Autologous Hematopoietic Stem Cell Transplantation Improves Long-Term Survival

Data From a National Registry

Norbert Blank; Marc Schmalzing; Pia Moinzadeh; Max Oberste; Elise Siegert; Ulf Müller-Ladner; Gabriela Riemekasten; Claudia Günther; Ina Kötter; Gabriele Zeidler; Christiane Pfeiffer; Aaron Juche; Ilona Jandova; Jan Ehrchen; Laura Susok; Tim Schmeiser; Cord Sunderkötter; Jörg H. W. Distler; Margitta Worm; Alexander Kreuter; Gernot Keyẞer; Hanns-Martin Lorenz; Thomas Krieg; Nicolas Hunzelmann; Jörg Henes

Disclosures

Arthritis Res Ther. 2022;24(258)

Abstract and Introduction

Abstract

Background: Current recommendations on the management of systemic sclerosis (SSc) suggest that autologous hematopoietic stem cell therapy (HSCT) can be a rescue therapy for patients with rapidly progressive SSc.

Objectives: To assess the safety and efficacy of HSCT for patients with SSc and to compare these with non-HSCT patients in a control cohort with adjusted risk factors.

Methods: A retrospective analysis of data from the multicentric German network for systemic scleroderma (DNSS) with 5000 patients with SSc. Control groups consisted of all patients with diffuse cutaneous (dc)-SSc (group A) and an adjusted high-risk cohort of male patients with Scl70-positive dc-SSc (group B).

Results: Eighty SSc patients received an HSCT 4.1 ± 4.8 years after SSc diagnosis. Among them, 86.3% had dc-SSc, 43.5% were males, and 71.3% were positive for Scl70 antibodies. The control group A (n=1513) showed a significant underrepresentation of these risk factors for mortality. When the survival of the control group B (n=240) was compared with the HSCT group, a lower mortality of the latter was observed instead. Within 5 years after HSCT, we observed an improvement of the mRSS from 17.6 ± 11.5 to 11.0 ± 8.5 (p=0.001) and a stabilization of the DLCO. We did not see differences in transplant-related mortality between patients who received HSCT within 3 years after SSc diagnosis or later.

Conclusion: Our analysis of real-life data show that the distribution of risk factors for mortality is critical when HSCT cohorts are compared with non-HSCT control groups.

Introduction

Systemic sclerosis (SSc) is a complex multisystem autoimmune disease, which affects the skin and internal organs, such as the lung, heart, gastrointestinal tract, musculoskeletal system, and kidneys.^[1] Until today, effective treatment options are very limited. Immunosuppression, especially in early disease (<2 years from first non-Raynaud phenomenon), is recommended using methotrexate or cyclophosphamide.^[2] A randomized controlled trial showed equivalent efficacy of mycophenolate and cyclophosphamide in patients with SSc-associated interstitial lung disease (ILD).^[3] Nintedanib was effective in reducing the progression of SSc ILD as an antifibrotic treatment.^[4] Very recently, tocilizumab showed some benefit with regard to the lung involvement but not for the skin sclerosis.^[5] Furthermore, an observational study of rituximab showed some benefit for the skin sclerosis but not for the lung function parameters.^[6] Currently, no biologic treatment option has been approved for SSc skin sclerosis.

Risk factors for the progressive disease have been identified during the last years, and male patients with early diffuse cutaneous skin manifestations and anti-topoisomerase I (Scl70) antibodies are at high risk for disease-related mortality.^[7,8]

Autologous hematopoietic stem cell transplantation (HSCT) is a very effective and meanwhile well-established treatment option for SSc patients with a severe course of the disease. Therefore, HSCT was included in the current EULAR management guidelines.^[2] Three randomized controlled trials proved its superiority over standard treatment with cyclophosphamide pulses in severe cases,^[9–11] and a recent non-interventional trial showed its effectiveness also in a real-life setting.^[12] The aim of the treatment strategy is improvement of long-term survival by eliminating the auto-aggressive immune system using high-dose chemotherapy in combination with lymphoablative antibodies or myeloablative radiation. Major points of criticism are side effects, especially the treatment-related mortality (TRM) between 5 and 10%.^[9–12] Therefore, it is very important to discuss and compare the risk for disease-related mortality with TRM. To investigate long-term survival in a subgroup of patients with a high risk for disease-related mortality, we compared data of patients with and without HSCT from the registry of the German Network for Systemic Scleroderma.

