly any long-term outcomes and outcomes for progressive MS are sparse and very divergent. The group of Prof. Dr Saccardi from Florence is working on a publication on this subject, based on the information available from the EBMT registry. It cannot be concluded from the preliminary results that were presented, that one protocol is superior to the other, but the TRM (treatment-related mortality, the risk of death) is slightly higher with the BEAM protocol.
In the future, the hope is that equally effective treatment can be achieved with targeted, less intensive and less risky medication.
In the treatment protocol used in Mexico, the four days on which the chemical agent cyclophosphamide is given are split by a period of one week. Does this have a negative effect on the effectiveness of the treatment? Why is this treatment schedule only applied in Clínica Ruiz?
This was not discussed during the conference. No one was present from the treatment centre in Mexico. Partly the same answer applies as for questions 4 and 5. To be absolutely certain, a solid randomized comparative study would need to be conducted. Hopefully, results will be shared worldwide between practitioners and researchers so that this can lead to new insights into this question.
I myself have previously discussed this topic with Dr Guillermo Ruiz himself and Dr Juan Carlos Olivares-Gazca. They believe that administering the same amount of cyclophosphamide divided into two blocks of two days with a week of rest has no adverse effect on the effectiveness of the treatment. After all, rebuilding the immune system is a process that takes many times longer than this break. On the other hand, this treatment method is far less stressful for other cells in the body.
To what extent this is correct could be verified by looking at the ‘new’ immune system that has emerged after treatment, and comparing this with that of other patients treated with a different protocol. This has not been done yet and is not planned for the near future.
Why are there no articles published in renowned scientific journals from the A.A. Maximov centre, which has already treated more than 1000 patients? This Russian centre the world’s highest number of people with MS treated with HSCT, sharing their knowledge could help many people.
What became clear during the congress is that the expertise that is present in Priogov hospital is essentially no different from that of the other experts. It is true that a large number of treated patients and results are of enormous value to researchers around the world. Researchers in the field of HSCT have long been working closely together in Europe through the EBMT. Results from the US will also be openly shared in the future. Russian HSCT-research has so far not reported to the EBMT-registry. The congress was also very valuable in that sense because practitioners from Russia indicated that they want to be more involved in future collaborative studies.
Opinions on how to handle vaccinations after HSCT vary considerably between centres. In general, only vaccinations with live attenuated viruses are considered a higher risk of inducing a recurrence of MS. However, some centres discourage the use of vaccines, some find it unnecessary, and others use a vaccination schedule. What is the general opinion about this? Are vaccinations necessary or bad?
This was not discussed during the congress. Most clinics follow their own guidelines here. There is no reason to believe that non-living vaccines could cause an MS relapse. However, it is unclear to what extent it is necessary to revaccinate after an HSCT treatment. The strength of the chemotherapy used in the protocol certainly plays a role in this. To be sure whether re-vaccination is necessary individually, a so-called ‘titer’ of the number of immune cells present for different diseases can be measured with a blood test.
When after HSCT treatment, a relapse occurs, what is the recommended treatment?
This has been discussed briefly a number of times during the various presentations. As of yet, there is no consensus on this, and it is currently being decided by the treating specialists, per individual patient. Rituximab is a regularly suggested treatment, but a second HSCT treatment can also be considered. There is little experience with this in adults, hopefully, this will be elucidated in the future.
I am very interested in the long-term effectiveness of the treatment. Some studies have been started in the past, that resulted in some long-term measurements3 e.g. the study by Shevchenko4, there has been a retrospective multi-centre cohort study5 and a report on a single centre’s experience6. Logically, an overview of the long-term effectiveness of the more recently introduced lower-intensity regimens is lacking. Can you make an educated guess about the difference in the effectiveness of these new regimen compared to the older, higher-intensity protocols?
Like in answers 4 & 5, there is the general feeling amongst experts that there is no significant difference between the effectiveness of the different protocols. However, to be sure, a long-term randomized trial would have to be conducted, this will not happen in the near future. What will happen is that more outcome-data will be shared through the EBMT-registry. Analysis of this data will most likely shed more light on the subject.
The educated guess is
1) Currently, there are no apparent difference in effectiveness
2) Risk of side-effects is higher with higher-intensity protocols.
Results from Muraro’s article, based on information from the EBMT register, were discussed in Dr Saccardi’s presentation. The long-term results are (certainly for progressive forms of MS) based on a very small number of patients. That is why Russian colleagues were once again invited to share their results with the EBMT.
If the chances of success are really as high as those reported by Dr Fedorenko, why is this method not used worldwide for all people with MS?
There is no reason to believe that treatment, as it is being done in Russia, is superior to treatment in other centres. Also in Russia, the conclusion is that the best candidate for HSCT treatment is a young patient with (very) active RRMS, a low EDSS and a relatively short time since diagnosis.
HSCT remains a treatment with a risk of side effects that seems many times greater than that of regular MS drugs. For many patients, these drugs are still a better solution than HSCT. It is very important to define for which group of patients HSCT forms a good balance between effectiveness and risks.
In addition to these questions, there are still many questions that require further research. It is essential that the right patients can be selected for treatment. The underlying mechanism of aHSCT needs to be elucidated at a fundamental level. Hopefully, in the future targeted, less burdensome, equally effective therapies will be developed. At the moment it is not clear which treatment-protocol can best be followed. Another important open question, which is important for all these future studies, is how to measure ‘success’.
A lot of questions remain (partly) unanswered. These questions hopefully will be researched soon. Especially promising is the intent of various Russian centres to participate in collaborative studies in the future.
- EBMT: “aHSCT may play a role in the treatment of the progressive forms of MS. However, based on scientific insights, the authors recommend aHSCT only when a patient has had inflammation in the central nervous system in the past year. It is preferable to offer treatment with HSCT as part of a clinical study.”
- EBMT: “Due to a lack of data on the effectiveness of other treatment regimens, the authors recommend the use of the EBMT-recommended regimen with cyclophosphamide 200 mg/kg + ATG or BEAM + ATG.”
- See Table 1 of Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience
- Long-term outcomes of autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis: physician’s and patient’s perspectives
- Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis
- Long-term follow-up more than 10 years after HSCT: a monocentric experience