A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation

Oliveira, Maria Carolina; Elias, Juliana Bernardes; Moraes, Daniela Aparecida de; Simões, Belinda Pinto; Rodrigues, Morgani; Ribeiro, Andreza Alice Feitosa; Piron-Ruiz, Lilian; Ruiz, Milton Arthur; Hamerschlak, Nelson

doi:10.1016/j.htct.2020.03.002

Maria Carolina Oliveira

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil

http://orcid.org/0000-0003-0691-2222

Juliana Bernardes Elias

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil

Daniela Aparecida de Moraes

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil

Belinda Pinto Simões

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil

http://orcid.org/0000-0003-4508-8934

Morgani Rodrigues

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

http://orcid.org/0000-0002-0061-7882

Andreza Alice Feitosa Ribeiro

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

Lilian Piron-Ruiz

Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil

http://orcid.org/0000-0002-3602-5897

Milton Arthur Ruiz

Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil

http://orcid.org/0000-0003-2212-4883

Nelson Hamerschlak ^**Corresponding author at: Unidade de Transplante de Medula Óssea do Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520, São Paulo, SP CEP: 05652-900, Brazil. E-mail address: hamer@einstein.br (N. Hamerschlak).

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

http://orcid.org/0000-0002-5140-5310

*Corresponding author at: Unidade de Transplante de Medula Óssea do Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520, São Paulo, SP CEP: 05652-900, Brazil. E-mail address: hamer@einstein.br (N. Hamerschlak).

Conflicts of interest

The authors declare no conflicts of interest.

Autoimmune diseases	n
Multiple sclerosis	Total:	1415
Connective tissue diseases	Total:	771
Systemic sclerosis	609
Systemic lupus erythematosus	110
Polymyositis-dermatomyositis	17
Sjogren's syndrome	4
Antiphospholipid syndrome	6
Other connective tissue diseases	25

Rheumatoid arthritis (inflammatory arthritis)	Total:	190
Inflammatory bowel diseases	Total:	200
Crohn's disease	179
Celiac disease	16
Ulcerative colitis	2
Other inflammatory bowel diseases	3
Hematologic diseases	Total:	56
Immune thrombocytopenia	28
Autoimmune hemolytic anemia	13
Evans' syndrome	10
Other hematological diseases	5

Vasculitis	Total:	48
Granulomatous and polyangiitis	10
Behcet's disease	9
Takayasu's arteritis	3
Polyarteritis	3
Churg Strauss syndrome	2
Other vasculitis	21

Other neurological diseases	Total:	109
Insulin dependent diabetes	Total:	20
Other autoimmune diseases	Total:	23