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Arthritis Res Ther. 2022;24(258) © 2022 BioMed Central, Ltd.
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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. The epidemiology of HSCT, dc-SSc control group A, and male+Scl70+ dc-SSc control group B showed the prevalence of risk factors for progressive SSc in all three cohorts at baseline
Baseline DNSS visit		HSCT	all dcSSccontrols A	p	dcSSc+ Scl70+ male controls B	p
Patient number (N)		80	1513	---	240	---
Age at SSc diagnosis (mean ± SD)		38.3 ± 11.7	46.6 ± 14.2	<0.001	46.5 ± 12.1	<0.001
Age at HSCT		43.0 ± 10.9
Time diagnosis to HSCT		4.1 ± 4.8
Age at DNSS baseline		44.3 ± 10.8	53.3 ± 13.6	<0.001	50.3 ± 12.0	0.002
Clinical course	Limited	10 (12.5)	0		0
	diffuse	69 (86.3)	1433 (94.7)		240 (100.0)
	other	1 ( 1.3)	0		0
Male gender		35 (43.8)	406 (26.8)	0.003	240 (100.0)
ANA positive (>1:80, N (%))		73 (91.3)	1236 (81.7)	1.0	240 (100.0)
Anti Scl70/topoisomerase		57 (71.3)	812 (53.7)	0.034	240 (100.0)
Body mass index (kg/m²)		22.8 ± 4.2	24.3 ± 4.6	0.015	25.0 ± 4.5	0.001

Table 2. The prevalence and the extent of skin sclerosis, lung, and heart involvement at the first DNSS visit were indicated for HSCT and control groups A and B
Baseline DNSS visit		HSCT	all dc-SSc controls A	p	dc-SSc+ Scl70+ male controls B	p
Patient number (N)		80	1513	---	240
Patient number valid n (%)		78 (97.5)	1241 (82.0)	---	218 (90.3)
mRSS (mean ± SD)		17.7 ± 11.7	15.6 ± 9.9	0.156	17.2 ± 9.7	0.860
mRSS < 10 (N (%))		25 (32.1)	423 (34.1)	0.805	59 (27.1)	0.464
mRSS > 10		53 (68.0)	818 (65.9)		159 (72.9)
mRSS > 15		42 (53.8)	557 (44.9)	0.128	115 (52.8)	0.895
mRSS > 20		32 (41.0)	350 (28.2)	0.020	70 (32.1)	0.167
Lung involvement	PAH only	0	58 ( 3.8)	0.186	9 (3.8)	0.288
	ILD only	42 (52.5)	658 (43.5)		113 (47.1)
	PAH + ILD	11 (13.8)	171 (11.3)		28 (11.7)
	none	26 (32.5)	522 (34.5)		87 (36.3)
DLCO SB valid data (N (%))		60 (75.0)	829 (54.8)	0.001	163 (67.9)	0.147
DLCO SB (%, mean ± SD)		53.9 ± 17.9	63.2 ± 21.9	0.006	59.1 ± 21.3	0.124
DLCO SB <75% (N (%))		53 (88.3)	633 (76.4)		129 (79.1)
Heart involvement (N (%))		19 (23.8)	243 (16.1)	0.131	52 (21.7)	0.756

Table 3. The protocols used for mobilization of hematopoietic stem cells, graft manipulation, and conditioning chemotherapy
Mobilization		Manipulation	Conditioning
Cyc g/m²	Plerixafor	CD34 enrichment	Cyc or Mel	Thiotepa	TG or ATG
37 × 4 g/m²	-	76 × yes	60 × Cyc 200 mg/kg	-	39 × ATG 15–40 mg/kg
6 × 3 g/m²	1×	4 × no	10 × Cyc 100 mg/kg	10 × Thio 10 mg/kg	31 × TG 5–7.5 mg/kg
36 × 2 g/m²	2×		10 × Mel 200 mg/m²	-	10 × none
1 × 1 g/m²	-			-

