You said Stop STAR-MS. I say No.

Y

 You said “STAR-MS trial to compare HSCT to alemtuzumab.”

Stop..it’s been done…published April 14, 2020….Autologous hematopoietic stem cell transplantation versus alemtuzumab in aggressive MS: a retrospective real-word study.

What does this mean. Well STAR-MS is a trial that ProfG mentioned many years ago and called it the Zeus trial. The idea is to put to bed the doubting minnies that HSCT is superior to other DMT in a randomised controlled trial. ProfBurt claimed to have done that but offered people non-depleting HSCT compared to MS DMT….HSCT won the battle, but people in the comparitor group were put on copaxone. In a head to head most more modern DMT would triumph in terms of effects on relapse rate over copaxone. If you were willing to take the risk of HSCT and you end up on copaxone there is something fishy. So the the STAR plans to put the big guns against HSCT.

The current study (below) shows why you need trials to put this to bed beyond doubt, because in the Italian study comparing alemtuzumab to HSCT the groups were not matched. The HSCT group was younger (they will do better than older), more active (so will respond to anti-inflammatories).

However will the STAR-MS trial change the result. YES.

I think not in terms of the efficacy because if you can read, you can see the 46% NEDA is about exactly what was got in the CARE-MS trials with alemtuzumab and the 71% NEDA (no evident disease activity) in the HSCT group is exactly what has been shown in a number of HSCT trials.

So after a £2.5 million pound trial you will get the result that alemtuzumab is associated with more secondary autoimmunities and a NEDA rate of 50% and HSCT I suspect will better. It is surely a biological no brainer if you remove the immune system things will work better than depleting the immune system partially. Now we are in 2020 and I have to say if you look on the NIHR website the trial was supported in 2017. Things have changed since then. Alemtuzumab which was the natural challenger to HSCT has not got a black mark against it, with the development of strokes and ocrelizumab is the likely contender. Do a delay there and now COVID-19 and another delay as HSCT is not being done.

So how will the result change things. First 180 get the option of a highly active treatment. I doubt the end result is in doubt but the game changer comes when the safety is found to be acceptable, If it is then all the neurologists feeing people into that trial will be more comfortable with the result, so the change is familiarity and confidence.

The original trial is here

AIMS: 1. To determine whether autologous haematopoietic stem cell transplantation (aHSCT) has superior clinical efficacy to highly effective Disease Modifying Therapy (DMT; Alemtuzumab or Ocrelizumab) with acceptable safety profile, in patients with relapsing remitting multiple sclerosis (RRMS) who continued to relapse on first line DMT.

2. To advance understanding of mechanisms of action of aHSCT by hypothesis-driven laboratory studies.

B. DESIGN: Multicentre parallel-group rater-blinded RCT

C. POPULATION: patients with RRMS with 2 or more relapses, or 1 relapse and evidence of MRI activity at a separate time point, in the preceding 12 months despite being on first line DMT, age 16-55, EDSS 0-6.0 (EDSS 0-1.5 must be accompanied by poor prognosis, EDSS 6.0 must be due to relapse rather than progressive disease), clinically stable for >30 days following last relapse. Exclusion of primary or secondary progressive MS, disease duration >10 years, previous treatment with Alemtuzumab, Ocrelizumab, Cladribine or aHSCT, or specific medical co-morbidity.

D. INTERVENTIONS: Investigative arm: aHSCT (Cyclophosphamide 2g/m2 mobilization and harvest followed by Cy/ATG followed by unselected autologous graft); patients will otherwise receive routine standard of supportive care according to EBMT and IDSA guidelines (2.42). Comparator: Alemtuzumab or Ocrelizumab, depending on current guidelines and clinician/participant preference, given and monitored as per licence.

E. PRIMARY OUTCOME: Maintained No Evidence of Disease Activity (NEDA, 14) at 2 years. SECONDARY & EXPLORATORY OUTCOMES:

1) SAFETY i) Serious adverse events ii) mortality rate iii) combined grade 4 and 5 SAE rates iv) number of SAEs per participant in the 100 days post-randomisation v) total number of adverse events vi) long term safety events to 2 years

2) DISABILITY: Patient and physician outcome measures.

3) Quality of Life (QoL)/Health Economic measures.

