by Tom Jenkins
For March 2019, we have selected: Burt RK Balabanov, MD Burman J, et al. Effect of nonmyeloablative haematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis. JAMA 2019;321(2):165-174.
Stem cells are a highly topical research area in clinical neurology. Approaches vary from attempts at nerve regeneration to exploitation of immunological effects. Our paper of the month reports an open label trial, assessing the effect of haematopoietic stem cell transplantation (HSCT), which seeks to harness the latter mechanism of action, in patients with relapsing-remitting multiple sclerosis (MS). Following cyclophosphamide induction, the authors propose that a “reset” of the immune system occurs after subsequent repopulation with autologous peripherally-harvested haematopoietic stem cells. Encouraging outcome data are presented.
The first author of this international multi-centre open label trial is based at Northwestern University in Chicago, USA, and the study was performed in collaboration with three other centres from Sheffield, UK, Uppsala, Sweden and Sao Paolo, Brazil. One hundred and ten patients with highly active relapsing-remitting MS and moderate disability scores were recruited over 11 years. Inclusion criteria were age 18-55 years, relapsing-remitting MS by standard McDonald criteria, with two or more clinical relapses (or one relapse and gadolinium enhancement at a separate timepoint) within 12 months despite treatment with an established disease-modifying therapy, and an Expanded Disability Status Score (EDSS) of 2-6 (mobile patients, at worst using one stick to walk). Exclusion criteria were progressive MS, hereditary neurological diseases, pregnancy, pulmonary, cardiac, renal or liver dysfunction, abnormal platelet or white cell counts, active infection, prior treatment with alemtuzumab (this was justified on the basis that persistent lymphopenia could increase risk in the setting of a HSCT) or mitoxantrone, use of natalizumab within the last 6 months, fingolimod within 3 months or persistent elevated teriflunomide levels despite cholestyramine treatment.
Patients were randomised either to HSCT or a disease-modifying therapy of higher efficacy or a different mechanism of action to their previous treatment, at the discretion of their treating neurologist. In this control group, additional treatment with steroids, rituximab, intravenous immunoglobulin or cyclophosphamide was allowed, but octrelizumab was not. After a year of treatment, patients in the disease-modifying therapy group were allowed to cross over to HSCT if they had experienced progression of disability.
In the HSCT group, disease-modifying therapies were discontinued and there was a washout period of 6 months for natalizumab, 3 months for fingolimod, and dimethyl fumarate, 4 months for rituximab, and treatment with either cholestyramine or charcoal clearance for teriflunomide. Interferon and glatiramer acetate were continued until initiation of HSCT. No other immune-based therapies were given after HSCT unless the patients experienced clinical relapse, or new lesions on MRI (the numbers in whom this was necessary were not reported).
Peripheral blood stem cells were collected 10 days after intravenous cyclophosphamide (2g/m2) and 5 days after subcutaneous filgrastim (5-10 micrograms/kg). Immune ablation was achieved with intravenous cyclophosphamide 50mg/kg from days -5 to -2 and rabbit antithymocyte globulin from days -5 to -1 before stem cell infusion on day zero. An oral tail of steroids was given from day zero to day 11. The median hospital stay was 10 days. Oral acyclovir was given for a year and trimethoprim-sulphamethoxazole or nebulised pentamidine for 3 months.
The primary outcome was time to MS-related disease progression, defined as worsening of EDSS by at least one point on two evaluations by a blinded neurologist six months apart after at least one year of treatment. Evaluations were postponed in cases of intercurrent fever/infection. To avoid unblinding of assessors, all study participants wore wigs at these evaluations. Secondary outcomes were survival, relapses (defined as new neurological symptoms >24 hours in absence of infection and requiring treatment with steroids), neurologic rating scale scores, MRI T2-weighted lesion volume, SF-36 quality of life questionnaire and MS functional composite scores. No evidence of disease activity (NEDA), defined as no clinical progression, no relapses and no MRI activity was added as a post-hoc outcome. Adverse events were graded according to established criteria.
Nine hundred and thirty six patients were evaluated, of whom 110 met inclusion criteria. Fifty five patients were randomised to each group. Use of interferon-1a was more common in the control group; there were no other between-group differences at baseline. Three patients in the HSCT group and 4 in the control group withdrew. Therapies given in the control group were natalizumab (21), dimethyl fumarate (14), fingolimod (14), glatiramer (9), interferon beta-1a (7), mitoxantrone (6) and teriflunomide (1), steroids (38), rituximab (2), and one each received plasmapheresis, cyclophosphamide and intravenous immunoglobulin.
