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Author: Zhou Qinghe This article is authorized by the author to publish by Yimaitong, please do not reprint without authorization
.
Immune thrombocytopenia (Immune thrombocytopenia, ITP) is caused by accelerated platelet destruction and insufficient platelet production by megakaryocytes.
It is a complex autoimmune disease with thrombocytopenia
.
The first-line treatment of ITP is corticosteroid therapy, such as prednisone 1mg/kg/d, for 2-4 weeks, and then gradually reduce the dose, mainly used to inhibit autoantibody production and platelet degradation
.
Splenectomy, rituximab, and thrombopoietin receptor agonists (TPO-RAs, such as Eltrodippa and Romipristin) are commonly used as second-line treatments and have a curative effect on some patients, but individual There is a big difference in reaction between
.
About 20%-30% of patients have low or no response to first-line and second-line treatment, and may develop relapse/refractory (R/R) ITP
.
R/R ITP patients refer to ITP patients who have little or no response after second-line treatment, and require long-term hospitalization to reduce bleeding and improve health-related quality of life
.
Splenectomy is an effective treatment for R/R ITP
.
Studies have shown that 1 year after splenectomy, 88.
7% of splenectomy patients achieve complete remission [1].
However, because the operation is invasive and may be related to infection and thrombosis, many R/R ITP patients refuse to undergo splenectomy.
.
Rituximab can also be used to treat ITP with a response rate of 40%-50%
.
In a clinical study, Tran et al.
reported [2] the efficacy of rituximab in the treatment of R/R ITP.
The response rate at 8 weeks after infusion was 44%, failing to reach the primary endpoint of 50% response.
.
Thrombopoietin (TPO) receptor agonists, such as Eltropopag and Romigrastim, have been shown to be safe and effective in the treatment of ITP
.
In a study in China, 57.
7% of patients with chronic ITP who were treated with Eltropopag had a platelet count of ≥50×109/L [3]
.
Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor.
It is widely used for immunosuppression after organ transplantation or hematopoietic stem cell transplantation.
However, some current studies have found that sirolimus can treat ITP and mTOR activation.
It is a sign of certain autoimmune diseases, such as systemic lupus erythematosus and ITP[4].
Studies have found that sirolimus can improve ITP caused by systemic lupus erythematosus[5]
.
The results of a single-center, prospective, one-arm study from Xinqiao Hospital indicate that sirolimus can promote and rebuild peripheral tolerance by regulating the T, B and myeloid cell subsets of patients with refractory ITP.
It is a safer and more effective second-line drug for the treatment of refractory ITP [6]
.
In this prospective one-arm study, 86 refractory ITP patients (22 men, 64 women) with platelet counts <50×109/L were eventually selected for the clinical trial
.
Inclusion criteria: Patients are required to fail corticosteroid therapy (prednisone, methylprednisolone, or dexamethasone) and have received at least one second-line treatment (including TPO, cyclosporine, splenectomy, rituximab or traditional Chinese medicine)
.
Sirolimus is administered orally at a dose of 2 mg/day (maximum initial dose is 4 mg/day), and the goal is to have a circulating plasma concentration of 5-15 ng/ml
.
The expected treatment time of sirolimus is 3 months, and then gradually reduced by 0.
5 mg/2 weeks
.
The patient received 12 months of follow-up care
.
The platelet count is measured every two weeks
.
The study found that by the third month, 40% of patients (34/86) achieved complete remission (CR), 45% of patients (39/86) achieved partial remission (PR), and the overall response rate (ORR) was 85 %
.
After 6 months of treatment, 41% of patients (32/78) got CR, 29% of patients (23/78) got PR, ORR was 70%, and there were no serious side effects
.
After 12 months of follow-up, the ORR remained at 65%
.
The study also found that through univariate analysis, the ORR in the third month after sirolimus treatment was 85%, 70% in 6 months after treatment, and 65% in 12 months after treatment (see the figure below)
.
The study also found that sirolimus showed higher efficacy in ITP patients who were younger than 40 years old or were steroid dependent
.
In responding patients, sirolimus treatment is associated with a decrease in the percentage of Th2 and Th17 cells, as well as an increase in the percentage of myeloid-derived suppressor cells (M-MDSC) and Treg, indicating that sirolimus may rebuild peripheral tolerance.
These results indicate that mTOR inhibitors can effectively treat refractory ITP, and mTOR inhibitors combined with low-dose steroids can provide a new and promising option for the treatment of ITP
.
References: 1.
Montalvo J, Velazquez D, Pantoja JP, Sierra M, López-Karpovitch X, Herrera MF.
Laparoscopic splenectomy for primary immune thrombocytopenia: clinical.
outcome and prognostic factors.
J Laparoendosc Adv Surg Tech A.
2014, 24: 466–470.
2.
Tran H, Brighton T, Grigg A, McRae S, Dixon J, Thurley D, et al.
A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study).
Br J Haematol.
2014, 167:243–251.
3.
Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, et al.
Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia.
Br J Haematol.
2017,176:101–10.
4.
Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE , et al.
Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.
Blood.
2016, 127:17–28.
5.
Lai ZW, Kelly R, Winans T, Marchena I, Shadakshari A, Yu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Poke" to read Original ", we make progress togetherYu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7 : 110.
Poke "read the original text" and we will make progress togetherYu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7 : 110.
Poke "read the original text" and we will make progress togetherSingle-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Stamp "Read the original" and we will make progress togetherSingle-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Stamp "Read the original" and we will make progress together
.
Immune thrombocytopenia (Immune thrombocytopenia, ITP) is caused by accelerated platelet destruction and insufficient platelet production by megakaryocytes.
