1. D R E L I S I L B E R
K I N G S C O L L E G E H O S P I TA L
HSCT FOR MS: THE LONDON EXPERIENCE
2. MIXTURE OF INFLAMMATION AND
DEGENERATION
• There is a window of opportunity
• Inflammation drives degeneration both due to relapses, silent lesions and in
NAWM
3. ALL DMT’S TO DATE WORK BY REDUCING THE IMMUNE
RESPONSE TO A GREATER OR LESSER DEGREE
Safety
Beta interferon
Copaxone
Nil
Natalizumab JCV +ve
Alemtuzumab
Mitoxantrone
Fingolimod
DMF
Natalizumab
If JCV -ve
Teriflunomide
0% 30% 50% 70%
Ocriluzimab
HSCT
Cladribine
4. AHSCT IN MS
• AHSCT confers benefits for patients with MS by achieving radical suppression of inflammatory MS
activity with qualitative changes in the reconstituted immune system (leads to a change in an individuals
immune cell profile)
• Complete suppression of MS disease activity for 4–5 years has been documented in 70–80% of patients
with RRMS Post AHSCT; neurological improvements have also been demonstrated
• Optimal candidates for AHSCT based on meta-analyses are/have:
• Young
• Ambulatory (EDSS<6.0)
• A high frequency of relapses
• MRI markers of inflammation
• Shorter disease duration
Muraro et al (2017) Nat.Rev.Neurol
8. HOW MAY HSCT WORK
Immune suppression
• Replacement of autoreactive immune
cells
• Down regulation of immune response
? Non-immunosuppressive
• Trophic factors
• Promotion of remyelination
9. THE NUMBER OF CENTRES TREATING AND THE NUMBER OF PATIENTS
BEING TREATED IS INCREASING (THIS EXCLUDES THOSE SITES THAT ARE NOT SHARING DATA)
10.
11.
12. AHSCT STUDY DESIGNS
Study Design N= Disease
course
Follow up
Yrs (range)
Conditioning regimen etc Deaths
Italian
experience
Uncontrolled case series 74 RR/SP 4
(0.6-10.5)
Intermed
(BEAM/ATG)
3
Swedish
experience
Uncontrolled, prospective
case series
48 RR/SP/P
P
4 (3-8) Intermed
(BEAM/ATG)
0
ASTIMS Randomised, open label,
active control phase 11,
worsening EDSS and
Gd+on therapy
21 RR/SP 4 High
(cyc,fil/car,cytetopmelp,ATG)
or Mitox 20mg/month
0
HALT-MS Uncontrolled,, prospective,
open label, single arm
phase 11, worsening EDSS
on therapy
24 RR 3.6
(?)
High
(carm,etop,cytar,ATG)
CD34 selected
2
(+2suicide
attempt)
NWU Case
series
Uncontrolled case series
(outcome on 148)
151 RR/SP/P
P
2
(0.7-22.0)
Low/Intermed
(cyc,filg,alem,ATG)
0?
(1lymphoma)
Canadian
phase 2
Uncontrolled phase 11,
poor prognosis
24 RR 6.7
(3.9-12.7)
High
(cyc,bus,ATG)
CD34 selected
1
TRM: High 4.3%; Intermed/low 1.1%
Burman J JNNP 2014, Mancardi GL Neurology 2015, Nash RA JAMA 2015, Burt RK JAMA 2015, Atkins Lancet 2016, Mancardi MSJ 2012
16. HISTORY – AHSCT IN LONDON
• Ad hoc - compassionate use
• Formalised
• MDT
• Treatment criteria
• Audit (retrospective and prospective) – supported by MS trust
• Centres
• King’s
• Imperial (Charing X and Hammersmith)
• Now also Royal London, UCH/Queen Square
20. BASELINE CHARACTERISTICS:
PREVIOUS DMT USE
Previously used N (%)
Any highly active
DMT
64 (71.1)
Natalizumab 52 (57.8)
Alemtuzumab 19 (21.1)
Natalizumab
AND
Alemtuzumab
12 (13.3)
Mitoxantrone 7 (7.8)
• Excluding those with PPMS – although one patient did receive fingolimod
as part of clinical trial
22. BASELINE CHARACTERISTICS:
DISEASE ACTIVITY
• Time from diagnosis to HSCT
• Mean – 9 years
• Median - 9 years (1 – 29)
• Relapses in 2 years prior to HSCT
• RRMS only Mean – 0.93
• RRMS + SPMS Mean - 0.91
• MRI lesions pre-transplant
• New lesions on MRI pre-transplant – 85 (74.6%)
• Enhancing lesions – 47 (41.2%)
23. OUTCOMES: CUT OFF
• Data presented for all patients who had been transplanted as of Jan 2017 – 54 patients
• Median follow up time: 23 months (6 – 48)
• Data for all those transplanted up until November 2017 currently being analysed
26. COMPLICATIONS
• 4 ITU admissions - median length of stay (LOS): 4 days (3 – 8)
• Median total hospital LOS for AHSCT procedure: 22 days (17 – 81)
• 12 re-admissions post-transplant with median LOS: 9 days (3 – 119)
• No deaths in these 54 patients
• However, there have subsequently been 3 deaths in patients who have undergone HSCT
• 2 considered treatment related mortalities (TRM) – one developed pulmonary oedema and acute respiratory distress
syndrome and died following a stay in ITU. The other died suddenly – likely cardiac
• Third death was many months post therapy
• Treatment related mortality rate overall – 1.75%
27. RELAPSES
Of those with RMS, 5
of 30 (16.7%)
experienced
symptoms consistent
with a clinical relapse
post-AHSCT –
steroids were
prescribed for all of
these events
Median time to 1st
relapse for these
patients: 11 months
(6 – 12)