Total		2809

Site/year of publication(ref)	Study design	Comparisons	Endpoints	Inclusion criteria/	N	Transplant regimen	PFS/outcomes	Relapse/progression rate	Non-relapse mortality	OS	Follow-up
Retrospective studies
Italy 2012⁴⁹49 Mancardi GL, Sormani MP, Di Gioia M, Vuolo L, Gualandi F, Amato MP, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler. 2012;18(6):835-42.	Retrospective case series	None	EDSS progression free-survival	MS treated previously with DMT with severe clinical course past year (EDSS worsening ≥ 1.0)	74 (33 RRMS and 41 SPMS)	BEAM + rabbit ATG	EDSS PFS at 5y 66% for all patients RRMS EDSS PFS 5y 71%	30% for RRMS vs 10% for SPMS	2.7%	95.9%	Median 4 years (8 mo-10.5 yrs)
Swedish 2014⁵⁶56 Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85(10):1116-21.	Retrospective case series	None	Relapse free survival, MRI event free survival, EDSS PFS and DFS	MS treated previously with DMT	52 but analyzed 41 (40 RRMS, 5 SPMS, 2 PPMS,)	BEAM + ATG in 41 and Cy (200 mg/kg) + ATG in 7	At 5y: EDSS PFS 77%; clinical relapse free survival 87%; MRI event-free survival 85% and DFS: 68%	At 5 years, 4 patients had clinical relapse, 5 had MRI activity, 8 had EDSS progression	Zero TRM	100%	Mean 4.0 years (1-9 yrs)
Northwestern/Chicago 2015⁵⁵55 Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis. JAMA. 2019;321(2):165.	Retrospective case series	None	Time to EDSS improvement and time to EDSS worsening both at least 1.0 point	RRMS failed DMT, with 2 or more treated relapses or 1 treated relapse with Gd lesion at a separate time/RRMS 123, SPMS 28	151 but 145 analyzed	CY 200 mg/kg + alentuzumab 20 mg or rabbit ATG 6 mg/kg	EDSS improved 50% at 2 years, 64% at 4 years Relapse-free survival was 89% at 2 years and 80% at 4 years; PFS was 92% at 2 years and 87% at 4 years and disease activity-free survival was 80% and 68% respectively	The proportion of patients with a 1.0 or greater change in EDSS score was 10% in 19 of 112 patients with an indication of progression at 1 year and 11% in 9 of 82 for progression at 2 years; and 11% in 7 of 64 for progression at 3 years; and 8% in 3 of 36 for progression at 4 years; and 5% in 4 of 27 for progression at 5 years.	Zero TRM	99.3% (1 death due hypertensive cardiovascular disease)	2,5 years (6 month-5 yrs)
CIBMTR/EBMT Review⁵³53 Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017;74(4):459.	Retrospective registry review	None	PFS	Data base of AHSCT for MS/46 RRMS, 186 SPMS, 32 PPMS, 17 PRMS	RRMS failed DMT, with 2 or more treated relapses or 1 treated relapse with Gd lesion at a separate time/RRMS 123, SPMS 28	High intensity in 53/281 (18.9%); intermediate intensity in 49/281 (17.4%); low intensity in 49/281 (17.4%).	Overall PFS was 46%; among patients with RRMs/PRMS PFS was 82% at 3 years and EDSS PFS 73% at 5 years		2.8%	93% at 5 years	Median 6.6 yrs
Czech Republic 2010³⁹39 Krasulová E, Trneny M, Kozák T, Vacková B, Pohlreich D, Kemlink D, et al. High-dose immunoablation with autologous haematopoietic stem cell transplantation in aggressive multiple sclerosis: a single centre 10-year experience. Mult Scler. 2010;16(6):685-93.	Retrospective case series	None	Reported efficacy of AHSCT experience in MS	All patients treated with AHSCT 10 years 11 RRMS, 15 SPMS	Data base of AHSCT for MS/46 RRMS, 186 SPMS, 32 PPMS, 17 PRMS	BEAM in 26 and BEAM + ATG in 16	PFS at 3 years 70.8% and 29.2% at 6 years	Median annual relapse rate within the year before ASCT was 2, while the median annual relapse rate was 0 within the first 2 years after ASCT	Zero	96.1% (1 death due to glioblastoma multiforme at 60 months of follow-up)	Median 66 months (11-132)
Spain 2017⁵⁷57 Casanova B, Jarque I, Gascón F, Hernández-Boluda JC, Pérez-Miralles F, de la Rubia J, et al. Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis. Neurol Sci. 2017;38(7):1213-21.	Retrospective case series	None	Reported toxicity and the long-term efficacy of AHSCT	RRMS/SPMS under treatment with one of the MS-approved drugs for more than 1 year, who experienced one or more relapses in the previous year and worsening of at least 1 point in disability (EDSS) 22 RRMS, 9 SPMS	31	BEAM + rabbit ATG	100% of RRMs were free of disability at 6 months; and 60% achieving sustained disability recovery at 6 months; 22% of SPMS were free of disability at 6 months; and 10% achieving sustained disability recovery at 6 months	32.3% (10) had at least one relapse post-AHSCT; 6 in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). 7 (22.6%) experienced progression of disability, all within SP form.	Zero	96.7% (1 death 13 years after transplant from aspiration pneumonia after progressing and reaching an EDSS of 9.5.)	Median 8.4 years (2-16)

