Cyclosporine and MTX have been the standard therapy for GVHD prophylaxis [1
]. Recently, many studies have demonstrated the advantage of using tacrolimus and MTX for GVHD prophylaxis in adult patients [6
]. In addition, it has also been shown that minidose MTX does not compromise the efficacy of GVHD prophylaxis, and it simultaneously reduces the risk of severe treatment-related mucositis [7
]. The use of tacrolimus and minidose MTX in the prevention of aGVHD has been extensively evaluated in adults undergoing allogeneic HSCT [7
]; however, studies on their activity in pediatric patients are limited [13
]. The results from our study demonstrate that the use of tacrolimus and minidose MTX in aGVHD prophylaxis is safe and effective in pediatric patients.
Przepiorka et al. [13
] reported the cases of 10 pediatric patients who underwent mismatched CB transplants. In their study, the incidence of grade II aGVHD was 77% with no grade III-IV aGVHD, and cGVHD was found in 22% cases and limited to the skin. Yanik et al. [14
] reported the cases of 41 pediatric patients who received tacrolimus and standard doses of MTX for GVHD prophylaxis during HSCT from related and unrelated donors. In their study, the incidence of grades II-IV and III-IV aGVHD was 55% and 30%, respectively, in unrelated transplant recipients; 19% of related transplant recipients developed grade III-IV aGVHD, while 43% developed cGVHD. In a study involving 24 pediatric patients who had undergone 26 HSCT procedures reported by Sabapathy et al. [15
], the incidence of grade II-IV aGVHD was 17%, with 4% of the patients developing grade III aGVHD and 5% developing extensive cGVHD; there was no incidence of grade IV aGVHD.
In our study, grade II-IV aGVHD occurred in 5 patients (31%). Only 1 patient who received an unrelated BM transplant developed grade III-IV aGVHD (6.2%). The incidence of aGVHD was 22.2% in the related donor group, and 42.8% in the unrelated donor group. Grade III-IV aGVHD was not found to occur in the related donor group. There was no incidence of cGVHD in our study. Our results show that the frequency and severity of aGVHD are similar to those reported in previous pediatric studies; however, the frequency of cGVHD is lower than that reported earlier. It was not possible to accurately assess the risk of GVHD in our study due to the small study cohort, the variety of the sources of stem cells used, and the degree of the HLA matching.
The assessment of the tolerance of the drug regimen, especially in pediatric patients, was one of the principal aims of our study. The major adverse events associated with tacrolimus in adult allogeneic HSCT include nephrotoxicity (32-93%), neurotoxicity, hyperglycemia, and hypertension [3
]. In contrast to adult trials, hypomagnesemia was the most common adverse event observed in our study, occurring in 88.2% of pediatric patients. Nephrotoxicity and hyperglycemia occurred in 23.5% of the patients, but did not require hemodialysis or insulin medication. Hypertension occurred in 5.8% of our patients, which was lower than that observed in the adult trials. Unlike earlier adult studies, neurotoxicity and HUS/TTP were not significant in pediatric patients.
For tacrolimus, optimal efficacy with minimal toxicity is maintained by careful monitoring to ensure levels between 5 and 15 ng/mL. Results of pharmacokinetic studies in children undergoing solid organ transplantation suggest that clearance of tacrolimus was increased, and hence, the dosage required for children might be different from that required for adults [21
]. Additional data has shown that pediatric patients undergoing HSCT have a higher clearance of tacrolimus than that of adults [22
]. Our results show that an increased mean dose of tacrolimus was required to maintain therapeutic blood levels in the younger group (<8 years old) compared to the older group (≥8 years of age).
In summary, tacrolimus and minidose MTX in pediatric patients undergoing allogeneic HSCT were well tolerated and may be considered an effective therapy for the prevention of aGVHD. In addition, young children (<8 years old) undergoing HSCT may need to receive a higher initial dose of tacrolimus in order to maintain therapeutic levels. However, the limitations in our study for assessing the efficacy of tacrolimus and minidose MTX in children could arise from the small study cohort, the variety of stem cell sources used, and the degree of the HLA matching. Further evaluation consisting of prospective large, controlled studies to assess effective GVHD prophylactic regimens in pediatric patients is warranted.