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In multiple sclerosis (MS), a disease that strips away the sheaths that insulate nerve cells, the body’s immune cells come to see the nervous system as an enemy. Some drugs try to slow the disease by keeping immune cells in check, or by keeping them away from the brain. But for decades, some researchers have been exploring an alternative: wiping out those immune cells and starting over.

The approach, called hematopoietic stem cell transplantation (HSCT), has long been part of certain cancer treatments. A round of chemotherapy knocks out the immune system and an infusion of stem cells—either from a patient’s own blood or, in some cases, that of a donor—rebuilds it. The procedure is already in use for MS and other autoimmune diseases at several clinical centers around the world, but it has serious risks and is far from routine. Now, new results from a randomized clinical trial suggest it can be more effective than some currently approved MS drugs.

“A side-by-side comparison of this magnitude had never been done,” says Paolo Muraro, a neurologist at Imperial College London who has also studied HSCT for MS. “It illustrates really the power of this treatment—the level of efficacy—in a way that’s very eloquent.”

Nearly 30 years ago, when hematologist Richard Burt saw how HSCT worked in patients with leukemia and lymphoma, he was struck by a curious effect: After those patients rebuilt their immune systems, their childhood vaccines no longer protected them, recalls Burt, now at Northwestern University’s Feinberg School of Medicine in Evanston, Illinois. Without a new vaccination, the new immune cells wouldn’t recognize viruses such as measles and mumps and launch a prompt counterattack. That suggested that in the case of an autoimmune disease, reseeding the immune system might help the body “forget” that its own cells were the enemy.

Burt and others have since used HSCT for a variety of autoimmune diseases, including rheumatoid arthritis and lupus. In the past few years, several teams have reported encouraging results in MS. But only one study—which evaluated just 17 patients—directly compared HSCT to other available drug treatments.

In the new trial, Burt and his colleagues recruited 110 people with the most common form of MS, known as relapsing-remitting. In that form of the disease, patients can go long periods without symptoms—which include muscle weakness and vision problems—before inflammation flares up. Trial participants had at least two such relapses in the previous year, despite being on one of several approved MS drugs.

Half the participants continued with drug treatment but switched from a drug that wasn’t working for them to a drug of a different class. The other half underwent HSCT. First, the researchers collected their blood to reinfuse later. Then, they gave patients a combination of drugs to kill most of their immune cells. In this trial, the patients would have regenerated their own immune systems with stem cells in bone marrow that were spared annihilation, Burt notes. But they received the reinfusion of their own stem cell-rich blood to help speed recovery by several days.

A year later, the researchers evaluated how far the disease had progressed in each of the patients. According to a zero-to-10 scale of disability that includes measures of strength, coordination, and speech, roughly 25% of those in the drug treatment group showed at least a one-point worsening in their score, compared with just 2% of those in the transplant group, the researchers report online today in The Journal of the American Medical Association (JAMA).

MRI scans also revealed less extensive brain lesions in the transplant group and improvements in a patient survey about quality of life. (Survey scores worsened slightly in the drug-treated group.) Five years after treatment, about 15% of people in the transplant group had had a relapse, versus about 85% of the control group.

The two groups diverged “in a massive way,” Muraro says. But he adds that two of the most effective MS drugs weren’t included in the control group. One, ocrelizumab, had not been approved when the study was enrolling participants. Another, alemtuzumab, was excluded because it also depletes immune cells…

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Progress for Stem Cell Transplant in MS

A small, preliminary study in JAMA has found that hematopoetic stem cell transplant (HSCT) may be more effective than disease modifying drugs in patients with highly active relapsing-remitting multiple sclerosis (MS).1 The study is the first randomized trial of HSCT in relapsing-remitting MS. Findings were published online on January 15, 2019 in JAMA.

Researchers also found that patients treated with HSCT had less progression, and more of them had no signs of disease activity than those treated with disease modifying drugs. “This degree of improvement has not been demonstrated in pharmaceutical trials even with more intensive DMT [disease modifying treatments] such as alemtuzumab,” wrote first author Richard Burt, MD, of Northwestern University Feinberg School of Medicine (Chicago, IL), and colleagues.

Relapsing-remitting MS affects about 85% of patients with MS.2 Treatment with disease modifying agents, such as interferons, glatirameracetate, fingolimod, natalizumab, or dimethyl fumarate, carries a high price tag—up to $60,000 per year per patient.3 But these drugs may only slow disease progression rather than halting it. Most patients eventually develop irreversible damage and progressive disability, for which no effective therapies exist.

HSCT may offer the chance get rid of the immune cells that cause MS, basically giving the immune system a fresh start to improve remission rates.