Single-arm prospective study
Russia 2015⁵⁸58 Shevchenko JL, Kuznetsov AN, Ionova TI, Melnichenko VY, Fedorenko DA, Kartashov AV, et al. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012;40(11):892-8.	Single arm clinical trial	None	Safety and efficacy (treatment response)	All patients treated with AHSCT 6 years: EDSS 1.5-8.0, ±Gd lesions, and no treatment with interferons or immunosuppressive agents within 3 months before enrollment	99 (43 RRMS, 56 SPMS, 18 PPMS, 3 PRMS)	Reduced intensity conditioning regimen based on BEAM	EFS for the whole group was 80%. In the group with RRMS, EFS was 83.3% and in the group with progressive course 75.5% 92% EDSS PFS 5 years	16.7% at 8 years.	Zero	100%	Median 48.9 months
Northwestern/Chicago 2009⁵⁹59 Burt RK, Loh Y, Cohen B, Stefoski D, Stefosky D, Balabanov R, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009;8(3):244-53.	Single arm clinical trial	None	EDSS PFS and reversal of neurologic disability	RRMS with 2 steroid treated relapses in previous 12 month.	21 (21 RRMS)	Cychophosphamide + alemtuzumab/rabbit ATG	100% EDSS PFS 3 years	5 patients (24%) relapsed but achieved remission after further immunosuppression After a mean of 37 months (range 24-48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses	Zero	100%	Mean 3.1 years (1.5-10)
Canada 2016⁶²62 Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576-85.	Single arm clinical trial	None	MS activity-free survival (absence of clinical relapse, new MRI lesion or progression of EDSS)	Disease activity despite 1 year of DMT.	24 (12 RRMS, 12 SPMS)	Cyclophosphamide/busulfan	70% PFS 3 years	No clinical relapse	4.2%	95%	Median 6.1 year (±2.5)
HALT-MS 2015, 2017⁶⁰60 Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS). JAMA Neurol. 2015;72(2):159.^,⁶¹61 Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology. 2017;88(9):842-52.	Single arm clinical trial	None	Time to treatment failure (death or MS activity)	RRMS with failure of DMTs during the prior 18 months	24 (24 RRMS)	BEAM + rabbit ATG	70% NEDA 5 years, 91% EDSS PFS	Two participants had disease progression and died at .2.5 years and .3.5 years after AHSCT; a third participant also had disease progression at 15 months and died at 4.5 years post-HCT Of 24 patients 7 did not maintain EFS by close of follow-up by an increase in EDSS 0.5 (n = 2), clinical relapse (n = 3) or development of new MRI lesions (n = 2)	Zero	87.5%	Median 4.9 year (6-12)
Australia 2018⁶³63 Moore JJ, Massey JC, Ford CD, Khoo ML, Zaunders JJ, Hendrawan K, et al. Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(5):514-21.	Single arm clinical trial	None	EFS (NEDA)	RRMS with at least 1 relapse or one new MRI lesion in the past year despite DMT/SPMS worsening with at least 1 MRI lesion in the past year.	35 (20 RRMS, 15 SPMS)	BEAM + horse ATG	60% NEDA 3 year	Clinical relapses occurred in 3 patients at 12, 13 and 14 months, respectively after AHSCT	Zero	100%	Median 6.9 year (0.7-21.6)

