Low-dose immune tolerance induction for severe hemophilia A inhibitor patients:Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL

Importance:It remained unclear that the efficacy comparison between low-dose immune tolerance induction(LD-ITI)incorporating immunosuppressants(IS)when severe hemophilia A(SHA)patients had inhibitor-titer≥200 Bethesda Units(BU)/mL(LD-ITI-IS^(200) regimen)and LD-ITI combining with IS when SHA patients had inhibitor-titer≥40 BU/mL(LD-ITI-IS^(40) regimen).Objective:To compare the efficacy of the LD-ITI-IS^(200) regimen with that of the LD-ITI-IS^(40) regimen for SHA patients with high-titer inhibitors.Methods:A prospective cohort study on patients receiving LD-ITI-IS^(200) compared to those receiving LD-ITI-IS^(40) from January 2021 to December 2023.Both received LD-ITI[FVIII 50 IU/kg every other day].IS(rituximab+prednisone)was added when peak inhibitor tier≥200 BU/mL in the LD-ITI-IS^(200) regimen and≥40 BU/mL in the LD-ITI-IS^(40) regimen.Success is defined as a negative inhibitor plus FVIII recovery≥66%of the expected.Results:We enrolled 30 patients on LD-ITI-IS^(200) and 64 patients on LD-ITI-IS^(40),with similar baseline clinical characteristics.A lower IS-use rate was discovered in the LD-ITI-IS^(200) regimen compared to the LD-ITI-IS^(40) regimen(30.0%vs.62.5%).The two regimens(LD-ITI-IS^(200) vs.LD-ITI-IS^(40))had similar success rate(70.0%vs.79.7%),median time to success(9.4 vs.10.6 months),and annualized bleeding rate during ITI(3.7 vs.2.8).The cost to success was lower for LD-ITI-IS^(200) than for LD-ITI-IS^(40)(2107 vs.3256 US Dollar/kg).Among patients with peak inhibitor-titer 40-199 BU/mL,10 non-IS-using(on LD-ITI-IS^(200) regimen)and 28 IS-using(on LD-ITI-IS^(40) regimen)had similar success rates(70.0%vs.78.6%)and time to success(9.0 vs.8.8 months).Interpretation:In LD-ITI,IS are not necessary for inhibitor titer<200 BU/mL.

PK-tailored tertiary prophylaxis in patients with severe hemophilia A at beijing Children’s Hospital

Importance:Tertiary prophylaxis using a low-dose regimen is usually insufficient to prevent recurrent joint bleeding and deterioration in joint diseases in children with severe hemophilia A.Pharmacokinetic(PK)dosing is a useful approach to increase the precision and efficiency of prophylaxis.Objective:To explore the efficacy of PK-tailored tertiary prophylaxis in children with severe hemophilia A.Methods:We implemented a PK-tailored tertiary prophylaxis program for 15 boys with severe hemophilia A aged 5-16 years at Beijing Children’s Hospital.Following PK testing and a 6-month evaluation period(phase I),15 patients were divided in two groups according to individual PK data and actual bleeding:(1)a PK-tailored group[modified prophylaxis regimen according to PK data for the next 6 months(phase II);n=8]and(2)a maintenance group(continued the original regimen for the next 6 months;n=7).We compared the bleeding rate,infusion frequency,and factor VIII(FVIII)consumption between the two groups.results:In the PK-tailored group,the median annual joint bleeding rate was reduced from 7.8 in phase I to 1.4 in phase II,mean annual total factor consumption increased from 1619.0 IU/kg in phase I to 2401.9 IU/kg in phase II,and median infusion frequency for prophylaxis increased from 104 times/year in phase I to 156 times/year in phase II(P<0.05).Although the FVIII consumption increased,it remained at approximately half of the standard method.Interpretation:PK-tailored prophylaxis may represent a more efficient approach to individual prophylaxis in China,but further studies are required to verify this.

Pharmacokinetic variability of factor VIII concentrates in Chinese pediatric patients with moderate or severe hemophilia A

Importance:The use of factor VIII(FVIII)concentrates under pharmacokinetic(PK)guidance has become the main approach for treatment of hemophilia.However,limited PK research has been conducted in Chinese pediatric patients.Objective:To investigate the PK parameters of various FVIII concentrates in Chinese pediatric patients.Methods:Seventy-nine patients were enrolled(28 treated with Kogenate FS^(®),23 treated with Advate^(®),and 28 treated with GreenMono^(™)).All enrolled patients participated in single-dose PK analysis after at least a 3-day washout period.Blood samples were collected predose,as well as at 1 h,9 h,24 h,and 48 h after infusion;FVIII levels were measured using a one-stage clotting assay,von Willebrand Factor Antigen(VWF:Ag)levels and blood types were also determined.PK parameters were evaluated by WAPPS-Hemo.Results:Mean values of terminal elimination half-life time(t_(1/2))for the Kogenate FS^(®),Advate^(®),and GreenMono^(™)FVIII groups were 12.24 h,10.18 h,and 9.62 h;median clearance values were 4.16,6.23,and 5.11 mL kg^(-1)h^(-1);and median in vivo recovery values were 1.97,1.55,and 1.61 IU/dL per IU/kg.Longer t_(1/2),higher in vivo recovery,and lower clearance were observed in patients with higher VWF:Ag level who were treated with recombinant concentrates.Interpretation:Chinese pediatric patients with hemophilia had FVIII PK characteristics similar to those previously observed in non-Chinese children,including large variation among individuals.VWF:Ag level and FVIII brand were associated with differences in FVIII PK.Thus,PK-guided dosing should be used to optimize individualized therapy in Chinese children.