Life after Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis

Figures & data

Figure 1 Schematic representation of the transplant procedure. Autologous stem cells are mobilized from the bone marrow to the peripheral blood, from where they are harvested by leukapheresis and cryopreserved (1). The graft can be selected before cryopreservation or remain unmanipulated. The patient then undergoes an immunoablative conditioning regimen (2), followed by intravenous administration of the autologous cells, which are thawed immediately before infusion (3). After a period of aplasia, there is reconstitution of the immune system (4), and the patient is discharged from the hospital. Long-term outcomes are evaluated over time.

Table 1 Main Characteristics of Non-Randomized Phase I/II, Retrospective and Observational Studies

	Henes et al. 2012^Citation31	Burt et al. 2013^Citation32	Helbig et al. 2018^Citation33	Nakamura et al. 2018^Citation34	Ayano et al. 2019^Citation29	Guillaume-Jugnot et al. 2019^Citation35	Van-Bijnen et al. 2020^Citation36	Henes J et al. 2021^Citation30	Henrique-Neto et al 2021^Citation37
Country	Germany	USA/Brazil	Poland	Japan	Japan	France	Netherlands	Europe/Brazil	Brazil
Study design	Prospective Phase I/II 1997–2009	Retrospective 2002–2011	Prospective Phase I/II 2003–2016	Long-term follow-up of phase II 2000–2012	Post-hoc analysis of phase I/II 2002–2009	Retrospective 1997–2013	Retrospective multicenter 1998–2017	Prospective observational multicenter 2012–2016	Retrospective study 2009–2016
Inclusion criteria	Inefficacy of CY pulse therapy or progressive disease with indicators of bad prognosis	mRSS ≥14 plus interstitial lung disease or abnormal EKG or GI tract involvement	≤70 y of age Karnofsky >80 Disease <10 y mRSS ≥15 or mRSS <15 plus progressive pulmonary disease	Diffuse SSc Disease <3y mRSS ≥15 plus refractory digital ulcers or interstitial lung disease	16–65 y of age mRSS ≥15 plus worsening lung or heart or kidney involvement, or mRSS <15 plus pulmonary progression	Not described	Same as in ASTIS trial^Citation17	18–65 y Progressive disease	18–60 y of age Worsening diffuse skin if mRSS >14 or progressive lung function
Exclusion criteria	Karnofsky <70 PAPsys >50mmHg DLCO<40% predict	PAPsys >40mmHg LVEF <40% FVC<45% predict	PAH Cardiac Insuf. Renal Insuf. DLCO<40% predict	>60 years of age <16 years of age Uncontrolled arrhythmia LVEF <50% DLCO<45% predict	Uncontrolled arrhythmia Severe heart failure PAH Pulmonary or renal failure	Not described	Same as in ASTIS trial^Citation17		LVEF <40% Diastolic dysfunction PAPsys >40mmHg PAPm >27mmHg FVC <45% predict DLCO<40% predict
N	26	90	18	14	19	56	89	80	70
Median age	39 y	42 y	51.5 y	44.5 y	53.7 y	48 y	46 y	43 y	35.9
Median disease duration	27 y	25 mo	14 mo	22.5 mo	15 mo	25 mo	18 mo	23.8 mo	2y
Transplant regimen	CY200 + rATG or CY100 + Thiotepa	CY200 + rATG	CY200 + rATG CY 200 + Alemtuz Mel + Alemtuz CY200 alone	CY200	CY 200	Multiple regimens	Cy200 + rATG	CY200 + ATG CY100+Thiotepa + ATG	CY200 + rATG Flu + Mel + ATG
CD34+ selection	Yes	No	No	Yes in 5 patients	Yes in 11 patients	Yes in most, but not specified for SSc patients	Yes	Yes in 35 patients	No
Follow-up	4.4 y	5 y	42 mo	11 y	8 y	7 y	4.6 y	2 y	8 y
Overall survival	74% at 3 y	78% at 5 y	61% at 42 m	93% at 5 y 93% at 10 y	79% (15/19)	73.7% at 5 y 55.4% at 10 y	77% at 55 mo	91.2% at 1 y 90% at 2y	91.8% at 3 y 85% at 5 y 81% (8y)
Transplant-related mortality	4% (1/26)	6% (5/90)	22% (4/18)	7.1% (1/14)	Zero	8.9% (5/56)	11% (8/89)	6% (5/80)	4% (3/80)
Progression-free survival or Event-free survival	Progression-free survival 53% at 3 y	Event-free survival 70% at 5 years	Progression-free survival 33% at 42 mo	Event-free survival 50% at 5 y 40% at 10 y	Progression-free survival 68.4% at 5 y 51.3% at 8 y	Progression-free survival 44.2% at 5 y 44.1% at 10 y	Event-free survival 78% at 5 y 76% at 10 y 66% at 15 y	Progression-free survival 87.5% at 1 y 81.8 at 2 y	Progression-free survival 71.8% at 3 y 71.8% at 5 y 70.5% at 8 y
Relapse/ progression	30.4% at 3 y	14.4% at 5 y	27.7% at 42 mo	42% at 5 y	Not available	Not available	24% at 5 y	Progression of 6.3% at 1 y and 11.9% at 2 y	24%
mRSS	78.3% improved at 6 mo	Improved up to 5y	No scores available. Improved at 12mo	71% of patients improved at 12 mo	Improved up to 5 y Stable up to 8 y	Not available	Improved up to 5 y	Improved up to 2 y	Improved up to 5 y
FVC and DLCO	FVC improved at 12 mo DLCO unchanged	FVC improved up to 36 mo DLCO stable	No scores available Stable over 12 mo	85% of patients stable at 12 mo	FVC improved until 8 y DLCO stable	Not available	FVC and DLCO improved up to 5 y	FVC improved up to 2 y DLCO stable	FVC and DLCO stable up to 5 y