EDSS worsened by at least one point in 3 patients in the HSCT group and in 34 in the control group after median follow-up of 2 years (mean 2.8 years). Mean EDSS improved by 1.02 points at 1 year in the HSCT group and worsened by 0.67 points in the control group. Median time to progression was not calculable in the HSCT group because too few events occurred. There were no deaths in either group. Results of relapse rates, EDSS disability scores, neurologic rating scale scores, SF-36 quality of life, MS functional composite scores, T2 lesion volume and proportion of patients with NEDA all favoured the HSCT group at 1 year. For relapses and NEDA, improvements appeared maintained in the smaller numbers with available follow-up to 4-5 years.
Three inpatient infections (one C difficile diarrhoea, one E.coli urinary tract infection and one culture-negative pneumonia) were reported in the HSCT group. Thirty one post-transplant infections occurred in the HSCT group and 25 in the control group. Two cases of idiopathic thrombocytopenic purpura occurred in the HSCT group, one of whom had also received fingolimod, and there were three cases of thyroid dysfunction, all in patients who had been previously treated with interferon.
The authors concluded that their first randomised trial of HSCT in relapsing-remitting MS showed prolonged time to disease progression, and the degree of improvement is the largest seen to date. Limitations include the relatively small numbers, inability to assess longer-term outcomes in the control group given the crossover study design, the non-inclusion of alemtuzumab as an active comparator, and the lack of masking for relapse evaluators. The pragmatic open label study design is less robust than a fully blinded placebo-controlled trial but the nature of the intervention makes inclusion of a sham control group practically difficult. The findings now need to be replicated and longer term outcomes assessed.
“This is a very exciting therapy. The improvements in EDSS score and NEDA data are unprecedented”, said Prof Basil Sharrack, Department of Neurology, Sheffield Institute for Translational Neuroscience (SITraN) University of Sheffield, who was one of the Principal Investigators at the UK trial site. “In addition, HSCT using this regimen appears safe, which had been a concern with some of the previous studies. Further work is now needed to define the place of HSCT in the armamentarium of the neurologist treating patients with MS”
Prof David B. Vodusek, Division of Neurology, University Medical Center Ljubljana, Slovenia commented: “This is a most promising work. It will be important that these safety and efficacy data are replicated in other patient populations and that long term outcomes are evaluated. It would be interesting to see a direct comparison with patients treated with alemtuzumab, and further work to determine the relative contributions of cyclophosphamide conditioning and the stem cells themselves to the observed therapeutic effect.”
The other nominees for March 2019 Paper of the month are:
- Verschuur CVM, Suwijn SR, Boel JA, et al, for the LEAP Study Group. Randomized delayed-start trial of levodopa in Parkinson’s disease. NEJM 2019;380:315-324. The potential effects of levodopa as disease-modifying drug was studied in this multicenter, double-blind, placebo controlled, delayed-start trial. A total of 445 patients with Parkinson’s disease were assigned to receive 100 mg levodopa TID as an early-start (222 patients followed for 80 weeks) or delayed-start (223 patients who had placebo for 40 weeks followed by levodopa for another 40 weeks). No differences were found between groups in the mean changes from baseline to week 80 in the UPDRS scores. Moreover, there were no differences in dyskinesia and motor fluctuations.
- The RIGHT-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based,randomised, sham-controlled, blinded, phase 3 trial. Lancet Neurology February 6, 2019. Doi.org/S0140-6736(19)30194-1. In this multicenter, ambulance-based, randomized, sham-controlled study, the authors analyzed the effects of early administration of transdermal nitroglycerine on post-stroke functional outcome. A total of 1,149 patients were recruited in UK. No differences in outcome was found between the nitroglycerine group (568) and the sham group (581) at 90 days.
- Hanley DF, Thompson RE, Rosenblum M, et al, for the MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet Neurol February 7, 2019. doi.org/10.1016/S0140-6736(19)30195-3. Functional outcome after minimally invasive catheter evacuation of supratentorial intracerebral hematomas of moderate to large size followed by thrombolysis (MISTIE) was assessed in this open-label, phase 3, multicenter trial. No differences were found between the 255 patients allocated to MISTIE and the 251 who received standard medical care.
- Connolly SJ, Crowther M, Eikelboom JW, et al., for the ANNEXA-4 Investigators. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM February 7, doi: 10.1056/NEJMoa1814051. A total of 325 patients with acute major bleeding (intracranial or gastrointestinal) were assessed after administration of the factor Xa inhibitor andexanet. Treatment could reduce anti-factor Xa activity and provide satisfactory hemostatic effect at 12 hours.