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J, Henes et al.
x-rays or abnormal high-resolution computed tomography was reported in 70 (87%) patients. Heart involvement with an abnormal 24 h electrocardiogram was reported in 12/60 (20%) or with abnormal cardiac MRI in 11/59 (19%) patients. Among the 11 patients with abnormal MRI at baseline, echocardiography showed normal LVEF in all cases and pericardial effusion in one patient, the resting ECG was abnormal in one patient and the 24 h ECG was abnormal in two patients; baseline RHC performed in six patients (with fluid challenge in 2 cases) was normal. Overall, 21 patients (26%) were transplanted without any prior cardiac MRI or RHC at baseline; among these, two had pericardial effusion and seven had a systolic pulmonary artery pressure above 25 mmHg on echocardiography, one had ventricular distur- bances on resting ECG (n=20), and 2/8 had an abnormal 24 h ECG.
Mobilization and conditioning procedures
All patients were mobilized using cyclophosphamide with a median dose of 2 g/m2 (range, 1-4 g/m2) plus G-CSF. The median duration of hospitalization was 4 (1-30) days for mobilization with large variation according to centers. CD34+-cell selection was performed in 35 (44%) patients (Table 2).
The median time from mobilization to the start of the conditioning regimen for autologous HSCT was 52 (22-254) days. The conditioning regimen included cyclophos- phamide in all 80 patients, alone in 76 (95%) patients, with a median total dose of 200 (50-240) mg/kg. Four patients (5%) received thiotepa 10 mg/kg with a total cyclophos- phamide dose of 100 mg/kg as a single-center treatment for patients with cardiac abnormalities at the pre-transplant evaluation. Additional rabbit antithymocyte globulin (ATG), with different doses according to the brand, was also includ- ed in the conditioning regimen for all patients and adminis- tered over 4 to 5 days. Sixty-seven patients (82%) received methylprednisolone during the ATG treatment. No patient received total body irradiation. A median number of 5.2 x 106/kg (2.53-23.31) CD34+ cells were reinfused at transplan- tation. Following autologous HSCT, G-CSF was adminis- tered to 34 (43%) patients for a median duration of 5 (1-13) days. Following autologous HSCT, the median time to neu- trophil engraftment was 11 (8-24) days and the median time to platelet engraftment was 9 (1-25) days. In 13 (16.9%) patients, the platelet counts were never below 20x109/L. There was an inverse correlation between the number of CD34+ cells infused and the time to engraftment (Spearman: r2= -0.31; P<0.01), while the number of infused CD34+ cells and addition of G-CSF until recovery of aplasia were not associated with a reduced number of infectious complica- tions (P=0.32). The median duration of inpatient hospitaliza- tion for conditioning, autologous peripheral blood stem cell re-infusion and subsequent supportive care until engraft- ment and discharge was 24 (8-128) days (Table 2).
Efficacy
At 1 and 2 years after autologous HSCT, the PFS rate was 87.5% (95% CI: 80.2-94.7) and 81.8% (95% CI: 73.1-90.5), respectively, and the rate of response to treatment was 75% (95% CI: 63.7-83.2) and 88.7% (95% CI: 79-94.1), respec- tively. At the 1- and 2-year time-points, the incidence of pro- gression was 6.3% (95% CI: 2.3-13.1) and 11.9% (95% CI: 5.8-20.5), respectively, and the overall survival rate was 91.2% (95% CI: 85.1-97.4) and 90% (95% CI 83.4 - 96.6) at 1 and 2 years, respectively (Figure 1). Three of the four
Table 2. Treatment regimen used for mobilization and conditioning.
Parameter
Mobilization
CYC 2 g/m2 CYC 4 g/m2 Other dose Missing = 2 G-CSF, yes Leukapheresis
1 2 3
CD34+ selection
Yes
None
Conditioning regimen
CYC 200 mg/kg
CYC other dose mg/kg
CYC 100 mg/kg + Thiotepa 10 mg/kg Rabbit ATG, yes
Thymoglobulin (Sanofi/Genzyme), mg/kg Grafalon (Neovi/Fresenius), mg/kg
Growth factors
G-CSF administration after conditioning
N. of days of administration
Cells infused
CD34+ cells reinfused, 106/kg
Duration of hospitalization
Mobilization, days
Conditioning, days
N (%) or median (range)
45 (57.7%) 23 (29.5%) 10 (12.8%)
80 (100%)
61 (77.2%) 11 (13.9%) 7 (8.9%)
35 (43.8%)
45 (56.3%)
72 (90.0%) 4 (5.0%) 4 (5.0%) 80 (100%) 7.5 (2.5-7.5) 40 (30-41)
34 (43.0%)
5 (1-13)
5.2 (2.53-23.31)
4 (1-30)
24 (7-128)
CYC: cyclophosphamide; G-CSF: granulocyte – colony-stimulating factor; ATG: antithymocyte globulin;
patients transplanted with thiotepa and a reduced-dose cyclophosphamide regimen responded; one with worsening skin and lung involvement at day 350 was then treated with prednisone, mycophenolate mofetil and rituximab. By mul- tivariate analysis, mRSS >24 at baseline and older age at transplantation were significantly associated with a lower PFS with hazard ratios of 3.33 (95% CI: 1.04-10.62) and 1.77 (95% CI: 1.07-2.94), respectively. CD34+-cell selection was associated with a better response to therapy (HR: 0.46; 95% CI: 0.27-0.76).
Figure 2 illustrates the evolution of the parameters over time. The mean mRSS decreased from 23.9 (standard devia- tion [SD] 9.7) at baseline to 14.2 (SD 9.2) at 1 year and 12.6 (SD 8.3) at 2 years (n=55, P<0.001). Regarding lung function, the mean FVC increased from 73.6% (SD 16.9) of predicted value at baseline to 79.5% (SD 16.9) at 1 year and 80.6% (SD 19.1) at 2 years (n=37, P<0.001); the mean DLCO was 60.2% (SD 19.3) at baseline, 59.7% (SD 17.7) at 1 year and 60.4% (SD 19.1) at 2 years (n=35). The sHAQ score was available in 15 patients and decreased significantly from 0.96 (SD 0.8) at baseline to 0.73 (SD 0.6) at 1 year and 0.70 (SD 0.6) at 2 years (P<0.001). The mean erythrocyte sedimenta- tion rate decreased from 23.2 mm/h (SD 19.8) at baseline to 16.1 mm/h (SD 11.3) at 1 year and 18.7 mm/h (SD 23.6) at 2 years (n=38, P<0.001). Anti-Scl-70 and anti-centromere autoantibodies did not change after autologous HSCT.
Safety
The NRM rate at 100 days and 2 years was 6.25% (95% CI 2.3-13) (Figure 1). Four of the five deaths not due to
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