Haematopoietic stem cell transplantation in MS

jan fagius, neurologkliniken Haematopoietic ti stem cell transplantation in MS Living with MS: Today and tomorrow, Göteborg Oct 12, 2010 Jan Fagius, Dept of Neurology Akademiska sjukhuset / University Hospital Uppsala, Sweden

jan fagius, neurologkliniken Haematopoietic stem cell transplantation, HSCT Leukaemia patients with autoimmun disease treated dby HSCT show long time remission of AID. EAE (animal model of MS) strongly improved dby HSCT Uppgrading g of the immune system - but what happens?: repair of immunological imbalance total (?) () elimination of autoreactive lymfocytes y In theory a way to cure MS?!? (Hintzen, Mult Scler 8:155, 2002) If so, must be performed before parts of CNS are irreversibly damaged, i.e. early treatment emphasized as always in MS

The importance of early treatment

HSCT in autoimmune disease Animal studies allogeneic (syngeneic), since around 1980 autologous since around 1990 EAE early 90s (Burt et al 1995) Patient treatments allogeneic for AID - too dangerous! autologous 1995 - first attempt jan fagius, neurologkliniken 1996 European Blood and Marrow Transplant (EBMT) Working Party for Autoimmune Disorders

1. Mobilisation Cyclophosphamide and G-CSF; bone marrow cells exit to circulation 2. Cell harvest after 10 days leukapheresis HCST, procedure 3. Conditioning therapy kill the immune system myelo- / immunoablation cytotoxic treatment (chemotherapy, radiation, antibodies) 4. Reinfusion of stem cells / (purging) one week later. Anti-thymocyte globulin, ATG The stem cells start to produce The stem cells start to produce a new, purified immune system 1 2 3 4

jan fagius, neurologkliniken Our first patient t Woman aged 31, healthy. Sept 2003 facial palsy; recovered Dec weakness one leg, marked fatigue, recovered January 2004 unsteady gait Januari bilateral optic neuritis. MRI MS February subtotal paraparesis, urinary bladder paresis Steroids, vision och leg function improved, able to go March right hemiparis, total paraparesis. Steroids 0 effect Two weeks later tetraparesis; EDSS 9,0 Intense plasmapheresis, arms improved To our hospital April 2004, EDSS 8,0

8 10 12 10 9 8 7 E D S S 6 5 S 4 3 2 1 0 Patient no 1, woamn 32 år, HSCT MAY2004 IB -14-12 -10-8 -6-4 -2 0 2 4 6 Months before and after HSCT -16-18

jan fagius, neurologkliniken HSCT Procedure Dept of Haematology, Uppsala: (Ova / sperm saving; heart & thyroid function) Mobilisation Cyclophosphamide + G-CSF (Neupogen) Harvest 10 days Conditioning, myeloablation y BEAM BCNU, etoposide, cytosine-arabinoside, melphalan) Reinfusion day 6-7 ATG, antithymocyte globulin

15 pts (10 women) having undergone HSCT; Sept -10 ~10 relapses/8 mo 0 relapse/77 mo 8 relapses /10 mo 0 relapse/71 mo 14 relapses /11 mo 0 relapse/65 mo 7 relapses /6 mo 0 relapse/64 mo 10 relapses /10 mo 1 relapse/59 mo 6 relapses /7 mo 0 relapse/56 mo 6 severe relapses /4 mo 0 relapse/71 mo Totally 99 relapses/158 patient mo 3 relapses/695 patient mo 10 9 8 4 patients on EDSS 6,0-7,0; too late 8 patients on EDSS 0-2,5, ADL healthy 3 patients on EDSS 3,0-3,5 ADL slight disturbance IB EE EJ SP E D S S 7 6 5 4 3 2 1 JL MP ASU EH DG TF LÅ MC TM SA 0 MA -18-15 -12-9 -6-3 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time, months 45 48 51 54 6 59 62 65 68 71 74 77

