Early administration of cyclosporine may reduce the incidence of cytokine release syndrome after HLA-haploidentical hematopoietic stem-cell transplantation with post-transplant cyclophosphamide.

Cytokine release syndrome (CRS), occurring in more than 70% of HLA-haploidentical hematopoietic stem-cell transplantations with post-transplant cyclophosphamide (PT/CY-haplo), can lead to hemodynamic instability and worsen clinical outcomes. A calcineurin inhibitor is initiated after cyclophosphamide administration in the commonly used PT/CY regimens. Here, we conducted a phase I/II, prospective, single-center trial of PT/CY-haplo to evaluate the safety and efficacy of cyclophosphamide on days 3 and 5 along with cyclosporin and mycophenolate mofetil started from day - 1. Thirty-five adults with hematologic malignancies were enrolled. Myeloablative and reduced-intensity conditioning were used in 25 and 10 patients, respectively. Graft sources were bone marrow in 11 patients and mobilized peripheral blood stem cells in 24 patients. Disease-free survival on day 100, the primary endpoint, was 86% (95% confidence interval (CI), 69-94), which was over the predefined threshold of 50%. Unexpectedly, only 20% (95% CI, 8.4-37) of patients developed fever of > 38 °C early after graft infusion, all CRS grade 1, and all of which resolved just after cyclophosphamide administration. The cumulative incidences of grades II-IV acute graft-versus-host disease (GVHD), III-IV acute GVHD, and moderate-severe chronic GVHD were 23% (95% CI, 11-38), 6% (95% CI, 1-17), and 11% (95% CI, 4-25), respectively. The 3-year overall survival rate was 49% (95% CI, 31-64). Our results suggest that administration of cyclosporine and mycophenolate mofetil prior to PT/CY can reduce the frequency and severity of CRS without increasing GVHD. UMIN Clinical Trial Registry numbers: 000006631 and 000015694.