28. DISABILITY PROGRESSION
• 8 of 54 (14.8%) patients experienced disability progression across the entire cohort post-AHSCT with
a median time to disability progression in these patients of 8 months (3 – 25)
• 86% of patients were free from disability progression at 24 months
• 82% of patients were free from disability progression at 36 and 48 months
• 3 patients with RMS (10%) experienced disability progression
• 5 patients with PMS (20.1%) experienced disability progression
• No significant difference in progression free survival times between the RMS and PMS groups (log
rank test p=0.243)
29. DISABILITY PROGRESSION: TOTAL
Disability progression was defined as a sustained EDSS increase of 1 point for patients with baseline EDSS ≤
5.5 and 0.5 points if baseline EDSS ≥ 6
30. DISABILITY PROGRESSION: BY SUBTYPE
Disability progression was defined as a sustained EDSS increase of 1 point for patients with baseline EDSS ≤
5.5 and 0.5 points if baseline EDSS ≥ 6
31. MRI LESIONS
• 5 of 54 (9.3%) patients developed new enhancing or T2 lesions post-AHSCT with a median
time to 1st lesion for these patients of 6 months (5 – 24)
• 3 patients with RMS (10%) developed new MRI lesions – 2 of these patients experienced
symptoms consistent with a clinical relapse
• 2 patients with PMS (8.3%) developed new MRI lesions
34. CONCLUSION FROM LONDON HSCT DATA
• In this non-trial setting with a heterogenous patient population, outcomes following AHSCT
with respect to subsequent relapses, disability progression and development of new MRI
lesions were consistent with previously reported cohorts
• Longer follow up is required to see if treatment responses are maintained
• AHSCT warrants ongoing investigation as a treatment option in highly active relapsing MS
as well as in progressive disease with disease activity
35. IS HSCT SUPERIOR TO EXISTING DISEASE MODIFYING IMMUNE
THERAPIES?
36.
37.
38.
39. NEW TRIALS IN RR MS
•BEAT MS
• Multinational NIHR funded
• HSCT vs. best available
•STAR-MS
• Multiple UK sites
• HSCT vs. Alemtuzumab
40. WHAT ABOUT PROGRESSIVE MS?
• Hope vs. nihilism
• Saving upper limbs?
• Immune modulating/ suppressant
• Non-immune Biotin?
• Appropriate selection
• Recent onset
• Lower disability
• Evidence of clinical or radiological activity
41. IS HSCT HELPFUL IN PROGRESSIVE MS?
Results Valid data were obtained from 25 centres in 13 countries for 281 evaluable patients, with median follow-up of
6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median
EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI,
1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The
5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and
overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after
transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33;
95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline
EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
Conclusions and Relevance In this observational study of patients with MS treated with AHSCT, almost half of them
remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer
prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results
support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
Treatment criteria – have been evolving – important to note that not all patients treated under same criteria
Retrospective data – have been collecting prospective data for almost a year
Total - 54
8 of 54 (14.8%) patients experienced disability progression across the entire cohort post-AHSCT with a median time to disability progression in these patients of 8 months (3 – 25)
86% of patients were free from disability progression at 24 months
82% of patients were free from disability progression at 36 and 48 months
3 patients with RMS (10%) experienced disability progression
5 patients with PMS (20.1%) experienced disability progression
There was not a significant difference in progression free survival times between the RMS and PMS groups (log rank test p=0.243)
8 of 54 (14.8%) patients experienced disability progression across the entire cohort post-AHSCT with a median time to disability progression in these patients of 8 months (3 – 25)
86% of patients were free from disability progression at 24 months
82% of patients were free from disability progression at 36 and 48 months
3 patients with RMS (10%) experienced disability progression
5 patients with PMS (20.1%) experienced disability progression
There was not a significant difference in progression free survival times between the RMS and PMS groups (log rank test p=0.243)