Efficacy And Safety Of Porcine ALG Compared To Rabbit ATG As First-line Treatment For Children With Acquired Aplastic Anemia

BackgroundAcquired aplastic anemia(AA)is a rare and life-threatening hematological disease characterized by pancytopenia and hypocellular bone marrow.Severe aplastic anemia(SAA)and very severe aplastic anemia(VSAA)are associated with high morbidity and mortality.AA is regarded as the result of autoimmune-mediated destruction of hematopoietic cells,as demonstrated by successful treatment with immunosuppressive therapy(IST).IST with horse ATG(h-ATG)and Ciclosporin(CSA)is a standard front-line treatment for SAA and transfusion-dependent NSAA when there is no histocompatible sibling donor for children and young adults or the patient’s age is>35-50 years old.However,h-ATG is not available in some countries,including China,due to manufacturing difficulties.Therefore,rabbit ATG(r-ATG)has been used as the first-line IST regimen in patients with AA.Porcine anti-lymphocyte immunoglobulin(p-ALG)was approved by the State Food and Drug Administration of China as a therapeutic agent in 2004.Despite its extensive use,no studies have compared the efficacy and safety of p-ALG vs.r-ATG combined with CSA as a first-line IST for children with AA.Purpose1.To compare the efficacy of p-ALG vs.r-ATG combined with CSA as a first-line IST for children with AA.2.To compare the safety of p-ALG vs.r-ATG combined with CSA as a first-line IST for children with AA.Methods1.Patients:Retrospectively analyzed the clinical data of pediatric patients with AA treated with first-line p-ALG or r-ATG plus CSA.2.The inclusion criteria:Patient≤16 years of age diagnosed with SAA or transfusion-dependent NSAA;no prior IST,except for CSA with or without androgens and corticosteroids and with or without intravenous immunoglobulin;ineligible for an HLA-identical sibling-donor hematopoietic stem cell transplantation(HSCT)or voluntarily chose IST,even if eligible for an HLA-matched sibling-donor transplant.3.Exclusion criteria:Diagnosis of Fanconi anemia,Dyskeratosis congenita(DKC)or other congenital bone-marrow-failure syndrome;evidence of myelodysplastic disease;paroxysmal nocturnal hemoglobinuria(PNH)and evidence of significant hemolysis;severe uncontrolled infection or unexplained fever>38.5℃;severe complications of the liver,renal,heart,or metabolic systems with a life expectancy<3 months.4.Treatment protocol:All patients were housed in sterile rooms with strict isolation from the start of therapy.Patients in the p-ALG group received 20 mg/kg/day p-ALG for 5 consecutive days;patients in the r-ATG group received 3 mg/kg/day r-ATG for 5 consecutive days.Prednisolone(1 mg/kg/day)was administered with the dose tapered over 1 month to prevent serum sickness.The CSA dose was 3-5 mg/kg per day administered from day 1 or diagnosis until the best response,then held for 3 months,followed by a slow taper until discontinuation.The blood trough concentration was monitored and maintained between 150 and 250 ng/Ml during CSA treatment before tapering.5.Response evaluation:Each patient was re-examined every 3-6 months after IST.We assessed the patient’s clinical manifestations and re-examined their complete blood cell count,hepatic and renal function,CSA concentration,PNH clone,or other clinical or laboratory evidence of clonal disease(including myelodysplastic syndrome and leukemia).Bone marrow smears and biopsies,as well as cytogenetic analyses,were re-examined according to clinical indications.Response was defined according to established criteria and was evaluated until the patient received further treatment.6.Endpoints:The primary endpoints were responses at 3,6,12,and 24 months after IST,and secondary endpoints were transplant free survival(TFS),Failure-free survival(FFS)and overall survival(OS)5 years after IST.Results1.Patient characteristics:189 consecutive AA patients who were≤16 years old received IST with p-ALG/r-ATG combined with CSA between January 2014 and November 2018.No significant differences in demographic or clinical features were observed between the two groups.The median follow-up for the p-ALG group was 1370(range,86-2025)days and that for the r-ATG group was 1416(range,22-2027)days.2.Response:There were no significant differences were observed in the overall response(OR)rates at 3,6,12,or 24 months(3 months:61.9%vs.67.4%,P=0.5;6 months:70.9%vs.73.9%,P=0.69;12 months:77.3%vs.73.3%,P=0.58;24 months:81.6%vs.78.6%,P=0.59)after either p-ALG-or r-ATG-based IST.No differences were found in the complete response(CR)rates between the p-ALG and r-ATG group(3 months:8.5%vs.6.5%,P=0.92;6 months:15.6%vs.17.4%,P=0.77;12 months:34.3%vs 40%P=0.49·24 months:57%vs 54.7%.P=0.8).3.Survival:There was no significant difference was found in 5-year OS between the p-ALG and r-ATG groups(88%for p-ALG group vs.92%for r-ATG group,P=0.64).No significant difference was observed in 5-year FFS between the two groups(65%for p-ALG group vs.63%for r-ATG group,P=0.49).No significant difference was detected in 5-year TFS between the two groups(84%for p-ALG group vs.78%for r-ATG group,P=0.087).4.Kinetics of lymphocyte depletion:There were significant differences in the absolute lymphocyte counts between the p-ALG and r-ATG groups on days 1,2,3,4,5,6,7,8,9,and 10,and at week 2,week 3,and 1 month after the IST treatment(P<0.05).5.Adverse events:No significant differences were observed between the p-ALG and r-ATG groups for most of the events,except fever and rigor,which were more prevalent in the r-ATG group(P=0.000 and P=0.000).Conclusions1.First-line IST use p-ALG or r-ATG combined with CSA induces high hematological recovery and excellent long-term survival for children with AA.2.The therapeutic efficacy and safety of p-ALG combined with CSA do not differ significantly from those of r-ATG combined with CSA as first-line therapy for children with AA.3.P-ALG has the advantage of significantly lower cost,less immunosuppressive and fewer transfusion reaction than r-ATG.