Clinical Study Of Improved Immunosuppressive Therapy In Children With Acquired Aplastic Anemia

Part 1 Clinical study of cyclosporine combined with prednisone in the treatment of children with acquired aplastic anemiaObjective To explore the clinical efficacy,influencing factors,adverse reactions and prognosis of improved immunosuppressive therapy cyclosporine combined with prednisone in the treatment of children with acquired aplastic anemia.Methods The clinical data of 76 children with aplastic anemia patients diagnosed and treated at the Department of Pediatrics in our hospital from January2015 to June 2021 were retrospectively analyzed.According to different treatment methods,they were divided into cyclosporine combined with intermittent prednisone pulse group(group A,n =44),cyclosporine combined with low-dose prednisone group(group B,n=32).The efficacy and safety of the two methods were evaluated,the efficacy of non-severe aplastic anemia and severe aplastic anemia were compared within the group;the efficacy and adverse reactions of each group were compared between the groups,and the influencing factors of the efficacy were discussed.Results After 6 months of treatment and the end of the follow-up,blood routine related indexes of the two groups were significantly improved compared with the initial diagnosis.At 6 months of treatment,4 cases achieved complete remission(3 cases in group A,1 case in group B),32 cases were in partial remission(19 cases in group A,13 cases in group B),and 40 cases were in non-remission(22 cases in group A,18 cases in group B),the overall response rate was 47.4%(50% in group A,43.8%in group B).The effective rates of severe aplastic anemia and very severe aplastic anemia in group A were both 50%,and the effective rates of severe aplastic anemia and very severe aplastic anemia in group B were 50% and 25%,respectively.As of December 31,2021,median follow-up was 36.7 months.23 cases achieved complete remission(14 cases in group A,9 cases in group B),29 cases were in partial remission(17 cases in group A,12 cases in group B),and 24 cases were in non-remission(13cases in group A,11 cases in group B)),the overall response rate was 68.4%(70.5%in group A and 65.6% in group B).The effective rates of severe aplastic anemia and very severe aplastic anemia in group A were 73.3% and 85.7%,respectively,and the effective rates of severe aplastic anemia and very severe aplastic anemia in group B were 66.7% and 25%,respectively.For very severe aplastic anemia patients,there was a statistically significant difference in curative effect between group A and group B at the end of follow-up(P<0.05).Multivariate analysis in group A showed that platelet count at the initial diagnosis was the influencing factor for the curative effect(P<0.05),and multivariate analysis in group B showed that the presence of autoantibodies at the initial diagnosis and the presence of very severe aplastic anemia were the influencing factors for the curative effect(P<0.05).Parallel multivariate analysis of the two groups showed that gender and the presence of autoantibodies at the initial diagnosis were the influencing factors of the curative effect(P<0.05).Male patients or patients with autoantibodies at the time of initial diagnosis have better efficacy.There were 3 patients(9.1%)and 1patient(4.5%)with recurrence in group A and group B,respectively.One patient in each group died,and no clonal evolution occurred in either group.There was no significant difference in the 5-year overall survival rate(97.2% VS 95.7%,P>0.05)and 5-year event-free survival rate(57% VS 63.5%,P>0.05)between groups A and B.The adverse reactions of the two groups of patients included hypertrichosis,hypothyroidism,hyperuricemia,gingival hyperplasia,full moon face,impaired liver and kidney function,short stature,precocious puberty,etc.Group A was more likely to have full moon face than group B(P<0.05).The patient’s adverse reactions improved after symptomatic treatment or reduction and withdrawal of immunosuppressive drugs.Conclusions 1.Cyclosporine combined with prednisone has good efficacy and safety in the treatment of children with acquired aplastic anemia,and can be used as an alternative treatment option when standard treatment methods cannot be selected.2.Cyclosporine combined with intermittent prednisone pulse therapy has a good effect in the treatment of very severe aplastic anemia;cyclosporine combined with prednisone has a better effect in the treatment of male or newly diagnosed aplastic anemia patients with autoantibodies.3.Compared with cyclosporine combined with low-dose prednisone in the treatment of aplastic anemia,cyclosporine combined with intermittent prednisone pulse is more likely to appear full moon face.In addition,it is recommended to pay attention to the adverse reactions related to the endocrine system in patients after immunosuppressive therapy,such as hypothyroidism,short stature,sexual precocious etc.Part 2 Clinical study of tacrolimus combined with prednisone in the treatment of children with acquired aplastic anemiaObjective To explore the clinical