Randomized study
ASTIMS 2015⁵²52 Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015;84(10):981-8.	Phase II, AHSCT vs mitoxantrone	AHSCT vs mitoxantrone	Cumulative number of new T2 lesion MRI 4 years after randomization	Worsening in EDSS and one or more MRI lesion last year despite DMTs	21 (9 to AHSCT) 7 RRMS, 13 SPMS, 1 PPMS	BEAM + ATG	New T2 lesion MRI: 2.5 AHSCT vs 8 mitoxantrone 4 years	EDSS progression was 57% in AHSCT vs 48% in the mitoxantrone (p = 0.5)	Zero	100%	4 years
MIST 2018⁵⁵55 Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis. JAMA. 2019;321(2):165.	Phase3 AHSCT vs conventional DMT	AHSCT vs DMT	6-Month worsening EDSS ≥ 1.0 after one year's post-AHSCT or DMT treatment	At least 2 clinical relapse, or one relapse in MRI lesion at different time in the last year despite DMT	110 (55 AHSCT) 110 RRMS	Cyclophosphamide + rabbit ATG	At 1 year, mean EDSS improved from 3.38% to 2.36% with AHSCT and worsened from 3.31 to 3.98 with DMTs. At 1 year, mean T2 lesion volume on MRI decreased in the AHSCT, but increased in The DMT group.	15.4% AHSCT vs 85.3% of relapse at 5 years. Disability worsening occur in 5.8% AHSCT vs 66.7% DMT group; median time to pression 24 months in the DMT.	Zero	100%	Up to 5 years

Site/year of publication(ref)	Study design	Comparisons	Endpoints	Inclusion criteria	N	Transplant regimen	PFS	Relapse/progression rate	Non-relapse mortality	OS
Single-arm studies
Europe + USA multicenter/2001⁹¹91 Binks M, Passweg JR, Furst D, McSweeney P, Sullivan K, Besenthal C, et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001;60(6):577-84.	Phase I/II	None, single arm	Feasibility, mortality and preliminary response to treatment	Diffuse SSc or limited SSC with interstitial lung disease or pulmonary hypertension	41 (37 transplanted)	Multiple, most CY 150-200 mg/kg ± ATG/alemtuzumab and/or TBI	46% at 4y	23% (7/30) at 4y	17% (7/41)	73% at 4y
France multicenter/2002⁹³93 Farge D, Marolleau JP, Zohar S, Marjanovic Z, Cabane J, Mounier N, et al. Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study. Br J Haematol. 2002;119(3):726-39.	Phase I/II	None, single arm	Feasibility, tolerance and efficacy	Early (<4y) diffuse SSc plus visceral involvement	12 (11 transplanted)	CY or Melphalan CD34+ selected graft	45% at mean 18 months	50% (5/10) at mean 18 months FU	9% (1/11)	64% at mean 18 months FU
USA multicenter/2002¹⁰⁴104 McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood. 2002;100(5):1602-10.	Pilot study	None, single arm	Safety and potential efficacy	Early (<3y) diffuse SSc plus visceral involvement or progressive interstitial lung disease	19	TBI 800 cGy + CY 120 mg/kg + 90 mg/kg eATG CD34+ selected graft	63% at mean 15 months	25% (4/16) at mean 15 months	16% (3/19)	79% at mean 15 months
Europe multicenter/2004⁹⁴94 Farge D, Passweg J, van Laar JM, Marjanovic Z, Besenthal C, Finke J, et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis. 2004;63(8):974-81.	Retrospective analysis of phase I and II studies	All studies were non-comparative, single arm	Safety and efficacy	Early (<3y) diffuse SSc or progressive interstitial lung disease	57	Multiple, most CY 150-200 mg/kg ± ATG/alemtuzumab and/or TBI	58% at 5y	48% at 5y	8.7% (5/57)	72% at 5y
USA multicenter/2007⁹⁵95 Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen C-S, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007;110(4):1388-96.	Phase II	None, single arm	Safety and efficacy	Early (<4y) diffuse SSc plus visceral involvement or progressive interstitial lung disease	34	TBI 800 cGy + CY 120 mg/kg + 90 mg/kg eATG CD34+ selected graft	64% at 5y	15% (4/26) at 5y	23% (8/34)	64% at 5y
USA (Chicago)/2007⁹⁶96 Oyama Y, Barr WG, Statkute L, Corbridge T, Gonda EA, Jovanovic B, et al. Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis. Bone Marrow Transplant. 2007;40(6):549-55.	Phase I	None, single arm	Safety (toxicity and transplant-related mortality)	Diffuse SSc plus visceral involvement or pulmonary disease regardless of skin involvement	10	CY 200 mg/kg + 7.5 mg/kg rATG Unselected graft	70% at mean 25.5 months	22% (2/9) at mean 25.5 months	Zero	90% at mean 25.5 months
Germany (Berlin)/2012¹²12 Henes JC, Schmalzing M, Vogel W, Riemekasten G, Fend F, Kanz L, et al. Optimization of autologous stem cell transplantation for systemic sclerosis - a single-center longterm experience in 26 patients with severe organ manifestations. J Rheumatol. 2012;39(2):269-75.	Retrospective analysis	None, single arm	Safety and efficacy	CY inefficacy or diffuse SSc with bad prognosis	26	CY 200 mg/kg + 40 mg/kg rATG* CD34+ selected graft	53% at 3y	39% (9/23) at 3y	4% (1/26)	74% at 3y
EUA (Chicago) and Brazil (Ribeirão Preto)/2013⁸⁹89 Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet. 2013;381(9872):1116-24.	Retrospective analysis	None, single arm	Efficacy and use of cardiac screening	Diffuse SSc plus visceral involvement or pulmonary disease regardless of skin involvement	90	CY 200 mg/kg + 4.5-6.5 mg/kg rATG No graft selection	70% at 5y	15% (13/85) at 5y	6% (5/90)	78% at 5y
Italy (Milan)/2017¹¹11 Del Papa N, Onida F, Zaccara E, Saporiti G, Maglione W, Tagliaferri E, et al. Autologous hematopoietic stem cell transplantation has better outcomes than conventional therapies in patients with rapidly progressive systemic sclerosis. Bone Marrow Transplant. 2017;52(1):53-8.	Phase II	HSCT vs historical cohort	Safety and efficacy	Diffuse SSc with progression of skin or of visceral disease	18 HSCT + 36 SSc controls	CY 200 mg/kg + 7.5 mg/kg rATG CD34+ selected graft	Not available. Significantly higher PFS in HSCT than in SSc control group	Not available. Significantly lower disease progression in HSCT than in SSc control group	5.6% (1/18) in HSCT group. Not available for SSc control group	89% in HSCT group and 39% in SSc controls, at 5y
Europe (multicenter) and Brazil (Ribeirão Preto)/2020¹⁰²102 Henes J, Oliveira MC, Labopin M, Badoglio M, Scherer HU, Del Papa N, et al. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica. 2020;(January), http://dx.doi.org/10.3324/haematol.2019.230128. http://dx.doi.org/10.3324/haematol.2019....	Prospective observational	None, single group	Safety and efficacy	Transplanted patients with progressive SSc with data registered to the EBMT database	80	In 76 patients: median CY 200 mg/kg + rATG In 4 patients: Thiotepa 10 mg/kg + CY 100 mg/kg + rATG CD34+ selection in 44%	82% at 2y	13% (11/85) in 2y	6.25% (5/80)	90% in 2y