Abbreviations: CY, cyclophosphamide; CY200, CY at the dose of 200mg/kg; ATG, anti-thymocyte globulin; rATG, rabbit ATG; Flu, fludarabine; Mel, melphalan; Alemtuz, alemtuzumab; SSc, systemic sclerosis; mRSS, modified Rodnan’s skin score; LVEF, left ventricle ejection fraction; FVC, forced vital capacity; DLCO, diffusing lung capacity for carbon monoxide; predict, % of predicted value; y, years; mo, months; GI, gastrointestinal; PAH, pulmonary artery hypertension; PAP, pulmonary artery pressure; PAPsys, systolic PAP; PAPm, mean PAP; EKG, electrocardiography; progression-free survival, proportion of patients who were alive and with no worsening of disease when compared to baseline; event-free survival, proportion of patients who were alive and with no worsening of disease from best improvement after transplant.

Table 2 Main Characteristics of Comparative Studies, Including Randomized Controlled Trials

	Burt et al 2011 (ASSIST)^Citation16	van Laar et al 2014 (ASTIS)^Citation17	Sullivan et al 2018 (SCOT)^Citation18	Del Papa et al. 2017^Citation38
Study design	Phase II, randomized 1:1, open-label cross-over to HSCT allowed at 12 mo North American single-center 2006–2009	Phase III, randomized 1:1, open-label European multicenter (EBMT) 2001–2009	Phase II, randomized 1:1, open-label North American multicenter 2005–2011	Phase II, retrospective historical SSc control group Italian, single-center 2003–2011
Comparisons	HSCT vs 6-mo intravenous CY	HSCT vs 12-mo intravenous CY	HSCT vs 12-mo intravenous CY	HSCT vs historical cohort
Inclusion criteria	<60 y of age Disease duration ≤4 y Diffuse SSc mRSS ≥15 Internal organ involvement	18–65 y of age Disease duration ≤2–4 y^a Diffuse SSc mRSS ≥15 Internal organ involvement	18–69 y of age Disease duration ≤4 y Diffuse SSc mRSS ≥16 Internal organ involvement	Diffuse SSc Disease duration ≤4 y mRSS ≥14 Clinical activity score (ESSG) ≥3
Exclusion criteria	PAPm >25mmHg or PAPsys >40mmHg LVEF <40% Creatinine >177µmol/L >6 Intravenous CY courses	PAPm>50mmHg LVEF <45% Creatinine >40mL/min Cumulative IV CY dose >5g or Cumulative oral CY dose >3g	Mean PAP >30mmHg LVEF<50% FVC <45% predicted DLCO <40% predicted Creatinine clearance <40mL/min Cumulative IV CY dose >3g/m^2 or Oral CY dose >4 months, or >6 Intravenous CY courses	PAH LVEF <45% DLCO <50% predicted, Prior renal crisis
Number of participants	19 (10 HSCT + 9 CY arm)	156 (79 HSCT + 77 CY arm)	75 (33 HSCT + 32 CY arm)	18 HSCT + 36 SSc controls
Median age	45 y	43.8 y	45.9 y	41 y
Disease duration	13.6 mo	16.8 mo	27 mo	24 mo
