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mize the risk of the transplant procedure.21,30,31 From 2013 to 2017, the EBMT and collaborative partners worked col- lectively to establish common standards for the use and interpretation of cardiac MRI results and RHC with fluid challenge for a rigorous cardio-pulmonary assessment of SSc patients, carefully defining eligibility and selection cri- teria for transplant referral.32
Optimized treatment regimens are warranted to improve the safety of autologous HSCT, even in patients without cardiac involvement. Interestingly, the NRM rate in the NISCC1 study was similar to the 6% reported among 32 SSc patients transplanted between 2005 and 2011, using a ‘myeloablative’ conditioning regimen com- prising total body irradiation (8 Gy), cyclophosphamide (120 mg/kg) and horse-derived ATG in the prospective SCOT randomized controlled trial.16 However, in the SCOT trial, NRM was primarily related to late fatal myelodysplastic syndromes, while no cyclophos- phamide toxicity was reported. Within the follow-up period of the NISSC1 study, there were no reports of myelodysplastic syndrome or other myeloid malignan- cies. In addition, there were no reports of serious late infectious complications or secondary autoimmune phe- nomena that may occasionally present as long-term com- plications following autologous HSCT in autoimmune diseases. Although further follow-up is required, it is possible that there are long-term advantages, in terms of late effects, of the ‘non-myeloablative’ regimen used in the NISCC1 study.
Early toxicity remains the principal challenge, including a NRM rate of 6%. To reduce toxicity and thus treatment- related mortality of the conditioning, a more individual- ized regimen with respect to heart, lung or kidney involvement might further improve patients’ safety, with- out excluding patients with organ manifestations. Two studies addressing patients with heart involvement are ongoing, both using a conditioning regimen with a reduced dose of cyclophosphamide and the addition of either thiotepa, as in four patients in our NISCC1 cohort (NCT01895244), or rituximab and fludarabine followed by reinfusion of autologous hematopoietic stem cells (NCT03593902), although the hematopoietic recovery from this reduced-dose regimen is prompt and reinfusion is not necessary in this setting.
Because mobilization with G-CSF alone may exacerbate autoimmune diseases, there is a clinical rationale for com- bining G-CSF with cyclophosphamide. The use of 2 g/m2 cyclophosphamide for mobilization was as effective as 4 g/m2 at achieving the EBMT recommended minimum CD34+-cell yield, supporting dose reduction in the mobi- lization regimen to limit early toxicity as well as long-term risks associated with cumulative doses of cyclophos- phamide. During the autologous HSCT procedures, inevitable infectious and non-infectious toxicity occurred especially following the high-dose cytotoxic conditioning and the cytopenic phase. A correlation between the num-
ber of infused CD34+ cells and a reduced duration of apla- sia after autologous HSCT has been described previous- ly,33,34 which was confirmed in the NISCC1 study, although CD34+-cell dose and addition of G-CSF until recovery from aplasia were not associated with a reduced number of infectious complications.
The NISCC1 study has several limitations. Since the study was a non-interventional trial, follow-up physical and laboratory evaluations, although recommended by EBMT guidelines,17 were not mandatory, and were not obtained at all time-points. The non-interventional study design was also the cause of significant variation in data collection practices by the 13 participating sites. Data were prospectively collected and checked for consistency by the EBMT study office; however, when some exami- nations were not performed, as may occur in routine clinical practice, data were classified as “missing”. The NISCC1 results showed significant variation in local practices when evaluating patients at baseline. Similarly, the number of reported days for mobilization varied largely according to centers; indeed, some patients were hospitalized for the whole duration of this procedure, whereas in other cases it was carried in part on an outpa- tient basis.
References
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2. Elhai M, Meune C, Boubaya M, et al. Mapping and predicting mortality from sys- temic sclerosis. Ann Rheum Dis.
2017;76(11):1897-1905.
3. Herrick AL, Peytrignet S, Lunt M, et al.
Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study. Ann Rheum Dis. 2018;77(4):563-570.
4. Fransen J, Popa-Diaconu D, Hesselstrand R, et al. Clinical prediction of 5-year survival in
systemic sclerosis: validation of a simple prognostic model in EUSTAR centres. Ann Rheum Dis. 2011;70(10):1788-1792.
5. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclero- sis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis. 2010;69(10):1809-1815.
We aimed to investigate the factors influencing the safety and efficacy of autologous HSCT. We used vali- dated parameters to assess post-transplant outcome, such as mRSS or lung function tests despite their large intra- and inter-individual variability. The results enable deeper analysis of the benefits and risks of the transplant procedure in relation to both SSc-related factors, includ- ing the extent of heart, lung and kidney involvement at the time of patient referral, and transplant-related factors such as the conditioning regimen and graft manipulation. No international consensus has yet validated a unique activity score in SSc and further studies will be necessary in the post-transplant setting to investigate disease activ- ity, the concept of drug-free remission and longer term outcomes, with or without post-transplant interventions.
In conclusion, the NISSC1 is a large prospective real‐world data study of importance for patients, clini- cians, and healthcare payers, given the poor prognosis and burden of disability of patients with severe SSc. It allowed us to assess multicenter adherence and compliance to good clinical practice and adds significantly to the evi- dence base supporting the delivery of autologous HSCT for severe SSc in routine clinical practice.
Disclosures
No conflicts of interests to diclose.
Contributions
JH, DF, MB, JS and ML: conception, study design, analyses and interpretation of data. MO, HUS, NDP, TD, MS, RS, TM, GP, BS, DM, EM, BL, JOB, MS, AH, FO, LK and ZM: acquisition of data.
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