efficacy,adverse reactions and prognosis of improved immunosuppressive therapy tacrolimus combined with prednisone in the treatment of children with acquired aplastic anemia.Methods A retrospective analysis of the clinical data of 24 children with aplastic anemia patients who were treated with tacrolimus at the initial diagnosis or changed to tacrolimus due to cyclosporine-resistance/intolerance in the pediatric department of our hospital from January 2015 to June 2021.According to different treatment methods,they were divided into tacrolimus combined with intermittent prednisone pulse group(n=8,3 cases of severe aplastic anemia,5 cases of non-severe aplastic anemia),tacrolimus combined with low-dose prednisone group(n=16,6cases of severe aplastic anemia and 10 cases of non-severe aplastic anemia).To evaluate the efficacy and safety of tacrolimus combined with prednisone,and to compare the adverse reactions of tacrolimus combined with prednisone and cyclosporine combined with prednisone.Results After 6 months of tacrolimus treatment,only 4 patients(16.7%)achieved partial remission(including 3 patients in the tacrolimus combined with intermittent prednisone pulse group),the rest were in non-remission.As of December31,2021,median follow-up was 31.3 months.The curative effect achieved complete remission in 2 cases(both in the tacrolimus combined with intermittent prednisone pulse group),partial remission in 9 cases(including 4 cases in the tacrolimus combined with intermittent prednisone pulse group),and non-remission in 13 cases,with the overall response rate was 45.8%.The overall response rate of patients with tacrolimus combined with intermittent prednisone pulse therapy was 75%,and the effective rates of severe aplastic anemia and non-severe aplastic anemia were 100% and 60%,respectively.In the treatment of tacrolimus combined with low-dose prednisone,5 patients achieved partial remission and 11 patients were in non-remission,with an overall response rate of 31.3%.The effective rates of severe aplastic anemia and non-severe aplastic anemia were 16.7% and 40%,respectively.There was no difference in the efficacy of tacrolimus combined with prednisone in the treatment of aplastic anemia in different gender,age,and classification at the time of initial diagnosis(P>0.05).Eight patients(3 cases of severe aplastic anemia,5 cases of non-severe aplastic anemia)were directly treated with tacrolimus at the initial diagnosis.The final curative effect reached 2 cases with complete remission,4 cases with partial remission,and 2 cases with non-remission.The overall response rate was 75%.The effective rates of severe aplastic anemia and non-severe aplastic anemia were 66.7% and 80%,respectively.The effective rates were 80% and 66.7% for those who were directly treated with tacrolimus combined with intermittent prednisone pulse therapy(n=5)and those who were directly treated with tacrolimus combined with low-dose prednisone(n=3),respectively.Sixteen patients(6 cases of severe aplastic anemia,10 cases of non-severe aplastic anemia)were cyclosporine-resistant/intolerant and then changed to tacrolimus.The final response was partial remission in 5 patients and non-remission in 11 patients.The overall response rate was 31.3%.The effective rates of severe aplastic anemia and non-severe aplastic anemia were 33.3% and 30%,respectively.The effective rates were 66.7% and 23.1% for those who were switched to tacrolimus combined with intermittent prednisone pulse therapy(n=3)and tacrolimus combined with low-dose prednisone therapy(n=13)due to cyclosporine-resistance/intolerance,respectively.Whether it was directly treated with tacrolimus at the initial diagnosis or switched to tacrolimus to treat aplastic anemia after cyclosporine-resistance/intolerance,there was no difference in the efficacy of different gender,age,and classification at the initial diagnosis(P>0.05).No recurrence or clonal evolution occurred in 24 patients,and only 2 died.Adverse reactions include hypothyroidism,hyperuricemia,impaired liver and kidney function,respiratory tract infection,etc.Compared with the adverse reactions of tacrolimus combined with prednisone and cyclosporine combined with prednisone,there were fewer adverse reactions of hypertrichosis and gingival hyperplasia(P<0.05).The patient’s adverse reactions improved after symptomatic treatment.Conclusions 1.Tacrolimus combined with prednisone has good efficacy and safety in the treatment of newly diagnosed children with acquired aplastic anemia,and can be used as an alternative treatment option when standard treatment methods cannot be selected,but whether it is recommended as second-line treatment after cyclosporine-resistance/intolerance still needs to be further explored.2.Compared with tacrolimus combined with low-dose prednisone in the treatment of aplastic anemia,tacrolimus combined with intermittent prednisone pulse may be more effective,especially for severe aplastic anemia.3.Compared with cyclosporine in the treatment of aplastic anemia,tacrolimus has fewer adverse reactions of hypertrichosis and gingival hyperplasia.