Intensive Immunosuppression Plus T-Cell Depleted Autologous Peripheral Blood Stem Cell Transplantation for Systemic Sclerosis.
Authors: BuchBarker Diane , Donnenberg Albert D. , Medsger Thomas A. , Carroll Michael P. , Griffin Deborah L. , Blair Carol , Lis Darrell , Yeager Andrew M. 
Published: October 2019

Autologous peripheral blood stem cell transplantation (PBSCT) may be therapeutic in patients (pts) with severe autoimmune disorders. A pre-PBSCT regimen that optimizes immunosuppression without excessive myelotoxicity would potentially have favorable safety and efficacy profiles in these pts. To test this hypothesis we are conducting a phase I trial of cyclophosphamide (CY) dose escalation (initial CY dose 200 mg/m2/day x 5, days −7 to −3) plus fludarabine (25 mg/m2/day x 5, days −7 to −3) and rabbit anti-thymocyte globulin (ATG; 2.5 mg/kg/day x 3, days −5 to −3) followed by T-cell depleted (TCD) autologous PBSCT in adults with systemic sclerosis (SSc). To date, 5 pts (2 male, 3 female; median age, 44 yr; range, 39–59 yr) have undergone TCD PBSCT. Each pt had satisfactory PBSC collection with one 4-hr large-volume leukapheresis (LVL) after mobilization with CY (2.0 g/m2) plus G-CSF. Mean yields of CD34+ and CD3+ cells by LVL were 18.8 (range, 10.5–33.0) x 106/kg and 1.23 (range, 0.37–2.45) x 108/kg, respectively. To deplete T cells in the PBSC product we used a combination of CD34+ selection (Isolex 300i v 2.5; Baxter Oncology) and ex vivo incubation with anti-CD3 antibody (OKT3; Ortho Biotech), which resulted in a mean 5.2-log reduction of T cells (range, 4.7–6.3 log). The final PBSC products contained a mean of 9.94 (range, 4.8–13.0) x 106 CD34+ cells/kg and 1.34 (range, 0.06–4.54) x 103 CD3+ cells/kg. The daily dose of CY was 200 mg/m2 in the first 3 pts and 400 mg/m2 in the next 2 pts. Using rare-event flow cytometry, we found that the mean half-life (t 1/2) of CD3+ cells in these pts was biphasic; t 1/2 was 0.8 days from day −7 to −5 and 0.2 days from −5 to −3 days, correlating with ATG administration. In contrast, the mean t1/2 of CD3+ cells was 2.5 days in pts with hematologic malignancies receiving a myeloablative preparative regimen of CY, busulfan and etoposide. After PBSCT, the median nadir of WBC, neutrophil and platelet levels were 1.2 (range, 0.4–2.0), 0.9 (range, 0.1–1.7) and 135 (range, 114–185) x 109/L, respectively. One pt at the second CY dose level developed pericardial effusion and tamponade at day +5 and required surgical intervention. No pts developed opportunistic infections. All pts are alive at a median of 6.5+ months (range, 4.9+–15.5+ months) after PBSCT. Compared with pre-PBSCT levels, Rodnan total skin score (TSS) decreased by 10, 11 and 15 points, respectively, in 3 pts and increased by 5 and 8 points in 2 pts. One pt with worsening TSS at 12 months after PBSCT developed SSc renal crisis and requires hemodialysis. Of 3 pts with improved TSS, 1 has worsening polymyositis and 1 has recurrence of palpable tendon friction rubs. Even at the lowest CY dose, this immunosuppressive regimen provides significantly greater and more rapid T-cell kill than a conventional myeloablative regimen. The efficacy of this regimen and TCD-PBSCT in SSc is encouraging but requires longer followup and experience with a larger number of pts.