To test the technique, researchers conducted an open-label study, called the Multiple Sclerosis International Stem Cell Transplant (MIST) trial. The study included 110 individuals with relapsing-remitting MS, moderate disability, and highly active MS (at least two relapses in the past year despite disease modifying therapy). Participants were recruited from four centers in the US, Europe, and South America between 2005 and 2016. The trial was composed of 66% women, with a mean age of 36 years.

Researchers randomized 55 participants to nonmyeloablative autologous HSCT, which is also called “mini-transplant” and uses a patient’s own stem cells with less aggressive pre-treatment to decrease toxicity. The HSCT group received pre-transplant conditioning with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg). The study also assigned 55 participants to disease modifying therapy (DMT) with higher efficacy or from a different class than drugs taken in the last year. Median followup was 2 years.

Results showed that three patients in the HSCT experienced disease progression, while 34 in the DMT group did so. The HSCT group also had significantly longer median time to disease progression compared to DMT (HR, 0.07; 95%CI, 0.02-0.24; P < .001). Median time to clinically significant progression was 24 months in the DMT group and could not be calculated in the HSCT group because of too few events.

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Stem cell therapy for relapsing MS proves effective and safe, study finds

 

A new Intense Stem Cell Therapy known as HSCT has shown promising results during a clinical trial. However, experts give words of caution, saying that it might not work for everyone.

Stem cells might prove to be an important breakthrough for the treatment of multiple sclerosis, but the road to there might be a long and painful one.

A new clinical trial tried to explain this. During the trial, participants with multiple sclerosis (MS)
that were using nonmyeloablative hematopoietic stem cell transplantation (HSCT) showed better results than the participants on disease-modifying treatments (DMTs).

This randomized clinical trial is the first one of its kind, comparing HSCT to DMTs.

Researchers involved in this trial stated that a significant portion of participants on HSCT treatment was successful in slowing down the progression of the disease, in comparison with the participants that were using DMTs.

Out of 103 participants, only three (on HSCT) showed disease progression when compared to the 34 that were on DMTs. Because of this, the research team made a conclusion that HSCT is better at slowing down progression than DMTs, but pointed out that it is important to come up with the right type of patients that will be subjected to what has been shown to be a rigorous and somewhat dangerous therapy.

This study was led by Dr. Richard Burt, chief of immunotherapy and autoimmune diseases at the Northwestern Feinberg School of Medicine in Illinois.

Dr. Barbara Geisser, 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 had this to say on the matter: “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.”

A rigorous treatment

HSCT works by using chemotherapy in order to aid cells to “forget” they have MS. By doing this, the immune system is brought down to some quite vulnerable levels. The patient has to be hospitalized and treated with the greatest care.

Bruce Bebo, PhD, an executive vice president of research at the National Multiple Sclerosis Society said: “HSCT is not one therapy but a range of therapies from a more mild type of chemo to a stronger type. Dr. Burt practices a more mild form of chemotherapy — more mild form of immunosuppression — so the risks are lower.”

The participants of the trial had relapsing MS, characterized with mild to moderate disabilities, with a range of 2 to 6 on the Expanded Disability Status Scale (EDSS).

Bebo said: “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,” adding that “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 further continued to explain the difficulty of this study in performance, and elaborated on how Burt and his team were able to create an unbiased way to make a comparison between HSCT and DMTs, by way of excluding ocrelizumab and alemtuzumab.

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Greater Benefits for Relapsing-Remitting MS Found with HSCT Therapy

Lesion load, disability improved for relapsing patients with highly active MS.

Stem cell transplantation was more effective than disease-modifying therapy (DMT) for patients with highly active relapsing-remitting multiple sclerosis (MS), a randomized clinical trial showed.

Over a median follow-up of 2 years, only three of 55 patients treated with non-myeloablative autologous hematopoietic stem cell transplantation (HSCT) had disease progression, compared with 34 of 55 patients on medication, according to Richard Burt, MD, of the Northwestern University Feinberg School of Medicine in Chicago, and colleagues.

Mean disability level improved in the HCST group during the first year, but worsened in the disease-modifying therapy (DMT) group, they reported in JAMA.

“This is the first randomized trial in relapsing-remitting MS patients of hematopoietic stem cell transplantation versus best-available DMT,” Burt told MedPage Today. “You need to look at the group we treated — they had aggressively relapsing MS with moderate disability — and the results were much better than standard drug therapies.”

Two newer drugs were not included in the study, Burt noted: ocrelizumab (Ocrevus), which had not been approved during the study enrollment period, and alemtuzumab (Lemtrada), due to the autoimmune effects it has been associated with. “Because we had a built-in cross-over in the study, we didn’t know what effect alemtuzumab might have if these patients crossed over to transplant,” he said.