F. ASSESSMENTS: Patients will be assessed for eligibility at a baseline visit (BLV) & followed up with clinical & safety assessments at 3,6,9,12,18 and 24 months (m) post randomisation, MRI (BLV,6,12 & 24m), pulmonary function & cardiovascular effects (BLV,12 & 24m), disability assessments & QoL evaluations (at BLV,3,6,9,12,18 & 24m). We will collect blood samples (all visits) for the mechanistic study. (Ongoing data will be recorded for aHSCT participants via routine EBMT registry follow up with analysis subject to additional funding and support).

G. SAMPLE SIZE & STATISTICAL ANALYSIS: Primary outcome is No Evidence of Disease Activity (NEDA) at 2 years. Assuming 40% NEDA in the control arm, and that an absolute increase of 25% to 65% NEDA is of clinical importance [see changes from first stage for justification], to have 90% power to detect this difference at the 5% (two-sided) level 90 patients per group are required (180 in total). Adjusting for a predicted drop-out rate of 10%, the project aims to recruit 198 patients. Statistical analysis will be performed on an intention-to-treat-basis and reported according to CONSORT guidelines (50).

NEDA (14), will be compared between the two groups (Control & aHSCT).

H. DURATION & RECRUITMENT RATE: 66m project: 12m set-up; 24m recruitment (incl. 6m internal pilot to test recruitment feasibility); 24m follow-up; 6m close-out, analysis & write-up. Recruitment window based on availability of eligible participants at 19 centres & adjusted for capacity of sites to deliver aHSCT procedure/likely refusal rate (all sites confirmed recruitment rate 8-10 pts/site/yr achievable) i.e. a rate of around 1.25 patients/month at anchor sites or 0.5 patients/month at other sites.

I. ECONOMIC BENEFIT:The one off cost of aHSCT is approx. £30,000. The cost for a 2 year course of Alemtuzumab is approx. £70,000 (with additional yearly dosing for emerging disease activity), and the cost for a 2 year course of Ocrelizumab is approx. £38,000; therefore the potential cost saving to the NHS is significant.

The AAN 2020 study is here

Autologous hematopoietic stem cell transplantation versus alemtuzumab in aggressive MS: a retrospective real-word study (4096) Caterina Lapucci, Giacomo Boffa, Elvira Sbragia, Elisabetta Capello, Daniela Currò, Alice Laroni, Luca Roccatagliata, Antonio Uccelli, Francesca Gualandi, Giovanni Luigi Mancardi, Matilde Inglese. Neurology 2020; 94 (15 Supplement):4096.

Objective: To evaluate efficacy and safety of series of aggressive relapsing-remitting (RR) MS patients treated with aHSCT and alemtuzumab in a single Italian MS center and followed for 3 years.

Background: Aggressive multiple sclerosis (MS) represents almost 10% of all MS cases. Treatment of these patients is challenging and optimal strategies have yet to be defined. Alemtuzumab and autologous hematopoietic stem cells transplantation (aHSCT) represent ideal candidates for managing aggressive MS because of their profound and immediate immune-ablative effects. However, experience is limited and uncertainty remains on correct patient selection.

Design/Methods: 61 patients with aggressive MS, according to the criteria of Rush et al. [CA Rush et al. Nat Rev Neurol 2015], were retrospectively collected from the MS center of Genova. 32 patients underwent treatment with alemtuzumab and 29 with aHSCT (conditioning regimen: carmustine/etoposide/ara-C/melphalan (BEAM) or cyclophosphamide). The proportion of patients with complete disease remission (no evidence of activity -NEDA-) was calculated at 3 years.

Results: At baseline, aHSCT patients were younger than alemtuzumab patients (t=2.16; p=0.035), had higher EDSS (Mann-Whitney U=106; p<0.001) and more active MRI scans (Fisher exact test=12.63; p=0.001) with a higher number of baseline T1-gadolinium enhancing lesions (Mann-Whitney U=100; p<0.001). Proportion of patients achieving NEDA at 3 years was 70.8% and 46.1% for the aHSCT and alemtuzumab group, respectively. Relapses occurred more frequently in the alemtuzumab group (p<0,001). The interaction treatment × time in RM-ANCOVA showed a significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab (mean difference [95% CI]= 2.15 [1.24–3.05], p<0.001). Early adverse events were more frequent in the aHSCT group, while late adverse events, especially autoimmune disorders, were more frequent in the alemtuzumab group (p< 0.001).

Conclusions: Intense immunosuppression followed by aHSCT is superior to alemtuzumab in reducing relapses and MRI activity in aggressive MS and promotes disability improvement.

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