Intense Stem Cell Therapy Shows Promise as MS Treatment
A therapy known as HSCT performed well in a clinical trial, but experts caution the treatment might not be for everybody.
HSCT IndiaStem cells may be an important pathway for the successful treatment of multiple sclerosis, although it can be a long and painful road getting there.
A recent clinical trial bore this out
In the trial, people with multiple sclerosis (MS) using nonmyeloablative hematopoietic stem cell transplantation (HSCT) performed better than those on disease-modifying treatments (DMTs).
The randomized clinical trial is the first to compare HSCT to DMTs.
Researchers said a significant number of patients on HSCT treatment were able to slow disease progression, compared to those using DMTs.
Of the 103 participants, only three of those on HSCT saw disease progression compared to 34 of those on DMTs.
The research team concluded that HSCT slows progression better than DMT, but they added it is imperative to find the right type of patient to undergo what is a rigorous and sometimes dangerous therapy.
The study was led by Dr. Richard Burt, chief of immunotherapy and autoimmune diseases at the Northwestern Feinberg School of Medicine in Illinois.
“This important study is the first randomized trial of HSCT vs. DMT, and demonstrated that HSCT was superior to conventional DMT in stabilizing persons with relapsing MS with respect to relapses and progression and improving some functions,” said Dr. Barbara Giesser, professor of clinical neurology at the David Geffen School of Medicine at the University of California Los Angeles (UCLA) and clinical director of the UCLA MS program.
An intense treatment
HSCT uses chemotherapy to help cells “forget” they have MS.
In doing so, the immune system is stripped down to vulnerable levels. Patients must be hospitalized and treated with extreme care.
“HSCT is not one therapy but a range of therapies from a more mild type of chemo to a stronger type,” Bruce Bebo, PhD, executive vice president of research at the National Multiple Sclerosis Society, told Healthline. “Dr. Burt practices a more mild form of chemotherapy — more mild form of immunosuppression — so the risks are lower.”
Trial participants had relapsing MS with mild to moderate disabilities, ranging from 2 to 6 on the Expanded Disability Status Scale (EDSS).
“This study stands above the others — first controlled randomized autologous stem cell transplant. Burt and his team should be applauded for taking this on. It’s what everyone was asking for,” Bebo said.
“A lot of groups are experimenting with this type of treatment — case studies and evidence is accumulating for its positive benefit and accumulating info for the best patient and approach for success,” he added.
Bebo explained how difficult this study was to perform and how Burt and his team created an unbiased way to compare HSCT to DMTs, excluding ocrelizumab and alemtuzumab, which were not included.
Due to potential visible side effects with the chemo such as hair loss, a “blind reader” reviewed the results of the tests during the trial. This reader was off site and had no access to the participants.
Greater Benefits for Relapsing-Remitting MS Found with HSCT Therapy
Nonmyeloablative hematopoietic stem cell transplantation (HSCT) was associated with prolonged time to disease progression when compared to disease-modifying therapies (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS), according to results published in Journal of the American Medical Association (JAMA).
Nonmyeloablative hematopoietic stem cell transplantation (HSCT) was associated with prolonged time to disease progression when compared to disease-modifying therapies (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS), according to results published in Journal of the American Medical Association (JAMA).
HSCT IndiaIn a randomized controlled trial, participants who met inclusion criteria for the trial (N=110) were randomized into the HSCT group (n=55) and continuation of DMT group (n=55). There were no significant differences between the HSCT and DMT groups in terms of sex, age, baseline expanded disability status scale (EDSS) scores, number of gadolinium-enhancing lesions, T2-weighted lesion volume on MRI before randomization, number of prior DMTs, or type of prior DMT or immune treatments.
Participants in the DMT group received a DMT of higher efficacy or a different class than the therapy taken at the time of randomization (based on decision of their treating neurologist). For patients in the HSCT group, DMT use was discontinued, followed by variable washout periods before admission for HSCT.
Peripheral blood stem cells were collected 10 days after intravenous cyclophosphamide (2 g/m2) and 5 to 10 μg/kg per day of subcutaneous filgrastim beginning 5 days after cyclophosphamide. The immune ablative regimen was intravenous cyclophosphamide, 50 mg/kg per day on days −5 to day −2 before stem cell infusion (day 0) and rabbit antithymocyte globulin, .5 mg/kg on day −5, 1 mg/kg on day −4, and 1.5 mg/kg on days −3, −2, and −1. Blood products were irradiated, cytomegalovirus safe, and leukocyte depleted. Filgrastim (5-10 μg/kg per day) was started on day +4 and continued until engraftment.
