Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I–II study

Abstract

Summary. Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc). A sequential Bayesian phase I-II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT. Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m 2 ) and recombinant human granulocyte colony-stimulating factor (5 lg/kg/d) and reinfused after positive CD34 + selection. Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m 2 ) according to cardiac function. The main end-point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34 + selection or intensification procedure, or by procedure-related death. Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34 + selection and one CD34 + intensification. Probability of graft failure was estimated at 0AE286 (95% confidence interval: 0AE095-0AE54). Autologous PBSC (n ¼ 10) or bone marrow (n ¼ 1) transplantation was actually performed in 11 patients with one procedurerelated death. Median time to neutrophil (> 0AE5 · 10 9 /l) and platelet (> 25 · 10 9 /l) haematopoietic reconstitution was 12 and 10 d respectively. After 18 months (range 1-26), eight out of 11 patients have shown major or partial response. Non-myeloablative conditioning, followed by a T cell-depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short-term clinical benefits.

Autologous hematopoietic stem cell transplantation for autoimmune diseases

“…These data extend preliminary results from early pilot and single disease focused studies. [10][11][12][13][14][15] They confirm the concept of dose intensification as a therapeutic strategy. Increasing intensity reduces the risk of disease progression.…”

“…9 Pilot series have established and defined response criteria. [10][11][12][13][14][15] Insufficient data were as yet available to assess factors associated with outcome; mechanisms of action remained hypothetical. The present analysis documents the feasibility and efficacy of the procedure, clarifies the role of dose intensification and forms the basis for the ongoing prospective randomized phase III trials.…”

Does ex vi vo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients?

“…Improved skin score and quality of life and at least stabilization of lung function were consistently reported in early phase II trials. [4][5][6][7][8] Recently, the phase II ASSIST 9 and the larger phase III ASTIS 10 prospective randomized trials showed better survival rates and improved skin, lung and functional status in patients treated with AHSCT as compared with monthly IV cyclophosphamide. Still, the transplant-related mortality reaching 10% and disease-progression rates of around 20-30% after AHSCT indicate that further improvements are still warranted.…”

The rationale behind autologous autoimmune hematopoietic stem cell transplant conditioning regimens: concerns over the use of total-body irradiation in systemic sclerosis

“…[57][58][59][60][61][62] TBI is not an essential agent and can be easily replaced with agents that have similar or higher immune ablative potential but without myeloablation, acute and chronic exacerbation of vascular injury, risk of damage to organ stem cell compartments, hindrance of repair mechanisms, and compared to TBI minimal risk of late malignancies.…”