written by Dr. Armistead Williams

A new report from an annual meeting of hematologists showed positive results for using hematopoietic stem cell transplantation (AHSCT) to treat relapsing-remitting MS. The results reflect what we already know about AHSCT: that it is highly effective in relapsing-remitting MS, but they don’t tell us whether this risky therapy is superior to the highly effective therapies available today.

The words “stem cell therapy” can be confusing because there are two very different categories of stem cell treatments. AHSCT is a therapy used for the past 20 years in MS. In this procedure, doctors give combination chemotherapy to destroy the immune system and then give stem cells to build the destroyed bone marrow. This is different than stem cells being investigated to promote neurological repair, as we are studying in our phase II stem cell trial.

This trial took 110 patients with highly active relapsing-remitting MS randomized them to continue drug therapy or to undergo AHSCT. These patients had 2 or more relapses in the year before the trial. After a mean of 3 years, 60% of patients on medication failed versus 6% of those who received AHSCT. In addition, on average the disability improved for those who received AHSCT vs a worsening for those who continued therapy. The results are from mid-way through the trial and were released as an abstract, not a full published paper.

We interpret these results with skepticism and would not recommend this therapy for our patients. The majority of those randomized to receive drug therapy were given relatively mild MS medications including Copaxone, Beta interferon, Tecfidera or Gilenya with only a minority receiving Tysabri. The full methods were not discussed in the abstract but it appears these highly active relapsing-remitting patients continued to take the very drug they were failing and were not put on a highly effective therapy or changed to another highly effective therapy. The trial reports that patients on AHSCT improved but this is what we expect if we give a highly effective therapy to someone with moderate disability and highly inflammatory disease. This trial does not prove that AHSCT is superior to highly effective MS therapy.

The promise of AHSCT has been that it might “cure MS” or eliminate the need for ongoing therapy but this still hasn’t been proven after 20 years of use in MS. The short-term benefits in this trial are very appealing however a meta-analysis of 15 AHSCT trials published in Neurology in 2017 showed that 30% of AHSCT recipients had disease activity by 4 years. We also know from previous trials that this therapy is ineffective for most people with progressive MS. We also need to know the long-term risks of this intervention. The short-term mortality risk used to be 1% per year but that up-front risk has improved with new procedures but the long-term risk is not known.

Each successful trial is a reason for optimism and brings us further along in understanding MS biology. We still have room to improve. Where can we go from the “immune ablation of AHSCT”? AHSCT fails to eliminate oligoclonal bands in the spinal fluid and this brain compartment of MS immune response may not be effectively treated by AHSCT.

Abstract

SS2-8 - NON-MYELOABLATIVE HAEMATOPOIETIC STEM CELL TRANSPLANTATION VERSUS CONTINUED DISEASE MODIFYING THERAPIES (DMT) IN PATIENTS WITH HIGHLY ACTIVE RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS)

Richard K Burt1, Roumen Balabanov2, John A Snowden3, Basil Sharrack4, Maria Carolina Oliveira5, Flavia Nelson6, Joachim Burman7 1Northwestern University, Division of Immunotherapy for Autoimmune Diseases, Chicago, IL, United States; 2Northwestern University, Department of Neurology, Chicago, IL, United States; 3Sheffield Teaching Hospitals NHS Foundation Trust, Department of Haematology, Sheffield, United Kingdom; 4Sheffield Teaching Hospitals NHS Foundation Trust, Department of Neurology, Sheffield, United Kingdom; 5University of São Paulo, Department of Internal Medicine, São Paulo, Brazil; 6University of Texas Health Science Center at Houston, Department of Neurology, Houston, TX, United States; 7Uppsala University, Department of Neuroscience, Uppsala, Sweden

Background: We previously reported (Journal of the American Medical Association, 2015) that non-myeloablative haematopoietic stem cell transplantation (HSCT) may be performed safely in patients with multiple sclerosis and is accompanied by long-term improvement in neurologic disability. We now report results on a randomized trial of non-myeloablative HSCT versus continued treatment with standard DMTs.

Methods: Patients on stable disease-modifying therapy (DMT) with > 2 relapses in the previous 12 months were randomized (1:1) to treatment with either cyclophosphamide and rabbit anti-thymocyte globulin followed by haematopoietic stem cell infusion or to a control arm with continued treatment with standard DMTs. Evaluating neurologists scoring the Expanded Disability Status Scale (EDSS) were blinded to treatment arms. Patients in the control arm who had 6 month confirmed EDSS increase of > 1 point despite at least one year of treatment (defined as treatment failure) were allowed to crossover to HSCT.

Results: 110 patients were randomized, 55 to each arm. Three HSCT patients were withdrawn: two for failing enrollment criteria, one for recurrent infections occurring before transplant. Five control patients were withdrawn after soliciting transplants at other centers. All patients are at least one-year post-enrollment. No deaths occurred and no CTC grade 4 non-hematopoietic toxicities occurred in the transplant arm. DMTs (number of patients) used in the control arm were: natalizumab (22), dimethyl fumarate (18), fingolimod (13) interferons (10), glatiramer acetate (8), mitoxantrone (5). During the first year after enrollment, one relapse occurred on the HSCT arm versus 39 on the DMT arm (P< 0.001). Mean EDSS improved from 3.5 to 2.4 after HSCT while it worsened from 3.3 to 3.9 on DMTs (P< 0.001). With a mean follow up of 3 years (range 1 to 5 years), treatment failure was 60% (30 of 50) for the control arm and 6% (3 of 52) for HSCT (P < 0.001). For the 30 patients who failed the control arm and crossed over to HSCT, by one year after HSCT, the mean EDSS improved from 5.2 to 2.6 (P< 0.001).

Conclusions: HSCT was statistically superior to continued DMTs in patients with RRMS with > 2 relapses a year

Clinical Trial Registry: NCT00273364, https://clinicaltrials.gov/ct2/show/NCT00273364

Conflict of interest: All the authors have nothing to disclose