Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disease which arises due to self-destruction of circulating platelets. Failure to respond or maintain a response to first-line treatment can lead to refractory/relapsed (R/R) ITP. The mechanism remains complicated and lacks a standard clinical treatment. Sirolimus (SRL) is a mammalian target of rapamycin (mTOR) inhibitor that has been demonstrated to inhibit lymphocyte activity, indicating potential for SRL in treatment of ITP. Activation of the mTOR pathway in autoimmune diseases suggests that SRL might be a useful agent for treating ITP. Accordingly, we initiated an open-label, prospective clinical trial using SRL for patients with R/R ITP (ChiCTR-ONC-17012126). The trial enrolled 86 patients, each dosed with 2-4 mg/day of SRL. By the third month, 40% of patients (34 of 86) achieved complete remission (CR) and 45% of patients (39 of 86) achieved partial remission (PR), whereby establishing an overall response rate (ORR) of 85%. By 6 months of treatment, 41% of patients (32 of 78) achieved CR and 29% of patients (23 of 78) achieved PR, establishing an ORR of 70% without serious side effects. After 12 months follow-up, the ORR remained at 65%. We also found that SRL treatment exhibited higher efficacy in achieving CR in ITP patients who were younger than 40 years old or steroid dependent by univariate analysis. Importantly, in patients who responded, SRL treatment was associated with a reduction in the percentage of Th2, Th17 cells, and increase in the percentage of M-MDSCs and Tregs, indicating that SRL may reestablish peripheral tolerance. Taken together, Sirolimus demonstrated efficacy as a second-line agent for R/R ITP.

Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern

“…Recently, sirolimus has shown some promise for treatment of relapsed/refractory ITP, with a response rate of 85% in ITP patients after 3 months of treatment and 75.6% in patients with ITP or other autoimmune cytopenias after a median of 14 months’ treatment and 18 months’ follow‐up; treatment was generally well tolerated. 50 , 51 The combination of danazol plus all‐trans retinoic acid was recently evaluated in a phase 2 trial for second‐line management of adults with primary ITP. After 52 weeks of follow‐up, 38% of patients (20/45) achieved complete response versus 8% of patients (4/48) receiving danazol alone.…”

Decreasing lncRNA PVT1 causes Treg/Th17 imbalance via NOTCH signaling in immune thrombocytopenia

“…Treg cells inhibit the expression of IL-17 by secreting IL-10 and TGF-β, which plays an immunosuppressive role [19]. Studies have demonstrated that the imbalance of Treg/Th17 cells is involved in ITP pathogenesis and inhibition of Th17 cell differentiation can ameliorate ITP [4,[20][21][22]. Similarly, in our study, Th17 cells were up-regulated and Treg cells were down-regulated in CD4 + T cells from ITP patients compared with the NC group, indicating that the increase of Th17 cells resulted in an increased inflammatory response and a weakened immunosuppression function, further promoted the onset of ITP.…”

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside

“…Importantly, in patients who responded, SRL treatment was associated with a reduction in the percentage of Th2, Th17 cells, and increase in the percentage of monocytic-Myeloid-Derived Suppressor Cells (M-MDSCs) and T regulatory cells (Tregs), indicating that SRL may re-establish peripheral tolerance. To date, this is the largest prospective study to date evaluating SRL as a rescue therapy in patients with R/R ITP ( 105 ). ITP is a heterogeneous disease with a complex pathobiology; based on our experience and others’, we believe that mTORi can be effective in treating refractory ITP, but more randomized controlled trials (RCTs) are needed to support these observations.…”

“…Sirolimus has benefited patients with primary autoimmune cytopenias, possibly by stimulating Tregs ( 105 , 106 ). In the pathogenesis of AIHA, increased expansion or function of Treg cells can inhibit the over-activation of effector T cells and other immune cells, thus regulating the production of excess RBC antibodies ( 107 , 108 ).…”