100 90 80 70 HSCT for MS Outcome 8 previous series; median follow-up 16-35 mo 215 pats RRMS 32 SPMS 145 PPMS 38 60 improved Serie1 % 50 Serie2 40 worse Serie3 30 20 10 0 Fassas 1 Nash 2 Burt 3 Saiz 4 Sacc 5 Samijn 6 7Ni Su 8 Uppsala 9 n 85 26 21 14 19 14 21 15 9 unchanged

HSCT for MS Outcome 8 previous series; median follow-up 16-35 mo 215 pat RRMS 32 SPMS 145 PPMS 38 Δ ED DSS 7 6 5 4 3 Serie1 best 2 Serie2 di 1? 0-1 -2 1 2 3 4 5 6 7 8 9 Fassas Nash Burt Saiz Sacc Samijn Ni Su Uppsala n 85 26 21 14 19 14 21 15 9 median worst Serie3

jan fagius, neurologkliniken Review Burt et al, Arch Neurol 2005; 62:860-4 Review of international experiences so far by HSCT for MS. (Choice of myeloablative or lymfo/immunoablative treatment was discussed - se below) Little success with progressive avanced MS Conclusion - if treatment is taken into account, it should be in the inflammatory phase of MS, before irreversible degenerative changes are present

Degeneration continues after HSCT. Metz et al. Brain 2007; 130:1254-62 HSCT cases, 5 fatalities 20 days 1,5 years after HSCT. Histopatology of the brain. Totally 53 active and non-active lesions according to previously published criteriae were defined. No inflammatory cell infiltrates. Mk Makrophages 12 x more common in active lesions. Demyelinisation and axonal loss goes on, without inflammatory features.

HSCT for MS Why is the procedure effective? jan fagius, neurologkliniken The inflammatory tendency stopped/strongly inhibited Erroneously programmed lymfocytes eliminated (Almost) no further inflammatory attacks The CNS is given chance to manifest its recovery ability Recovery not due to the treatment, but given possibility to occur. How do we know that the immune system program error does not return with the reinfused stem cells with recurrent disaese activity later on? We do not know!

HSCT for MS Experiences after 15 Uppsala cases: jan fagius, neurologkliniken Fever/infections as expected (most patients) Sepsis 2 cases Relapse at mobilisation 1 case Serum sickness-like e reactions -from ATG?? 2 cases myalgia, shiering, fever (steroids added with ATG) Progressive visual loss 1 case Herpes zoster some months post-hsct 1 case 3 mild relapses 7, 18 and 32 months after HSCT No CMV or EBV reactivations so far 4 pregnancies, naturally occurring ; 2 deliveries

HSCT for MS Current indications in Uppsala (april 2010): Confirmed MS diagnosis Aggressive, malignant, disease, predominantly RRMS Short disease duration/ high activity duration Documented, recent ability for function recovery, ~ the last 3-6 months Low grade of irreversible lesions in CNS EDSS level?? > 5,5 at least during relapse MRI may contribute to the decision Dept of Neurology in collaboration with Dept of Haematology

HSCT for MS MRI findings may support treatment decision (MA, 35 yrs) T1, Gad > 50 Gadenhancing lesions 3 mo post- HSCT No Gad- enhancing lesion

HSCT for MS MRI findings may support treatment decision (MC, 25 yrs) T1, Gad > 50 Gadenhancing lesions 5 mo post- HSCT No Gad- enhancing lesion

jan fagius, neurologkliniken HSCT for MS Burt et al Lancet Neurol. Online January 30,2009 Lancet Neurol. 2009 Mar;8(3):244-53

jan fagius, neurologkliniken HSCT och MS Burt et al Lancet Neurology 2009 Mobilization: i Cyclophosphamide 2g/m 2 body surface Filgrastim i (G-CSF; Neupogen) s.c. 10 μg/kg from day 5 Conditioning: Cyclophosphamide 200 mg/kg, divided on 4 days (-5-2) [day 0 = reinfusion] (Alemtuzumab 17 pts) ; ATG (4 pts) From day 5 filgrastim s.c., 5 μg/kg/day until neutrophil recovery Rather heavy profylactic antibiotic treatment t t after HSCT

