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ASCT for progressive SSc
Autologous hematopoietic stem cell transplantation procedure
Data collected included details on the mobilization process with or without CD34+-cell selection, type of conditioning regimen; total dose of CD34+ cells infused; number of days of hospitaliza- tion for mobilization and conditioning, use and duration of gran- ulocyte colony-stimulating factor (G-CSF), and time to engraft- ment.
Endpoints
The primary endpoint was progression-free survival (PFS), defined as survival after autologous HSCT without death or evi- dence of progression of SSc (see Online Supplementary Appendix S1).
The secondary endpoints were: (i) infectious or non-infectious adverse events during the first 100 days after autologous HSCT; (ii) engraftment, defined as 3 consecutive days of neutrophils >0.5x109/L and platelets >20x109/L; (iii) response to treatment, defined as a >25% improvement in mRSS and/or ≥10% improve- ment in FVC or DLCO as compared to baseline and without need of further immunosuppression; (iv) incidence of progression; (v) non-relapse mortality (NRM), defined as any death without pro- gression; and (vi) overall survival.
Statistical analysis
Cumulative incidence functions were used to estimate response
to treatment, NRM, and progression to accommodate for compet- ing risks. Probabilities of overall survival and PFS were calculated using the Kaplan-Meier method. Univariate analyses were per- formed using the Gray test for cumulative incidence and the log rank test for overall survival and PFS. Multivariate analysis was per- formed using a Cox regression model including variables associated with the outcome with a P-value less than 0.10 in univariate analy- ses. Age was included as a continuous variable. A generalized linear model was used to analyze evolution over time of mRSS, FVC, DLCO and sHAQ. Results are expressed as a hazard ratio (HR) with 95% confidence interval (95% CI).
Results
Eighty patients (71.3% female), who had undergone a first autologous HSCT between December 2012 and February 2016 in 13 EBMT centers from six European countries and Brazil were included in this study. The centers are listed in Online Supplementary Appendix S2. The median (range) fol- low-up after transplantation was 24 (6-57) months. Table 1 summarizes the patients’ baseline characteristics. The medi- an disease duration since the diagnosis of SSc was 23.8 (5.3- 103.7) months.
At baseline, all 80 patients had skin involvement, and mRSS was above 15 in 64 (80%) of them. Abnormal chest
Table 1. Baseline characteristics of the patients (n=80). Parameter
Patients
Age at aHSCT, years
Sex, female
Disease duration from SSc diagnosis, months
Body mass index (BMI) BMI <18·5
BMI 18·5-30 BMI >30
Skin involvement
Modified Rodnan skin score (mRSS)
Lung involvement
Lung crepitations
Pulmonary function tests, done
FVC, % of predicted value FEV1, % of predicted value DLCO, % of predicted value
Chest imaging, done
Chest X-rays, abnormal
Thoracic computed tomography (HRCT), abnormal*
Cardiac involvement
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate
Resting ECG, abnormal
24h Holter ECG, abnormal Echocardiography, done
LVEF (in %)
Pericardial effusion, present sPAP by cardiac echo (mmHg)
Cardiac MRI, done
Cardiac MRI, abnormal**
N (%) or median (range)
80
43 (20-62)
57 (71.3) 23.8 (5.3-103.7)
8 (10.3) 65 (83.3) 5 (6.4)
24 (2 - 49)
41 (51.3)
80 (100)
72 (43-132) 78 (52-153.3) 59 (34.3-120) 80 (100)
31/71 (43.7) 66/77 (85.7)
110 (76-145) 70 (40-90) 82 (50-105)
4/80 (5) 12/60 (20)
80 (100) 65 (47-84)
5/79 (6.3) 29 (8-59)
59/80 (74) 11 (18.6)
Right heart catheterization, done PAP (mmHg)
PAP, systolic
PAP, diastolic
Fluid challenge, done
17/80 (21.3) 17 (8-23)
26 (16-33) 10 (6-16)
7 (41)
42 (52.5)
22 (27.5)
80 (16-1368)
9 (12.5)
111 (58-190) 9 (12)
7 (9.2)
74 (92.7) 57 (71.3) 3 (4.2)
76 (95.0) 48 (60)
6 (1-17) 46 (58.2) 16 (20.3) 64 (81.0)
8 (10.0) 2 (2.5) 3 (3.8)
Musculo-skeletal involvement Joints involvement
Muscle weakness
CK levels, U/L
Patients with CK level ≥ 250 U/mL Kidney function
Creatinine clearance, mL/min*** Proteinuria on labstix Haematuria on labstix
SSc auto-antibodies
Anti-nuclear antibody positive Anti-topoisomerase I (Scl70) positive Anti-centromere positive
Previous immunosuppressive SSc medication, yes**** Cyclophosphamide (i.v./oral)
Dose, g Methotrexate
Mycophenolate mofetil Prednisone or equivalent Azathioprine
ATG rabbit
Cyclosporine
If not otherwise stated all data are n (%) or median (range) *Abnormal computed tomography scan includes fibrosis, honeycombing or ground-glass pattern. **Abnormal cardiac magnetic resonance imaging includes reduced left or right ventricular function or late enhancement. ***The Cockcroft-Gault formula was recommended for estimating creatinine clearance, i.e., creatine clearance = (140 – age in years)/serum creatinine in mg/dL) x body weight in kg/72. ****Previous treatment ever before, multiple answers possible. aHSCT: autologous hematopoi- etic stem cell transplantation; SSc: systemic sclerosis; BMI: body mass index; FVC: forced vital capacity; FEV1: forced experiratory volume in 1 s; DLCO: diffusing capacity of lung for carbon monoxide; HRCT: high-resolution computed tomography; ECG: electrocardiography; LVEF: left ventricular ejection fraction; sPAP: systolic pulmonary artery pressure measured by echo; echo: echocardiography; MRI: magnetic resonance imaging; PAP: pulmonary artery pressure; CK: creatine kinase; SSc: systemic sclerosis; ATG: antithymocyte globulins;
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