The Optimal Initiation Timing for Cyclosporine in Allogeneic Transplantation, Earlier Is Better with the Price of Higher Rate of Chronic Gvhd.

Cyclosporine (CSA) is the backbone of graft vs. host disease (GVHD) prophylaxis in the last decades. It is established that CSA levels in the 1^st weeks after transplant are critical for the rate and severity of GVHD. Initially, we gave CSA starting on day -1 in all our protocols. However, 8 years ago, we have changed CSA initiation in most of our protocols to day -4 in order to have stable, controlled therapeutic blood levels of CSA prior to transplant. Since nowadays the use of CSA is the most widespread prophylaxis of GVHD, we found it essential to compare the initiation of CSA on day -4 to day -1, consecutively determining the preferred initiating timing of CSA for patients who undergo allogeneic transplantations.

Out of 1716 patients that underwent allogeneic transplantation, we identified 2 groups of patients that received T-cell repleted grafts in which only CSA was used for GVHD prevention, starting on days -1 or -4 (n=219 and 261 respectively). The guidelines for CSA cessation and DLI were uniform in both groups. Both groups were compared for age, sex, donor type and matching, disease, disease status upon transplant, graft type, engraftment, GVHD (both acute and chronic), GVHD associated death and overall survival.

The groups were found to be equal for age (p=0.83), sex (p=0.58), donor type (p=0.54), matching (p=0.98), disease type (malignant or non-malignant; p=0.25), graft type (PBSC or BM; p=0.45) and disease status (remission or active; p=0.42). The median time to ANC>500 was 16 and 15 days in the CSA -1 and -4 groups respectively with a trend toward better engraftment with initiation of CSA on day -4 (figure 1A, P=0.07). However, platelet engraftment was significantly better with CSA -4, with a median of 14 and 12 days in the CSA -1 and -4 groups respectively (figure 1B, p=0.0005). 112 and 138 patients developed acute GVHD (aGVHD) of any grade, respectively. Out of them 54% and 44% had severe (grade 3-4) aGVHD (p=0.45). The median time to aGVHD was similar, with a median of 29 and 28.5 days in the CSA -1 and -4 groups respectively (p=0.54). However, 64 patients developed cGVHD in the CSA -1 group, while 102 did so in the CSA -4 group (figure 2A, p=0.0002. Hazard ratio 0.59, 95% CI 0.37 to 0.73). Of these patients, 46.8% and 40.2% of the patients had extensive cGVHD (p=0.70), respectively. Additionally, despite lower GVHD rate in the CSA -1 group, GVHD associated death occurrence was more frequent then in the CSA -4 group (41/148 and 17/132 patients, p=0.02). Kaplan Meier analysis of all cause mortality showed higher mortality in the CSA -1 group (67.6% and 50.5%, figure 2B, p=0.074. Hazard ratio 1.24, 95% CI 0.98 to 1.58).

The initiation of CSA on day -4 improves engraftment, conversely increases the risk for cGVHD of any grade (possibly through prevention of tolerance), but reduces the risk of GVHD associated death and improves overall survival.

No relevant conflicts of interest to declare.