ARTICLE IN BRIEF
Three trials of stem cell transplants in aggressive forms of multiple sclerosis indicate that treatment can lead to long-term remission of disease activity, and may improve quality of life.
New results from three trials of stem cell transplants in aggressive forms of multiple sclerosis (MS) all indicate that treatment can lead to long-term remission of disease activity, and may improve quality of life. The results strengthen the call for a large randomized trial comparing transplantation to best medical therapy, according to experts, but that will require agreeing on an immunosuppressive regimen — an issue that sharply divides researchers.
The three trials differed in the degree of intended myeloablation and the drugs used, as well as patient population and other trial variables. One study was randomized, but compared transplantation against an immunosuppressive agent no longer in widespread use; the others had no comparator arm.
“This is a promising therapy, with the potential of changing the disease process,” said Richard Nash, MD, who led the High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) study, a multicenter, single-armed trial, whose findings were reported in the Dec. 29 online edition of JAMA Neurology.
HALT-MS enrolled patients with relapsing-remitting MS who had failed at least two approved medications, had an Expanded Disability Status Scale (EDSS) score between 3 and 5.5, and had experienced two or more relapses in the previous 18 months that were associated with a sustained worsening of disability. Patients received high-dose immunosuppression with multiple drugs, with a goal of ablating the blood- and immune-forming system. That treatment was followed by infusion of previously harvested autologous hematopoietic stem cells to regenerate the immune system. No further anti-MS treatments were given over the course of the study. Three-year results from this ongoing five-year trial were reported for 24 patients.
Virtually all patients experienced some type of adverse event, most commonly cytopenia or infection, which are also common in cancer patients treated with the same drugs. “The question was whether we would see any new neurological events in this population, and we did not,” said Dr. Nash, a hematologist at the Colorado Blood Cancer Institute at Presbyterian/Saint Luke's Hospital in Denver. “It was tolerated very well with respect to neurological status.”
The primary endpoint was time to treatment failure, defined as death from any cause, a sustained worsening of EDSS score of 0.5 points, a new neurologic sign or symptom lasting more than 48 hours, or two new MRI lesions after the first year of treatment.
Event-free survival was achieved by 78.4 percent of patients at the three-year time point. The median EDSS score improved by 0.5 points. Brain volume was decreased compared with baseline at six months post-treatment, but appeared to stabilize after that.
The only randomized trial to date, called Autologous Stem Cell Transplantation International Multiple Sclerosis (ASTIMS), was a multicenter trial that compared intense immunosuppression and hematopoietic stem cell transplantation (HSCT) with mitoxantrone. The details of the treatment regimen — reported in the Feb. 11 online edition of Neurology — differed from the HALT-MS trial, but the goal was the same — ablation of the hematopoietic system. But unlike that trial, enrollment was open to patients with the secondary-progressive form of the disease as well; two-thirds of enrolled patients were in this phase of disease. The primary endpoint was the number of new T2 lesions at four years after treatment. Twenty-one patients were randomized, and 17 patients were evaluated.
Patients receiving HSCT had a median of 2.5 new T2 lesions, versus eight in the mitoxantrone arm (rate ratio 0.21, p = 0.00016). No patients receiving HSCT had gadolinium-enhancing lesions at any time during follow-up, versus more than half of those taking mitoxantrone. There was no difference in outcomes by disease phase, although the number of patients was small.
There was also no significant difference between arms in disability scores, but study leader Luigi Mancardi, MD, of the University of Genova, Italy, noted that there were too few patients to properly evaluate this outcome. He said that the study was intended to be much larger, but most patients were reluctant to be treated with mitoxantrone, a powerful immunosuppressant that is no longer widely used in MS treatment.
Despite that limitation, he suggested that the magnitude of superiority of HSCT on imaging outcomes would likely mean a measurable difference in functional outcomes as well in a properly powered trial.
Richard Burt, MD, chief of the division of medicine-immunotherapy and autoimmune diseases at Northwestern University in Chicago, led the third trial, which differed in significant ways from the HALT-MS and ASTIMS trials. In this single-center, single-arm study reported in the Jan. 20 issue of JAMA, 123 patients with relapsing-remitting MS and 28 with secondary progressive MS who had failed at least one approved drug and had suffered relapses within the previous year received “nonmyeloablative” immune suppression followed by HSCT. They received no anti-MS drugs after treatment, and were followed for up to five years.
The goal of this milder treatment is not to destroy the hematopoietic tissue, but to stop inflammation. “Killing every last immune cell is a cancer concept. But immune cells aren't malignant entities,” Dr. Burt said. Once the inflammation is stopped, “you get regeneration of the immune system biased toward tolerance to self.”
Infections and cytopenia were the most common adverse events under this regimen, but were less common than with myeloablative treatment. Over the course of the multiyear study, treatment with alemtuzumab was discontinued in favor of antithymocyte globulin, which reduced the incidence of immune-mediated thrombocytopenia from 14 percent to 3 percent.
The primary endpoint for the study was a change in EDSS score by at least one point. The mean EDSS score fell from 4.1 at baseline to 3.0 after two years. Of the 81 patients with data at two years, 421 had improved by at least one point, 32 remained within a half point in either direction of baseline, and 9 had worsened by one point or more. Over longer-term follow-up, EDSS scores remained close to the two-year mean, albeit in diminishing numbers of patients. Imaging measures correlated with the observed clinical improvements.
SUPPORT FOR A RANDOMIZED TRIAL
The promising results from these trials, and from multiple other small trials and case series reported over the past decade, indicate it is time for a large randomized trial, all three investigators agreed. They suggested that the most likely patients to benefit were those still in the relapsing-remitting phase of disease who had failed one or more approved drugs.
Independent experts echoed the call for a new trial. Jeffrey Cohen, MD, a professor of neurology at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and director of the Mellen Center Experimental Therapeutics, said: “In these studies, the results seem very impressive. My main concern about the field in general is that we've seen a series of relatively small studies differing in methods of immunosuppression and follow-up. The field is still in need of a rigorously designed, randomized controlled trial against a contemporary potent therapy.”
The difficulty, said Mark Freedman, MD, a professor of neurology at the University of Ottawa and director of the Multiple Sclerosis Research Unit at Ottawa Hospital, is that there is little agreement among transplant researchers on the best immunosuppression regimen. A trial has been designed, but currently lacks funding, that would allow each center to compare its own preferred regimen to its own best medical therapy. Meanwhile, Dr. Burt is proceeding with a multicenter trial comparing his regimen to best medical therapy.
At his transplant center, Dr. Freedman uses an aggressive approach, believing the recurrence rates from non-ablative treatment are too high to justify the procedure. “We believe that if you are going to the extent of doing a bone marrow transplant, which is no small venture, you've got to pull out all stops. If all you are going to do is buy a few years, we've already got drugs that do that.” His results, which are likely to prompt yet more discussion in the field, are due out soon.
“I think stem cell transplantation is probably more potent than our commonly available therapies,” Dr. Cohen said. “But to get a better handle on the relative efficacy and safety profile, to determine where it is going to fit into the therapeutic sequence, that's what we are missing now.”
EXPERTS: ON STEM CELL THERAPIES FOR MS