Table 4. Patients in the HSCT group were predominantly treated before the age of 50 years (A). Patients with primary rapid progressive SSc were treated with HSCT within the first 3 years of the disease (B). Patients treated after 3 years had comparable survival rates after about 5 to 7 years of follow-up
A	Age at HSCT<50y	Age at HSCT≥50y		Time Dg to HSCT <3y	Time Dg to HSCT ≥3y
N	57 (76%)	18 (24%)	p	43 (56%)	34 (44%)	p
female	32 (56%)	9 (50%)	0.787	18 (42%)	23 (68%)	0.035
male	25 (44%)	9 (50%)		24 (56%)	10 (29%)
Age at Dg (mean ± SD)	33.9 ± 8.9	52.9 ± 5.7	<0.001	41.1 ± 11.6	35.0 ± 10.9	0.018
Age at HSCT	38.5 ± 8.2	57.3 ± 3.7	n.a.	43.2 ± 11.6	42.9 ± 10.2	0.949
Time Dg to HSCT	4.2 ± 4.8	3.8 ± 4.6	0.794	1.6 ± 0.8	7.4 ± 5.6	n.a.
diffuse cutaneous SSc	52 (91%)	14 (78%)	0.160	41 (95%)	27 (79%)	0.042
mRSS at HSCT	17.7 ± 11.7	19.4 ± 12.7	0.579	20.8 ± 11.5	14.5 ± 11.4	0.015
DLCO-SB at HSCT	56.0 ± 15.9	46.8 ± 18.4	0.261	52.3 ±17.0	55.6 ± 19.4	0.567
fVC at HSCT	73.8 ± 21.4	81.0 ± 18.4	0.261	76.1 ± 16.5	75.4 ± 24.8	1.000
ILD with PAH n(%)	5/56 (9%)	6/18 (33%)	0.024	7/42 (17%)	4/34 (12%)	0.328
Heart involvement	12/56 (21%)	7/18 (39%)	0.213	15/42 (36%)	4/34 (12%)	0.019
Time HSCT to last f-up	6.9 ± 4.8	4.3 ± 4.2	0.025	6.2 ± 4.7	7.0 ± 5.4	0.652
Alive at last f-up	54/57 (95%)	15/18 (83%)	0.145	38/43 (88%)	33/34 (97%)	0.220
Dead at last f-up	3/57 (5%)	3/18 (17%)		5/43 (12%)	1/34 (3%)

Table 5. The 5-year follow-up parameters for skin and lung involvement were indicated for HSCT and control groups A and B. The body mass index (BMI) was the lowest in the HSCT group and remained stable over the following 5 years
Follow-up	Year 0	Year 1	Year 3	Year 5
all dc-SSc controls A (n=1513)
mRSS (mean ± SD)	15.6 ± 9.9	12.8 ± 8.8	12.1 ± 8.5	12.4 ± 9.0
N valid; p-value*	1242; reference	594; <0.001	361; <0.001	299; 0.191
DLCO SB (%) (mean ± SD)	63.2 ± 21.9	63.0 ± 21.8	61.2 ± 20.0	60.7 ± 20.3
N valid; p-value*	872; reference	455; 0.015	256; <0.001	216; <0.001
BMI (kg/m2) (mean ± SD)	24.3 ± 4.6	24.5 ± 4.8	24.2 ± 4.6	24.3 ± 4.8
N valid; p-value*	758; reference	402; 0.577	311; 0.971	285; 0.417
male Scl70+ dc-SSc controls B (n=240)
mRSS (mean ± SD)	17.2 ± 9.7	14.2 ± 12.0	15.9 ± 9.0	15.5 ± 9.0
N valid; p-value*	218; reference	93; 0.050	45; 0.581	40; 0.957
DLCO SB (%) (mean ± SD)	59.1 ± 21.3	58.3 ± 23.7	56.7 ± 22.6	58.2 ± 25.3
N valid; p-value*	163; reference	78; 0.135	29; 0.192	35; 0.032
BMI (kg/m2) (mean ± SD)	25.0 ± 4.5	24.8 ± 4.1	25.0 ± 3.5	25.0 ± 4.1
N valid; p-value*	142; reference	68; 0.373	41; 0.948	38; 0.258
HSCT SSc (n=79)
mRSS (mean ± SD)	17.6 ± 11.5	12.1 ± 8.6	13.6 ± 8.7	11.0 ± 8.5
N valid; p-value*	72; reference	57; <0.001	34; 0.006	33; 0.001
DLCO SB (%) (mean ± SD); p	54.6 ± 17.8	61.2 ± 21.0	55.6 ± 15.6	60.0 ± 18.5
N valid; p-value*	55; reference	47; 0.222	24; 0.980	20; 0.964
BMI (kg/m2) (mean ± SD); p	22.9 ± 4.1	23.0 ± 4.6	22.6 ± 3.9	22.8 ± 3.6
N valid; p-value*	56; reference	47; 0.844	33; 0.727	32; 0.175