The trial included 110 patients with relapsing-remitting MS who had at least two relapses while receiving drug treatment in the prior year. These patients had an Expanded Disability Status Scale (EDSS) score of 2.0 to 6.0 (EDSS scores range from 0-10, with 10=worst neurologic disability) and were randomized at 4 U.S., European, and South American centers from 2005 to 2016. Mean age was 36 years and 66% were female.

Patients in the stem cell transplantation group had a non-myeloablative regimen — a lower-dose, short course of more tolerable immune-specific chemotherapy and antibodies to suppress the immune system — and discontinued DMTs prior to the trial, with variable washout periods. Patients in the DMT group were treated with a mean of 1.3 different DMTs: 21 patients received natalizumab (Tysabri), 14 received dimethyl fumarate (Tecfidera), 14 received fingolimod (Gilenya), nine received glatiramer acetate (Copaxone), seven received interferon beta-1a (Rebif), six received mitoxantrone, and one received teriflunomide (Aubagio). Patients whose EDSS worsened with continued DMT treatment could cross over to the HSCT group.

The randomized clinical trial is the first to compare HSCT to DMTs.

During the first year, mean EDSS scores improved from 3.38 to 2.36 in the HSCT group and worsened from 3.31 to 3.98 in the DMT group (between-group mean difference -1.7, 95% CI -2.03 to -1.29, P<0.001).

Clinically significant disease progression also occurred much less frequently in the HSCT-treated group than the DMT-treated group (HR 0.07, 95% CI 0.02-0.24). Rates of disease progression at 1 year were 1.92% in the HSCT group and 24.5% in the DMT group. At 5 years, they were 9.71% in the HSCT group and 75.3% in the DMT group.

The HSCT group also had fewer relapses, improved MRI lesion load, a higher proportion of patients maintaining no evidence of disease activity, and a better quality of life. There were no deaths, and no patients who received HSCT developed non-hematopoietic grade 4 toxicities, such as myocardial infarction, sepsis, or other disabling or potential life-threatening events.

“Most comparative trials between DMTs measure benefit as a slowing of MS manifestations; this trial showed a global improvement over time in the mean level of disability and MRI lesion load in the HSCT-treated group while deterioration occurred in the DMT-treated group,” noted Harold Atkins, MD, of the University of Ottawa, in an accompanying editorial.

“Despite the positive results, several aspects of this trial deserve comment,” Atkins observed. While chemotherapy doses used in this study resulted in less severe toxicity than doses used for other malignant diseases, many patients experienced moderate to severe acute toxicity soon after HSCT, he stated. No treatment-related mortality was reported here or in other published cohorts of HSCT for MS performed in this manner, but “caution in patient selection remains warranted, as deaths have been reported using the same HSCT procedure in other autoimmune diseases,” he wrote.

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Stem cell therapy for relapsing MS proves effective and safe, study finds

(CNN)-An experimental stem cell therapy proved effective and safe in patients with a relapsing form of multiple sclerosis , an autoimmune disease that affects the central nervous system, new research finds.

A stem cell transplant using a lower-dose regimen of chemotherapy plus immune system suppressors is more effective at preventing disease progression compared to currently used disease-modifying therapies, according to the new study published Tuesday in the journal JAMA. (The stem cell treatment is known as “autologous hematopoietic stem cell transplantation” or HSCT.)

“I never use the word ‘cure’ — never,” said Dr. Richard K. Burt, lead author of the study and chief of Immunotherapy and Autoimmune Diseases at Northwestern University Feinberg School of Medicine in Chicago. However, only a minority of patients receiving HSCT relapse by the five year mark, he said. “The vast majority don’t.”

How does this experimental stem cell therapy work?

HSCT essentially reboots the immune system.

HSCT India“Out with the old, in with the new” is the goal, said Burt, adding that it is a “one-time treatment. You’re done, you’re off drugs.” First a patient’s blood stem cells are collected and then the patient is treated with chemotherapy drugs. Then, blood stem cells are returned to the patient to jump start the development of a new immune system.

In contrast, disease-modifying therapies work differently. These are a dozen or more drugs designed to be chronic, continuous treatment that targets and modulates the immune system. The new comparison study took place at medical centers in the US, UK, Sweden and Brazil, where 110 patients with relapsing-remitting MS participated in the randomized clinical trial, a gold standard medical test. Patients received either the HSCT protocol or a different class of disease-modifying therapy than they’d previously used.

HSCT proved to be the more effective treatment: Of 55 patients receiving HSCT, only three patients showed disease progression at one year, the study showed. Yet, 34 of 55 patients in the disease-modifying therapy group showed disease progression at one year. Disease progression was measured using the Expanded Disability Status Scale, a method for monitoring changes in symptoms over time.

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Among the HSCT group, the proportion of patients with disease progression was (roughly) 2% up to two years, 5% at three years, and 10% at 4 and 5 years. Meanwhile, the proportion of patients with no evidence of disease — defined as no progression, no relapses, and no new or enlarging lesions on MRI scans — was (nearly) 98% at one year, 93% at two years, 90% at three years, and 78% at four and five years.

