Recombinant Human Thrombopoietin Plus High-dose Dexamethasone As Front-line Treatment For Adult Immune Thrombocytopenia

Objective:Primary immune thrombocytopenia(ITP)is an acquired thrombocytopenia without obvious prodromata resulting from increased platelet destruction and decreased platelet production.The pathogenesis of ITP involves antiplatelet antibodies,T cell immune abnormalities,and impaired megakaryocytopoiesis.The clinical presentations of adult ITP vary from no symptoms to severe bleeding.Corticosteroids are recommended as the standard front-line therapy for many years which can raise-platelet counts rapidly,however,the sustained response rates are low and the considerable adverse effects during long-term cannot be ignored.Better first-line therapies are needed.Recently,some combination therapies had the encouraging results as the first-line treatment in newly diagnosed ITP patients,such as rituximab plus high-dose dexamethasone(HD-DXM),which yielding higher sustained response rates at 6 months and longer time to relapse compared to HD-DXM monotherapy.However,there was no demonstrable difference in early response rates and the increased adverse events as well as higher costs should not be ignored.Thrombopoietin(TPO)is the primary regulator of thrombopoiesis.Many studies have found that TPO have profound effects on megakaryocyte development,platelet production and restoring immune tolerance.Recombinant human thrombopoietin(rhTPO)is a glycosylated,full-length peptide produced by CHO cells which is identical to the endogenous TPO.The efficacy of rhTPO in raising platelet count has been used in clinical trials with great success.As the immunosuppressive therapy,HD-DXM could reduce platelet destruction by modulating T-cell immune abnormalities.TPO can directly stimulate platelet production in addition to affecting immunomodulation.HD-DXM and rhTPO may have a synergistic effect based on these mechanisms.Recently,two small clinical studies have examined the efficacy and safety of TPO-RA as the frontline therapy in treatment-naive adult ITP patients.However,more clinical trails with advanced evidence-based medical evidence are needed.This is the first prospective,multicenter,randomized,controlled clinical trial on the largest cohort comparing the efficacy and safety of high-dose dexamethasone plus rhTPO vs HD-DXM monotherapy as the first-line treatment for newly diagnosed adult ITP patients.Methods:Newly-diagnosed,treatment-naive primary ITP patients were randomly assigned 1:1 to receive HD-DXM with or without rhTPO.A total of 240 patients(120 in each study group)were needed.DXM was administered orally with 40 mg daily for first 4 consecutive days to both groups.The 4-day administration of HD-DXM was repeated at days 11 to 14 if lack of response.The experimental group patients received subcutaneously rhTPO with a daily dose of 300U/kg body weight during the first 14 days.Patients with platelet counts>100×109/L or>50×109/L increase of the baseline PLT count can discontinue the rhTPO therapy.Study visits were scheduled every 1 month until the day of relapse.The follow-up time can be extended as long as possible if conditions allow.The primary endpoint was the initial response rates.The secondary endpoints were rates of sustain R and CR at the end of month 6,time to response(TTR),bleeding scores,duration of response and adverse events.Results:259 patients were screened,196 patients analyzed in the ITT population:100 in the HD-DXM+ rhTPO group and 96 in the HD-DXM group.For the primary endpoint,overall response was greater among patients in the HD-DXM+rhTPO group compared with those in the HD-DXM arm(89%vs 67%,P<0.001)at day 14.HD-DXM+ rhTPO also resulted in a higher incidence of CR,which was achieved in 75%(75/100)of patients in the HD-DXM+ rhTPO group compared with 43%(41/96)in the HD-DXM group(P<0.001).At the end of the 6th month,the sustained overall response rate was 51%in the HD-DXM+ rhTPO group,compared with the 37%achieved in the HD-DXM group(P=0.022,table 1),the CR rate was also greater in the experimental arm(46%vs 32%,P=0.043).The overall duration of response was higher in the HD-DXM+ rhTPO group throughout the follow-up period,analyzed by the Kaplan-Meier estimate.The median bleeding score was 2(0-5)in the two groups.The percent of patients with any bleeding symptoms was reduced to 1/3.There was no statistical difference in the time to response between the two groups[4(2-14)days in the HD-DXM+ rhTPO group vs 4(2-29)days in the HD-DXM group].No significant correlation was found between the presence of anti-GPIIb-IIIa autoantibody and the incidence of baseline platelet count,bleeding score,initial response and SR.20 patients(20%)in the HD-DXM+ rhTPO group and 22(23%)patients in the HD-DXM group received the second cycle of HD-DXM treatment(P=0.5),The study drugs were well tolerated generally.Most of the adverse events were mild.The total incidence of drug-related adverse reactions was not statistically different between the two arms.2 cases of cerebral hemorrhage and 1 cerebral infarction occurred in the experimental group.The cerebral hemorrhages were considered to be related to severe thrombocytopenia.Conclusions:1.The addition of rhTPO to DXM in treatment of newly diagnosed ITP improved the initial response rate obviously and yielded better sustained response rates at the end of the 6 month and 1 year than DXM alone.The duration of response was also longer in the experimental group.2.The study drugs were well tolerated.The relationship between cerebral infarction and the administration of rhTPO was uncertain,but we proposed that rhTPO should be carefully adjusted in rapid responders in order to reduce the risk of thrombosis.3.High-dose dexamethasone combined with rhTPO could be used as the first choice for first-line treatment of adult ITP.