Transplant regimen	CY200 + rabbit ATG	CY200 + rabbit ATG	TBI + CY120 + equine ATG	CY200 + rabbit ATG
Total body irradiation	No	No	Yes	No
CD34+ selection	No	Yes	Yes	Yes
Follow-up after AHSCT	2.6 y (median)	5.8 y (median)	4.5 y (minimum)	5 y (minimum)
Overall survival	100% at median 2.6 y for both groups	80% in HSCT vs 65% in CY at 4 y 75% in HSCT vs 60% in CY at 8 y	86% in HSCT vs 51% in CY at 6 y	89% in HSCT vs 39% in SSc controls at 5 y
Transplant-related mortality	0%	10.6% (8/79 HSCT)	3% (1/33 HSCT)	5.6% (1/18 HSCT)
Event-free survival	80% in the HSCT group at 2 y 11% in the CY group at 2 y	81% in HSCT vs 74% in CY at 4 y	79% in HSCT vs 50% in CY at 4.5 y 74% in HSCT vs 47% in CY at 6 y	Not described
Progression-free survival	100% in HSCT vs 11% CY at 1 y 88% in HSCT at 2.6 y	77% in HSCT vs 65% in CY at 5.8 y	Not described	Not available. Higher survival in HSCT than in the SSc control group
Disease progression	0 in HSCT vs 89% (8/9) in CY at 1 y	11% in HSCT vs 35% in CYC at 5.8 y	18% in HSCT vs 41% in CY at 6 years	Not available. Lower disease progression in HSCT than in controls
mRSS	Improvement up to 2 y in HSCT Worsening in CY group	Improvement at 2 y in HSCT HSCT better than CY at 2 y	Not described	Improvement from baseline to 12 mo after HSCT and stabilization thereafter
FVC/DLCO	FVC improved more in HSCT than in CY DLCO remained stable and not different between groups	FVC improved more in HSCT than CY DLCO remained stable and not different between groups	FVC improved/stabilized in more patients from HSCT than from CY group	Stabilization of FVC and DLCO No difference between HSCT and controls

Notes: ^aThe protocol was amended in 2004 to shorten maximum duration of disease for enrolment to 2 years, instead of the previous 4 years. Progression-free survival (PFS): proportion of patients who were alive and with no worsening of disease when compared to baseline; event-free survival: proportion of patients who were alive and with no worsening of disease from best improvement after transplant.

Abbreviations: SSc, systemic sclerosis; HSCT, hematopoietic stem cell transplantation; mRSS, modified Rodnan’s skin score; ESSG, European Scleroderma Study Group scoring system; LVEF, left ventricle ejection fraction; PAP, pulmonary artery pressure; PAPsys, systolic PAP; PAPm, mean PAP; CY, cyclophosphamide; CY200, CY at a dose of 200mg/kg; ATG, anti-thymocyte globulin; TBI, total body irradiation; PAH, pulmonary artery hypertension; FVC, forced vital capacity; DLCO, diffusing lung capacity for carbon monoxide; y, years; mo, months.

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