HSCT och MS Burt et al Lancet Neurology 2009 jan fagius, neurologkliniken IFN-treated t RRMS patients, t 18-55 yrs, treatment failure two steroid idtreated t relapses last t12 mo, or one steroid treated relapse +1MRIGd MRI-Gd-lesion on another occasion; last t12 mo (purely sensory relapses not incl criterium) > 3 months since last relapse EDSS 2,0-5,5; Pi Primary outcome measures: at t3 years progression-free survival and improvement of ffunction

jan fagius, neurologkliniken HSCT och MS Burt et al Lancet Neurology 2009 IFN-treated 21 pats (11 f) 2003-2005, median age 33 (20-53) EDSS level 3,1 (2,0-5,5); MS-dur 5 yrs (1,5-10) Follow-up median 37 (24-48) months 5 pats relapse 0 progress of dysfunction Total disease-activity-free survival 13 pat (62%) 17/21 pats improved 1EDSSstep Sign effects: EDSS, Scripps NRS, PASAT, 25-foot walk, SF-36

jan fagius, neurologkliniken HSCT och MS Burt et al Lancet Neurology 2009 An immuno-ablative regimen, not myelo-ablative! g, y Less dangerous. Fewer acute complications. Weaker effect??

HSCT och MS Burt et al Lancet Neurology 2009 17/21 pats improved EDSS 1 steps. Details: 7 pats 1-1,5 steps 6 pat 2-2,5 steps median value 4pats 3steps 2 pats 0,5 step 2 pats no change 0 pat deteriorated The Uppsala experience 13/15 pats improved EDSS 1 steps. Details: 4 pats 1-1,5 steps 2 pats 3,5 steps 4 pats 4 steps median value 2 pats 6,5-7 steps 1 pat deterioration 0,5 step jan fagius, neurologkliniken

HSCT och MS Burt et al Lancet Neurology 2009 Blood count recovery 13/21 pats needed derytrocyte transfusion 15/21 pats needed platelet transfusion (< 20 000 trc) Infections / complications i 5 pats neutropenic fever without signs of infection or detected patogen (NB prophylactic ab-treatment) No bacterical growth in any ypatient! jan fagius, neurologkliniken Discharge from hematologal oga ward median day 11 (8-13) Markedly fewer complications than our experience Somewhat less good results s than ours

HSCT for MS Probably the most effective treatment for MS might be a way to cure MS ; statement requiring a life-long follow-up High cost-effectiveness - one single procedure But formally not documented effect i.e. no controlled study performed ASTIMS - HSCT vs mitoxantron - still alive? MIST - slowly advancing, -neurologists hesitating, i the average neurologist is not brave! jan fagius, neurologkliniken

ASTIMS www.astims.org. BEAM + ATG is investigative e treatment. BCNU Etoposid cytosin Arabinoside Melphalan Mitoxantrone 20 mg + Methylprednisolone 1g each month for 6 months.

HSCT for MS Burt et al Lancet Neurology 2009 jan fagius, neurologkliniken MIST-study: http://clinicaltrials.gov/ct2/show/nct00273364 To assess the efficacy of autologous PBSCT versus FDA approved standard of care for inflammatory multiple sclerosis failing interferon therapy. Immuno-ablative regimen (= cyclophosphamide) vs /mainly/ natalizumab Primary Endpoint: Disease progression, 1 point EDSS at least 6 months apart Patients will be followed for 5 years after randomization. Secondary Endpoints: Number of relapses A number of detailed functions Ambulation index Twenty-five foot timed walk Nine hole PEG test PASAT SF-36 and MSQOL Scripps NRS Survival MRI enhancing lesions and T1 and T2 burden of disease

HSCT for MS Strong need for a controlled study immuno-ablative i HSCT cyclophosphamide/atg regimen vs best available routine treatment natalizumab inclusion i criteriae i corresponding to today s treatment indications for natalizumab jan fagius, neurologkliniken C h d b li d? Can such a study be realized? It must be!!

Thank you