Impact of Cyclosporine a (CsA) Concentration on the Incidence of Severe Acute Graft-Versus-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT).
Authors: Mallard Florent , Brissot Eolia , Chevallier Patrice , Guillaume Thierry , Delaunay Jacques , Ayari Sameh , Dubruille Viviane , Legouill Steven , Mahe Beatrice , Gastinne Thomas , Blin Nicolas , Saulquin Beatrice , Moreau Philippe , Harousseau Jean-Luc , Mohty Mohamad 
Published: April 2020

Abstract
CsA is widely used as the backbone immunosuppressive agent for GVHD prevention after allo-SCT. Previous studies have demonstrated that the immunosuppressive effects of CsA (eg. inhibition of calcineurine in lymphocytes) may be correlated with CsA blood concentration, especially in the context of solid organ transplantation. This report aimed to investigate the impact of CsA concentrations in the early post allo- SCT period, on the incidence of severe acute GVHD, in 85 consecutive patients treated in a single centre between Jan. 2006 and Jan. 2008, and for whom CsA concentrations in the blood were monitored weekly after the start of infusion. 85 patients (45 males) received CsA (usually at 3 mg/Kg/d, 2 or 3 days prior to graft infusion) as a 24-h continuous infusion until hematopoietic recovery and switch to oral formulation. Dose modifications of CsA were performed to maintain adequate trough blood levels and to prevent nephrotoxicity. Patients’ and donors characteristics were as follow: median age: 51 (range, 18–67), 46 (54%) female donors, 33 (39%) myeloid malignancies, 49 (58%) lymphoid malignancies, and 3 cases of SAA. The stem cell source was PBSC in 66 (78%) patients, while bone marrow was used in 19 (22%) patients. 37 (43.5%) were transplanted from a matched related donor, and 48 (56.5%) from a matched unrelated donor. A myeloablative conditioning regimen was used in 24 (28%) patients, and 61 (72%) received a reduced intensity regimen. The median concentrations of CsA in the blood at 1, 2, 3 and 4 weeks after allo-SCT were 348 (range, 172–733), 284 (range, 137–535), 274 (range, 107–649), and 247 (37–695) ng/mL respectively. All patients engrafted at a median of 17 (range, 0–42) days after allo-SCT. With a median follow-up of 16 (range, 5–29) months, grade 2–4 acute GVHD occurred in 36 patients (42%) at a median of 29 (range, 6–100) days after allo-SCT. The incidence of severe grade 3–4 acute GVHD was 23% (95%CI, 14–32%). In this cohort, all acute GVHD risk factors (age, donor-recipient gender, CMV serostatus, ABO compatibility, diagnosis, disease status, stem cell source, donor type, conditioning regimen type, GVHD prophylaxis regimen, CsA concentrations) were assessed. In multivariate analysis, we found that higher whole-blood CsA concentration in the first week following graft infusion, and before onset of acute GVHD was the strongest parameter significantly associated with a reduced the risk of severe grade 3–4 acute GVHD (P=0.01; RR=0.24; 95%CI, 0.08–0.73). Despite its retrospective nature, these data strongly indicate a close relationship between CsA trough blood concentration during the early post allo-SCT period and the severity of acute GVHD. Inadequate or insufficient early exposures of CsA can be a serious risk for developing severe acute GVHD. Therefore, precise monitoring of CsA concentrations and achievement of a high CsA target concentration may be an effective tool to prevent the onset of severe acute GVHD.