No new relapses seen in single-arm study with new transplant protocol
A myeloablative protocol similar to those used in hematologic malignancies is feasible as a prelude to autologous hemapoietic stem cell transplantation (aHSCT) aimed at halting inflammatory activity in multiple sclerosis, researchers found.
In an uncontrolled study of 24 patients, 70% of those who had near-complete immunoablation with busuflan, cyclophosphamide, and rabbit anti-thymocyte globulin, followed by transplantation of autologous CD34-selected hemapoietic stem cell grafts, met the primary endpoint of activity-free survival at 3 years, according to Harold Atkins, MD, of The Ottawa Hospital, and colleagues.
There were no relapses and no gadolinium-enhancing lesions or new T2 lesions among all the patients who remained in the study, which had up to 13 years of follow up (median 6.7 years), they reported online in The Lancet.
One death occurred in the trial, giving the procedure a mortality rate of 4%, which is typical for stem cell transplant in this population.
But it is still “unacceptably high” and therefore the study findings probably won’t change practice, according to Jan Doerr, MD, of Charite-Universitatsmedizin in Berlin.
“Over the longer term and in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonized and optimized, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified,” Doerr wrote in an accompanying comment.
Results for stem cell transplantation to treat multiple sclerosis have varied, as different protocols are used. While other protocols diminish the immune system, this protocol completely wipes it out, the researchers explained. Then, only select immune cells that have been harvested from the patient are returned in hopes of rebuilding an immune system that doesn’t attack myelin — thought to be the cause of multiple sclerosis.
Atkins and colleagues conducted the phase II, single-arm study at three centers in Canada, enrolling 24 patients with MS, ages 18 to 50, all of whom had a very poor prognosis, with an EDSS score of 3.0 to 6.0.
One patient died from necrosis and sepsis caused by immunoablation, 21 completed 3-year follow-up, and 13 enrolled in the long-term extension study.
In addition to the 70% of patients who met the primary endpoint, no relapses occurred in any patients and there were no gadolinium-enhancing lesions or new T2 lesions during follow-up, which ranged from 4 to 13 years.
None of the patients went back on disease-modifying drugs during that time, the researchers said.
They also found that the rate of brain atrophy decreased relative to that expected for healthy controls, and 35% of patients had sustained improvements in their EDSS score.
In terms of side effects, 8 patients (33%) had a moderate toxic effect and 58% had only a mild toxic effect related to transplantation, they reported.
Atkins and colleagues called it the “first treatment for multiple sclerosis to fully halt all detectable CNS inflammatory activity for a long period in the absence of disease-modifying drugs.”
But they warned that their study was small and lacked a control group, so larger trials will be needed to confirm the results.
“The strength of these data lies in the careful selection of patients with aggressive inflammatory disease who were deemed to have a very poor prognosis and long prospectively planned follow-up with methodically collected outcome data from regularly scheduled clinical and MRI assessments,” they wrote.
Doerr wrote that the study distinguishes itself from other aHSCT trials with a similar number of patients because so many reached complete disease control — an effect likely explained by the “different aHSCT protocols and particularly the ex-vivo selection of CD34 cells,” he wrote.
But he noted that the study wasn’t controlled — “an important limitation” — and that it probably won’t change practice in the short-term. Instead, aHSCT should “remain restricted to specialized centers experienced in both multiple sclerosis and hemopoietic stem-cell treatment” and physicians should make all efforts to prevent stem-cell tourism.
He also called for integration of the various aHSCT studies in order to optimize protocols and procedures.
This study was funded by the Multiple Sclerosis Scientific Research Foundation.
Atkins disclosed financial relationships with Amgen Canada.
Doerr disclosed financial relationships with Bayer, Novartis, Allergan, Biogen, Genzyme, Merck-Serono, and Teva.
