Discussions
death, IST, haematopoiesis, hair hyperplasia, gingival hyperplasia, aplastic anaemia
GINGIVAL HYPERPLASIA, APLASTIC ANAEMIA
As a TPO-RA, EPAG has been found to enhance haematopoiesis in AA patients and has recently been applied in AA treatment. Common EPAG application in AA includes EPAG monotherapy and EPAG combination therapy, among which EPAG + ATG+CsA or EPAG plus oral immunosuppressive therapy is the major option. A phase-3 randomized clinical trial found that EPAG + ATG+CsA was superior in terms of the ORR, CRR and duration of response compared with ATG+CsA for newly diagnosed SAA patients [For our primary outcome, we found that for refractory/relapsed AA patients, EPAG+tacrolimus was superior in terms of the ORR at the 6th month compared with EPAG monotherapy. Like CsA, Tacrolimus is also an inhibitor of calcineurin. Compared with CsA, tacrolimus has 100 times stronger inhibitory activity on calcineurin, no side effects of hair hyperplasia and gingival hyperplasia and less damage to renal function. Alsultan et al. [EPAG+tacrolimus was as tolerable as EPAG monotherapy in our trial. The AE rate of EPAG+tacrolimus in patients with refractory/relapsed AA was 20% to 30%, which was lower than the AE rate reported in previous studies on EPAG monotherapy for relapsed/refractory AA patients [In this study, there was no significant difference in the death rate or overall survival curves between the EPAG+tacrolimus group and the EPAG monotherapy group. In previous studies on refractory/relapsed AA patients receiving EPAG therapy, the reported clonal evolution rate ranged between 8.0% and 14.3%, and the death rate fluctuated between 0% and 8% [Our study also analysed the predictors that possibly affected the response/relapse rate for EPAG+tacrolimus or EPAG monotherapy. For the EPAG+tacrolimus group, OR patients had significantly higher absolute reticulocyte counts than NR patients, although multivariate analysis found that the absolute reticulocyte count was not independently related to the ORR in the EPAG+tacrolimus group. The correlation between the absolute reticulocyte count and the ORR was also reported in a study on EPAG + ATG+CsA for newly diagnosed SAA patients [The post hoc age subgroup analysis suggested that the superiority of EPAG+tacrolimus over EPAG monotherapy might be more prominent in the <60-year-old subgroup: the ORRs at the 6th month and the last follow-up were significantly higher, and the difference between RFS curves in this subgroup was also significant. The ORR of EPAG monotherapy group at 12A post hoc analysis of relapsed and refractory patients separately revealed that the advantage of EPAG+tacrolimus over EPAG monotherapy seemed to be more obvious in relapsed patients than in refractory patients. The baseline haemoglobin level of relapsed patients receiving EPAG+tacrolimus treatment was higher than that of patients receiving EPAG monotherapy, but baseline haemoglobin has not been identified as a factor related to response in previous studies on EPAG + IST or EPAG treatment for AA patients. This finding was reasonable since refractory patients had failed to respond to IST before they were enrolled, and the addition of tacrolimus, another immunosuppressant, might not be helpful for this subgroup of patients.This is a large study of EPAG treatment for refractory/relapsed AA patients, and to our knowledge, it is the first trial to compare the efficacy and safety of EPAG+tacrolimus and EPAG monotherapy in aplastic anaemia patients. The present study found that the clinical efficacy of EPAG+tacrolimus was better than that of EPAG monotherapy, and the safety and clonal evolution rate of the two groups were comparable. In addition, post hoc analysis indicated that the superiority of EPAG+tacrolimus tended to be more prominent in younger and relapsed patients. Nevertheless, further studies are needed to compare tacrolimus to CsA to figure out whether tacrolimus could become a superior alternative for CsA in terms of combination with EPAG. There are some limitations in our study: to guarantee a better tolerance of EPAG for enrolled patients, a 2-week ramp-up of EPAG to a maximum dose was set, and this regimen possibly contributed to the lack of a difference in patient response observed at the 3