Randomized studies
ASSIST (Chicago, USA)/2011⁹⁹99 Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011;378(9790):498-506.	Phase II, open label, randomized 1:1 Patient cross-over from CY to HSCT arm allowed at 12 months of FU.	HSCT versus 6 monthly IV CY pulses	Improvement in skin score or lung function in 12 months of follow-up	Diffuse SSc plus visceral involvement or progressive interstitial lung disease	19 (10 HSCT arm and 9 CY arm)	CY 200 mg/kg + 6.5 mg/kg rATG Unselected graft	100% in HSCT arm (10 patients) and 11% in CY arm, at 12 months FU. 7 patients from CY arm crossed over to HSCT at 12 months FU and all improved. At 2.6y of mean FU after HSCT, PFS was 88%	Zero in HSCT arm and 89% (8/9) in CY arm at 12 months of FU. 12% (2/17) in all transplanted patients (original and crossed-over) at mean 2.6y of FU	Zero in HSCT and CY arms, at mean 2.6y of FU	100% at mean 2.6y of FU
ASTIS (Europe multicenter)/2014⁸⁸88 van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311(24):2490-8.	Phase III, open label, randomized 1:1	HSCT versus 12 monthly CY pulses	Progression/relapse-free survival, toxicity, efficacy.	Early (<4y) diffuse SSc plus major organ involvement or progressive diffuse skin disease (<2y) with no visceral involvement	156 (79 HSCT arm and 77 CY arm)	CY 200 mg/kg + 7.5 mg/kg rATG CD34+ selected graft	77% in HSCT arm and 65% in CY arm, at 4y FY	11% (7/66) in HSCT arm and 35% (20/57) in CY arm at 4y FU	10% (8/79) in HSCT arm and zero in CY arm at 4y FU	80% in HSCT arm and 65% in CY arm at 4y FU
SCOT (USA multicenter)/2018¹⁰⁰100 Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378(1):35-47.	Phase II, open label, randomized 1:1	HSCT versus 12 monthly CY pulses	Global rank composite score at 54 months of FU	Any form of early SSc (<5y) plus interstitial lung disease or previous scleroderma renal crisis	55 (33 HSCT arm and 32 CY rm)	TBI 800 cGy + CY 120 mg/kg + 90 mg/kg eATG CD34+ selected graft	74% in HSCT arm and 47% in CY arm, at 72 months FU	18% (6/33) in HSCT arm and 41% (14/34) in CY arm, at 54 months FU	6% (2/33) in HSCT arm. Zero in the CY group	86% in HSCT arm and 51% in CY arm, at 72 months FU