The primary endpoint, defined as an increase in disease progression (EDSS score increase of ≥1) of at least 1 point on 2 evaluations 6 months apart after at least 1 year of treatment, occurred in 3 patients in the HSCT group and 34 patients in the DMT group, with a median follow-up of 2 years. The proportion of patients in the HSCT group with disease progression was 1.92% (95% confidence interval [CI], .27%-12.9%) at 1 year and 2 years, 5.19% (95% CI, 1.26%- 20.1%) at 3 years, and 9.71% (95% CI, 3%-28.8%) at 4 and 5 years.
The proportion of patients in the DMT group with disease progression was 24.5% (95% CI, 14.7%-39.1%) at 1 year, 54.5% (95% CI, 40.7%-69.4%) at 2 years, 62.5% (95% CI,48.3%- 76.7%) at 3 years, 71.2% (95% CI, 56.8%-84.2%) at 4 years, and 75.3% (95% CI, 60.4%-87.8%) at 5 years.
Mean EDSS score decreased (improved) in the HSCT group, from a pre-HSCT score of 3.38 to 2.36 at 1 year (mean change, −1.02 points), while the mean EDSS score increased (worsened) in the DMT group, from 3.31 to 3.98 at 1 year (mean change, +.67 points). The difference between the HSCT group and DMT group in the change in EDSS scores from baseline to 1 year was −1.7 (95% CI, −2.03 to −1.29; P <.001).
Notably, there was significant improvement in EDSS scores, NRS scores, and T2-weighted lesion volume percentages in the 31 patients who crossed over from the DMT group to receive HCST, suggesting that current definitions of progression for RRMS may not accurately assess irreversible disease progression for all patients.
Investigators noted this study was limited by its small sample size and the limited ability to collect follow-up data for patients receiving DMT and to assess longer-term secondary outcomes due to a study design that allowed patients in the DMT group in whom that treatment failed to cross over to receive HSCT.
HSCT is designed to eliminate autoreactive lymphocytes and “reboot” the immune system in a non-inflammatory environment. In an observational study of long-term disability outcomes of patients with relapsing and progressive forms of MS, researchers found that nearly half of these patients were free of neurological progression 5 years after receiving autologous HSCT1. Better outcomes were associated with younger age, relapsing form of MS, fewer prior immunotherapies, and lower EDSS score at baseline.
“We think what happens in HSCT is that the immune response is exposed to myelin in the absence of the danger signal,” Richard K. Burt, MD, principle investigator and chief, division of immunotherapy at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois, said in an interview with the National MS Society. “What we’re doing is stopping inflammation you need to treat when the disease in its inflammatory stage.”
New treatment can ‘halt’ multiple sclerosis, says study.
Aggressive chemotherapy followed by a stem cell transplant can halt the progression of multiple sclerosis , a small study has suggested.
The research, published in The Lancet, looked at 24 patients aged between 18 and 50 from three hospitals in Canada. For 23 patients the treatment greatly reduced the onset of the disease. An MS Society spokeswoman said this type of treatment does “offer hope” but also comes with “significant risks”.
Around 100,000 people in the UK have MS, which is an incurable neurological disease.
‘No Relapses’
The condition causes the immune system to attack the lining of nerves in the brain and spinal cord. Most patients are diagnosed in their 20s and 30s.One existing treatment is for the immune system to be suppressed with chemotherapy and then stem cells are introduced to the patient’s bloodstream – this procedure is known as an autologous haematopoietic stem cell transplant (HSCT). But in this study, Canadian researchers went further – not just suppressing the immune system, but destroying it altogether.
It is then rebuilt with stem cells harvested from the patient’s own blood which are at such an early stage, they have not developed the flaws that trigger MS. The authors said that among the survivors, over a period of up to 13 years, there were no relapses and no new detectable disease activity. All the patients who took part in the trial had a “poor prognosis” and had previously undergone standard immunosuppressive therapy which had not controlled the MS – which affects around two million people worldwide. One person died as a result of the strong effects of the chemotherapy, the authors said.
‘Disease Free’
Lead author Dr Mark Freedman admitted there were limitations to the study – such as the small sample size – and there was no control group used for comparison with those who were treated. He said: “Larger clinical trials will be important to confirm these results. “Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with HSCT and this treatment should only be offered in specialist centres experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial.”