By contrast, almost one quarter of the patients in the disease-modifying therapy group showed disease progression at one year, more than half at two years, and just under three-quarters at five years. And the proportion of patients with no evidence of disease was (about) 40% at six months, 21% at one year and 3% by years four and five.

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What are the side effects of HSCT?

Side effects of HSCT can include infertility, said Burt, who noted that women can choose to preserve their eggs before treatment. And some patients developed autoimmune thyroid disease, a treatable condition. He noted that the disease-modifying treatments also have side effects.

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Australian AHSCT Trial Results Released.

– The results of an observational study of 35 people with relapsing-remitting and secondary progressive MS who received the treatment in Sydney have just been released.

– Autologous haematopoietic stem cell therapy (AHSCT) uses a combination of chemotherapy and reinfusion of blood stem cells to rebuild and reset the immune system.

– In this study, 60% showed no evidence of disease activity for three years after the treatment and 13 participants showed improvements in their disability scores. 8 people had continued disability progression during the follow-up period.

– Immune cell analysis showed that after one year, attacking immune cells were still wiped out by AHSCT but cells that regulate the immune system were restored.


A Sydney team have published results from their study of Autologous Haematopoietic Stem Cell Therapy (AHSCT) in people with relapsing-remitting and secondary progressive MS.

AHSCT has been under investigation, worldwide and in Australia, as a treatment option for MS using different protocols and in different types of MS. Good results have been seen for many people with relapsing MS however, it is also a treatment with high risks and international clinical trials and studies have shown that it is not effective or suitable for everyone with MS.

AHSCT aims to reset the immune system using chemotherapy to wipe out most or all the immune cells and then the individual’s own blood stem cells are reinfused to rebuild the immune system. The hope is that the treatment puts MS into remission.

Researchers and clinicians at St Vincent’s Hospital in Sydney have been conducting a study of the treatment since 2010. Their results have been published in the Journal of Neurology, Neurosurgery and Psychiatry. The study included 20 people with relapsing-remitting MS and 15 people with secondary progressive MS, who have now been followed for an average of 3 years following the treatment.

This study used the “BEAM” chemotherapy protocol, which completely removes the immune system and is the one most commonly used in people with MS around the world, but with limited published clinical trial results.

Participants in this study had levels of disability that ranged from low to moderately severe (disability scores between 2 and 7 as measured by the expanded disability status score (EDSS)) and had failed to respond to at least two previous therapies for MS, including two thirds who had failed on natalizumab, a high potency MS medication.

The researchers tracked evidence of disease activity via relapses, brain lesions on magnetic resonance imaging (MRI) and disability progression. In this group of people with MS, 60% showed no evidence of disease activity for up to three years after the treatment. In the people with relapsing-remitting MS, the result was higher, with 70% showing no disease activity. 73% of participants had no disability progression during the follow-up period. In fact, 13 participants had improvements in their EDSS disability score of an average of 1.4 points – all but one of these had relapsing-remitting MS. However, eight participants had their disease continue to progress during the follow-up period, two with relapsing-remitting MS and six with secondary progressive MS.

83% of participants had no new or enlarging lesions at their last MRI scan and 96% showed no active lesions.

Participants experienced the expected side effects of high dose chemotherapy, including ulcers in the digestive tract, nausea and hair loss. One third required red blood cell transfusions and a half required platelet transfusions during their hospital stay. No-one died as a result of the treatment in this study which is in keeping with recent international AHSCT outcomes for people with MS receiving medium intensity chemotherapy where the treatment is provided at an experienced hospital centre

An important part of this study was the work conducted by MS Research Australia-funded PhD Student and clinician, Dr Jennifer Massey, who looked at the profile of immune cells in patients following the treatment. This work showed that the attacking types of T immune cell were still wiped out and that there was a sustained rise in other immune cells that work to calm and regulate the immune system. By comparison, these changes were not seen in patients who received the same AHSCT for lymphoma. This suggests that in people with MS, AHSCT may work by turning off the attacks as well as restoring the immune system’s ability to regulate itself. These results may help us work out how to better treat MS without needing to use intensive chemotherapy treatments.

This study shows that AHSCT can provide good outcomes for people with relapsing MS who do not respond to other types of MS treatments. The results are similar to those seen in other international studies and confirm that people with relapsing-remitting MS respond better to AHSCT than those with secondary progressive MS.

Each person’s situation is unique and decisions about any MS treatments, taking into consideration the potential benefits, risks and side effects, should be made in careful consultation with your medical team. A small number of Australian hospitals are currently providing this treatment for people with MS, but can only do so for patients who have failed to respond to other MS therapies and with a referral from a neurologist.

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