Site/year of publication(ref)	Study design	Comparisons	Endpoints	Inclusion criteria	N	Transplant regimen	PFS	Relapse/progression rate	Non-relapse mortality	OS
Single-arm studies
Italy (Milan) 2007¹³⁶136 Cassinotti A, Annaloro C, Ardizzone S, Onida F, Volpe AD, Clerici M, et al. Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn's disease. Gut. 2008;57(2):211-7.	Phase I/II Prospective	None, single arm	Safety and clinical/endoscopic response	CDAI > 250 Active intestinal lesions Failed > 2 IS C-reactive protein > 1 mg/dL	4	CY 200 mg/kg + 7.5 mg/kg rATG Unselected graft	75% at 16.5 months mean FU	25% (1/4) at 16.5 months mean FU	Zero at 16.5 months	100% at 16.5 months
EUA (Chicago) 2010⁴4 Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood. 2010;116(26):6123-32.	Phase I/II Prospective	None, single arm	Safety and clinical outcomes	CDAI > 250 Crohn's severity index > 16 Failed anti-TNF	24	CY 200 mg/kg + 6 mg/kg rATG or 90 mg/kg eATG CD34+ selected graft	19% at 5y	15/23 at mean FU of 4.4y	Zero TRM 1 accidental death at 3y	95% at 5y
Netherlands 2011¹³⁷137 Hommes DW, Duijvestein M, Zelinkova Z, Stokkers PCF, Ley MH, Stoker J, et al. Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn's disease. J Crohn's Colitis. 2011;5(6):543-9.	Case series	None, single arm	None described	Active disease Failed anti-TNF Risk of resection surgery	3 (only 2 transplanted)	CY 200 mg/kg + 90 mg/kg eATG CD34+ selected graft	Zero at 5y (both patients relapsed at 3 and 12 m post-AHSCT	100% (2/2) at 5y	Zero	100% at 5y
Germany (Freiburg) 2012¹³⁸138 Hasselblatt P, Drognitz K, Potthoff K, Bertz H, Kruis W, Schmidt C, et al. Remission of refractory Crohn's disease by high-dose cyclophosphamide and autologous peripheral blood stem cell transplantation. Aliment Pharmacol Ther. 2012;36(8):725-35.	Phase I/II Prospective	None, single arm	Safety, feasibility and efficacy	Active disease Failed conventional therapy	12 (only 9 transplanted)	CY 200 mg/kg CD34+ selected graft	17% (2/12) at mean follow-up of 3.1y	78% (7/9) at 3.1y	Zero at mean 3.1y	100% at mean 3.1y
United Kingdom (3 centers) 2014¹³⁹139 Snowden JA, Ansari A, Sachchithanantham S, Jackson G, Thompson N, Lobo A, et al. Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis. QJM. 2014;107(11):871-7.	Retrospective case series	None, single arm	Long-term clinical outcomes	Active disease failed conventional therapy	6	CY 200 mg/kg + 7.5 mg/kg rATG CD34+ selected graft in 2 patients	Zero (6/6 relapses)	100% at median 10 months after AHSCT	Zero	100% at median 87 months FU
Brazil (S. José do Rio Preto) 2017¹⁴²142 Ruiz MA, Kaiser Junior RL, Gouvêa Faria MA, de Quadros LG. Remission of refractory Crohn's disease after autologous hematopoietic stem cell transplantation. Rev Bras Hematol Hemoter. 2015;37(2):136-9.	Phase I/II Prospective	None, single arm	Safety and early clinical outcomes (first 30 days after AHSCT)	CDAI > 150 Active intestinal lesions Risk of resection surgery Failed anti-TNF	14	CY 200 mg/kg + 6.5 mg/kg rATG Unselected graft	93% at 30 days	1/14 at 30 days	Zero at 30 days	100% at 30 days
Europe multicenter (EBMT) 2018¹⁴³143 Brierley CK, Castilla-Llorente C, Labopin M, Badoglio M, Rovira M, Ricart E, et al. Autologous haematopoietic stem cell transplantation for Crohn's disease: a retrospective survey of long-term outcomes from the European Society for Blood and Marrow Transplantation. J Crohns Colitis. 2018;12(9):1097-103.	Retrospective survey	None, single arm	Safety and efficacy	Patients transplanted from 1997 to 2015 Excludes ASTIC patients	82	86% CY 200 mg/kg + ATG 11% CY 200 mg/kg + CD34 selection	54% at 1y 27% at 41 months	73% (60/81) at median 10 months after AHSCT	1.2% (1/82)	97% at 5y
Spain (Madrid) 2019¹⁴⁴144 Hernanz N, Sierra M, Volpato N, Núñez-Gómez L, Mesonero F, Herrera-Puente P, et al. Autologous haematopoietic stem cell transplantation in refractory Crohn's disease: experience in our centre. Gastroenterol Hepatol. 2019;42(1):16-22.	Retrospective case series	None, single arm	Safety and efficacy	Patients with active Crohn's disease transplanted from 2011 to 2017.	7	CY 200 mg/kg + rATG (dose not described) Unselected graft	29% at 48 months	71% (5/7) at 48 months	Zero	100%