Authors and Disclosures

Norbert Blank^1*, Marc Schmalzing², Pia Moinzadeh³, Max Oberste⁴, Elise Siegert⁵, Ulf Müller-Ladner⁶, Gabriela Riemekasten⁷, Claudia Günther⁸, Ina Kötter⁹, Gabriele Zeidler¹⁰, Christiane Pfeiffer¹¹, Aaron Juche¹², Ilona Jandova¹³, Jan Ehrchen¹⁴, Laura Susok¹⁵, Tim Schmeiser¹⁶, Cord Sunderkötter¹⁷, Jörg H. W. Distler¹⁸, Margitta Worm¹⁹, Alexander Kreuter²⁰, Gernot Keyẞer²¹, Hanns-Martin Lorenz¹, Thomas Krieg³, Nicolas Hunzelmann³ and Jörg Henes²² and on behalf of the German Network for Systemic Sclerosis

¹Internal Medicine 5, Division of Hematology, Oncology and Rheumatology, Department of Rheumatology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. ²Department of Rheumatology/Clinical Immunology, University Hospital Wuerzburg, Wuerzburg, Germany. ³Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany. ⁴Institute of Medical Statistics and Computational Biology, Faculty of Medicine, University of Cologne, Cologne, Germany. ⁵Department of Rheumatology, Charité Universitätsmedizin Berlin, Berlin, Germany. ⁶Campus Kerckhoff, Department of Rheumatology and Clinical Immunology, Justus Liebig University Giessen, Bad Nauheim, Germany. ⁷Department of Rheumatology, University Medical Center-UKSH, Luebeck, Germany. ⁸Department of Dermatology, University Hospital Carl Gustav Carus, Dresden, Germany. ⁹Department of Rheumatology and Immunology, University Hospital, Hamburg-Eppendorf and Rheumatology Hospital Bad Bramstedt, Bad Bramstedt, Germany. ¹⁰Department of Rheumatology, Johanniter-Krankenhaus im Flaeming Treuenbrietzen, Treuenbrietzen, Germany. ¹¹Department of Dermatology, University Hospital Munich, Munich, Germany. ¹²Department of Rheumatology, Immanuel Krankenhaus Berlin-Buch, Berlin, Germany. ¹³Department of Rheumatology, University Hospital Freiburg, Freiburg im Breisgau, Germany. ¹⁴Department of Dermatology and Venerology, University Hospital Muenster, Muenster, Germany. ¹⁵Department of Dermatology and Venereology, Ruhr-University-Bochum, Bochum, Germany. ¹⁶Department of Dermatology, St. Josef Hospital Wuppertal, Wuppertal, Germany. ¹⁷Dermatology, University Hospital Halle, Halle, Germany. ¹⁸Department of Rheumatology, University Hospital Erlangen, Erlangen, Germany. ¹⁹Department of Dermatology and Allergology, Charité Universitätsmedizin Berlin, Berlin, Germany. ²⁰Allergology, HELIOS St. Elisabeth Hospital Oberhausen, University Witten-Herdecke, Witten, Germany. ²¹Rheumatology, University Hospital Halle, Halle, Germany. ²²Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-inflammatory Diseases and Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology), University Hospital Tuebingen, Tuebingen, Germany.

*Correspondence
norbert.blank@med.uni-heidelberg.de

Authors' contributions
NB and JH panned the study and wrote the manuscript. NB and MO performed statistical analyses and prepared figures and tables. All authors contributed data to the DNSS registry and read and approved the manuscript.

Competing interests
The first author (Norbert Blank) and the last author (Jörg Henes) received speaking fees from Boehringer-Ingelheim (NB and JH) and Chugai (JH) and research grants from NEOVII (JH). All other authors declare no conflict of interest related to the present study.