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ASCT for progressive SSc
further deplete/eliminate residual autoreactive cells and
the use of post-transplant maintenance immunosuppres- sion.15,16,22-24
All patients in the NISCC1 study received a ‘non-mye- loablative’ cyclophosphamide-based conditioning regi- men, which included rabbit-derived ATG in all cases. The degree of T-cell depletion for each patient varied according to the type and total dose of ATG as well as timing of its administration in relation to the peripheral blood stem cell infusion, and whether the infused cells had undergone ex vivo CD34+ selection. In a previous retrospective EBMT analysis, we failed to demonstrate a benefit of ex vivo CD34+-cell selection23 in 138 SSc patients with similar baseline characteristics transplanted between 2000 and 2012. Surprisingly, the NISCC1 study showed a superior response to treatment in patients who received a CD34+- selected graft, with no increased rate of infectious compli- cations, consistent with the recent findings of Ayano et al. in a retrospective analysis of 19 SSc patients.24 The reason for the difference in outcomes between these studies is unclear, but the population included in the NISCC1 prospective cohort was more homogenous in terms of conditioning, including in vivo T-cell depletion with rabbit- derived ATG. All patients in the NISCC1 study received rabbit ATG formulations (although of different brands) while, in the EBMT retrospective study,23 64% of patients treated with ATG received a rabbit-derived product and 35% the horse-derived ATG formulation, which were shown to be associated with significantly different clinical outcomes in aplastic anemia.25 This important finding rais- es the question of whether a randomized, controlled trial should be performed to clarify whether more profound depletion of autoreactive cells from the peripheral blood stem cell graft by CD34+-cell selection may translate into sustained clinical benefit in SSc patients after autologous HSCT, without adversely affecting safety and cost-effec- tiveness.
During the immune reconstitution process, the re-emer- gence of naïve T and B cells, the renewal of the immune repertoire and reinstatement of synergistic immunoregula- tory mechanisms are expected. Therefore maintenance or rapid reintroduction of immunosuppression after autolo- gous HSCT may improve patients’ outcome. The ongoing open-label trial (ClinicalTrials.gov identifier: NCT01413100) analyzing the addition of mycophenolate mofetil for 2 years after autologous HSCT and the next NISCC2 study (ClinicalTrials.gov identifier: NCT 03444805) analyzing post- transplantation management may clarify the potential benefit of post-transplant maintenance immunosuppres- sion.
A critical point for autologous HSCT in autoimmune diseases is safety. The risks of early transplant-related complications and mortality vary according to the type of disease, pre-existing internal organ involvement, the expe- rience of the transplant center and the intensity of the con- ditioning regimen.12,26,27 Major cardiac adverse events and NRM after autologous HSCT in SSc are predominantly related to primary cardiac and lung involvement, which are underevaluated in the absence of systematic MRI and RHC at baseline.28,29 Our study revealed important varia- tions in clinical practice in the pre-transplant cardio-pul- monary evaluation process. Although all patients who died during the first 100 days had normal resting ECG and LVEF on echocardiography at baseline, they were not all assessed by 24 h ECG (3/5), MRI (4/5) or RHC with fluid
challenge (1/5). Overall, 24 h ECG was only used in 75% of the NISCC1 patients to detect subclinical rhythm or conduction disturbances at baseline, although it has been recommended since 2004.27 Similarly, cardiac MRI and RHC with fluid challenge were only performed in 74% and 21% of the patients, respectively, while their use has been advocated among expert centers since 2012 to mini-
Table 4. Complications reported in the 100 days following autologous hematopoietic stem cell transplantation among the 80 patients treated for severe systemic sclerosis.
Post-transplant non-infectious complications in 21 (26%) patients
Events (n=24)
CYC-related acute cardiomyopathy / 4 deaths 4
Cardiomyopathy with myocardial infarction 1 ARDS + acute heart failure 1 Arrhythmias 2 Pericardial effusion 1 Atrial flutter/fibrillation 2 Allergy to ATG with respiratory failure + pulmonary hemorrhagic syndrome 1 ATG-related fever 1 Acute pulmonary edema 1 Renal failure 3 Psychosis/depression 2 Epistaxis 1 Oral mucositis 1 Anal fissure 1 Hemorrhagic cystitis 2
Post-transplant infections reported in 60 (75%) patients
Events (n=95)
Neutropenic fever with no documented infection 25
Catheter infection 2 Sepsis, including 1 septic shock 2 Sinusitis 2 Pneumonia 8 Endocarditis 1
Bacterial
Pneumonia 4 Pleuritis 1 Sepsis Gram-positive bacillus 4 Sepsis Gram-negative bacillus 1 Catheter infection not documented 3 Cellulitis 3
Viral
CMV reactivation 13 EBV reactivation 13 Pneumonia 3 Herpes simplex infection 4 BK virus cystitis 1 Hemorrhagic cystitis, adenovirus-positive 1
Fungal
Fungal sinus infection 1 Skin infection-right foot--Fusarium spp- 1 Candida stomatitis 1
Parasitic
Toxoplasma reactivation 1
CYC: cyclophosphamide; ARDS: acute respiratory distress syndrome; ATG: antithymocyte glob- ulins; CMV: cytomegalovirus; EBV: Epstein-Barr virus.
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