Randomized study
ASTIC (EBMT, multicenter) 2016¹⁴⁰140 Hawkey CJ, Allez M, Clark MM, Labopin M, Lindsay JO, Ricart E, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease a randomized clinical trial. JAMA. 2015;314(23):2524-34.	Phase II, open label, randomized 1:1	Patients randomized after mobilization to immediate AHSCT or control treatment with AHSCT deferred for 1y	Sustained clinical and endoscopic/radiologic remission at 1 y	Active disease Impaired function/quality of life Failed ≥3 IS/biologicals	45 (23 AHSCT and 22 control treatment)	CY 200 mg/kg + 7.5 mg/kg rATG Unselected graft	8.7% (2/23) in the AHSCT group 4.5% (1/22) in the control group	95% (20/21) in the AHSCT group at 1y 94% (16/17) in the control group at 1y	4.3% (1/23) at 1y in the transplant group Zero in the control group	96% at 1y in the transplant group 100% in the control group

[1] *Corresponding author at: Unidade de Transplante de Medula Óssea do Hospital Israelita Albert Einstein, Av. Albert Einstein, 627/520, São Paulo, SP CEP: 05652-900, Brazil. E-mail address: hamer@einstein.br (N. Hamerschlak).

Brasil

Brasil

A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation

ABSTRACT