Dr Emma Gray, who is head of clinical trials at the MS Society, said: “This type of stem cell transplantation is a rapidly evolving area of MS research that holds a lot of promise for people with certain types of MS. “This treatment does offer hope, but it’s also an aggressive procedure that comes with substantial risks and requires specialist aftercare.
If anyone is considering HSCT we’d recommend they speak to their neurologist.” Prof Siddharthan Chandran at the University of Edinburgh described the work as “important and carefully conducted”.
“…[It] demonstrates that powerful chemotherapy-based treatment for a selected subset of MS patients with very aggressive disease is effective in preventing further disabling relapses and, in a proportion, appears to render them effectively disease-free,” he said. Meanwhile, Dr Stephen Minger, a stem cell biologist and independent consultant, described the study as “truly impressive”
He said: “It’s important to stress that this is a very early study, though with impressive long-term follow-up of treated patients.
“Nevertheless, the clinical results are truly impressive, in some cases close to being curative, though we need longer-term follow-up to know for certain whether the patients continue to do well or if there is a chance of relapse.”
Stem Cell Transplants Improve on Current MS Treatments
A one-time stem cell transplantation treatment for multiple sclerosis showed improvements over the current therapies, according to a preliminary trial published in the Journal of the American Medical Association (JAMA).
The process, called hematopoietic stem cell transplantation (HSCT), temporarily shuts down and reboots patients’ immune systems, allowing the body to rebuild damaged nerve cells. The success of this trial serves as a proof-of-concept for the treatment, according to Richard Burt, MD, chief of Immunotherapy and Autoimmune Diseases in the Department of Medicine and lead author of the study.
“This opens the door for this therapy,” Burt said. “Now we can work on improving it, refining it and making it safer.”
MS is an immune-mediated disorder of the central nervous system often arising in young adulthood. It damages the nerve cells in the brain and spinal cord, causing symptoms that range from fatigue to paralysis throughout life.
The current disease-modifying therapies are intense and personalized drug regimens that patients must take indefinitely, even as its effectiveness can eventually fade, according to Burt.
HSCT, however, relies on a different strategy: MS patients are given five days of immune-specific drugs to shut down their self-destructive immune system, then stem cells are transplanted into the patient’s blood. This produces new immune cells that several previous studies suggest may reset the immune system.
“When the immune system restarts in a non-inflammatory environment, it appears to default back to tolerance and stops the attack, allowing, depending on the stage of disease, for the body to repair itself to some extent,” Burt said.
Previously, HSCT found success in non-randomized patients in trials at Northwestern and elsewhere — including in Sweden and Canada, and at the Fred Hutchinson Cancer Research Center and Duke University — but the current study is the first fully-randomized trial that tested relapse-remitting MS (RRMS) against the current treatment, Burt said.
In the trial, 110 patients were randomized to receive either HSCT or the traditional drug therapy. At last follow-up, disease progression occurred in 34 patients in the drug therapy group, but in just three patients in the HSCT group.
Patients in the drug therapy group had worsening scores on the Expanded Disability Status Scale (EDSS) — a method of quantifying disability in patients with MS — while patients in the HSCT group actually saw improvements in their scores.
In addition to being more a more efficacious treatment, HSCT has the potential to be more cost-effective than the current drug therapy, according to Burt.
“A full cost analysis needs to be performed, because the current drugs are very expensive,” Burt said. “I would anticipate, since this is just one treatment, that it may be a win-win: patients undergo a one-time treatment and get off of the drug regimen, while possibly saving money from a public health perspective.”
However, Burt cautions that further investigations are still needed to replicate these findings, and that the treatment needs to be used in the right type of RRMS.
Other Northwestern authors include Borko Jovanovic, PhD, associate professor of Preventive Medicine in the Division of Biostatistics; Roumen Balabanov, MD, associate professor in The Ken & Ruth Davee Department of Neurology, in the Division of Multiple Sclerosis & Neuroimmunology; Xiaoqiang Han, MD; Irene Helenowski, PhD; Amy Morgan; Kathleeen Quigley; Kim Yaung; Carri Alldredge; Allison Clendenan; Michelle Calvario and Jacquelyn Henry.
Intense Stem Cell Therapy Shows Promise as MS Treatment
Greater Benefits for Relapsing-Remitting MS Found with HSCT Therapy
New treatment can ‘halt’ multiple sclerosis, says study.
Stem Cell Transplants Improve on Current MS Treatments