It is a complex autoimmune disease with thrombocytopenia
.
The first-line treatment of ITP is corticosteroid therapy, such as prednisone 1mg/kg/d, for 2-4 weeks, and then gradually reduce the dose, mainly used to inhibit autoantibody production and platelet degradation
.
Splenectomy, rituximab, and thrombopoietin receptor agonists (TPO-RAs, such as Eltrodippa and Romipristin) are commonly used as second-line treatments and have a curative effect on some patients, but individual There is a big difference in reaction between
.
About 20%-30% of patients have low or no response to first-line and second-line treatment, and may develop relapse/refractory (R/R) ITP
.
R/R ITP patients refer to ITP patients who have little or no response after second-line treatment, and require long-term hospitalization to reduce bleeding and improve health-related quality of life
.
Splenectomy is an effective treatment for R/R ITP
.
Studies have shown that 1 year after splenectomy, 88.
7% of splenectomy patients achieve complete remission [1].
However, because the operation is invasive and may be related to infection and thrombosis, many R/R ITP patients refuse to undergo splenectomy.
.
Rituximab can also be used to treat ITP with a response rate of 40%-50%
.
In a clinical study, Tran et al.
reported [2] the efficacy of rituximab in the treatment of R/R ITP.
The response rate at 8 weeks after infusion was 44%, failing to reach the primary endpoint of 50% response.
.
Thrombopoietin (TPO) receptor agonists, such as Eltropopag and Romigrastim, have been shown to be safe and effective in the treatment of ITP
.
In a study in China, 57.
7% of patients with chronic ITP who were treated with Eltropopag had a platelet count of ≥50×109/L [3]
.
Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor.
It is widely used for immunosuppression after organ transplantation or hematopoietic stem cell transplantation.
However, some current studies have found that sirolimus can treat ITP and mTOR activation.
It is a sign of certain autoimmune diseases, such as systemic lupus erythematosus and ITP[4].
Studies have found that sirolimus can improve ITP caused by systemic lupus erythematosus[5]
.
The results of a single-center, prospective, one-arm study from Xinqiao Hospital indicate that sirolimus can promote and rebuild peripheral tolerance by regulating the T, B and myeloid cell subsets of patients with refractory ITP.
It is a safer and more effective second-line drug for the treatment of refractory ITP [6]
.
In this prospective one-arm study, 86 refractory ITP patients (22 men, 64 women) with platelet counts <50×109/L were eventually selected for the clinical trial
.
Inclusion criteria: Patients are required to fail corticosteroid therapy (prednisone, methylprednisolone, or dexamethasone) and have received at least one second-line treatment (including TPO, cyclosporine, splenectomy, rituximab or traditional Chinese medicine)
.
Sirolimus is administered orally at a dose of 2 mg/day (maximum initial dose is 4 mg/day), and the goal is to have a circulating plasma concentration of 5-15 ng/ml
.
The expected treatment time of sirolimus is 3 months, and then gradually reduced by 0.
5 mg/2 weeks
.
The patient received 12 months of follow-up care
.
The platelet count is measured every two weeks
.
The study found that by the third month, 40% of patients (34/86) achieved complete remission (CR), 45% of patients (39/86) achieved partial remission (PR), and the overall response rate (ORR) was 85 %
.
After 6 months of treatment, 41% of patients (32/78) got CR, 29% of patients (23/78) got PR, ORR was 70%, and there were no serious side effects
.
After 12 months of follow-up, the ORR remained at 65%
.
The study also found that through univariate analysis, the ORR in the third month after sirolimus treatment was 85%, 70% in 6 months after treatment, and 65% in 12 months after treatment (see the figure below)
.
The study also found that sirolimus showed higher efficacy in ITP patients who were younger than 40 years old or were steroid dependent
.
In responding patients, sirolimus treatment is associated with a decrease in the percentage of Th2 and Th17 cells, as well as an increase in the percentage of myeloid-derived suppressor cells (M-MDSC) and Treg, indicating that sirolimus may rebuild peripheral tolerance.
These results indicate that mTOR inhibitors can effectively treat refractory ITP, and mTOR inhibitors combined with low-dose steroids can provide a new and promising option for the treatment of ITP
.
References: 1.
Montalvo J, Velazquez D, Pantoja JP, Sierra M, López-Karpovitch X, Herrera MF.
Laparoscopic splenectomy for primary immune thrombocytopenia: clinical.
outcome and prognostic factors.
J Laparoendosc Adv Surg Tech A.
2014, 24: 466–470.
2.
Tran H, Brighton T, Grigg A, McRae S, Dixon J, Thurley D, et al.
A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study).
Br J Haematol.
2014, 167:243–251.
3.
Yang R, Li J, Jin J, Huang M, Yu Z, Xu X, et al.
Multicentre, randomised phase III study of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia.
Br J Haematol.
2017,176:101–10.
4.
Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE , et al.
Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial.
Blood.
2016, 127:17–28.
5.
Lai ZW, Kelly R, Winans T, Marchena I, Shadakshari A, Yu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Poke" to read Original ", we make progress togetherYu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7 : 110.
Poke "read the original text" and we will make progress togetherYu J, et al.
Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.
Lancet.
2018, 391:1186–96.
6.
Feng Yimei,Xiao Yunshuo,Yan Hongju et al.
Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study[J] .
Front Med (Lausanne), 2020, 7 : 110.
Poke "read the original text" and we will make progress togetherSingle-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Stamp "Read the original" and we will make progress togetherSingle-Arm Study[J] .
Front Med (Lausanne), 2020, 7: 110.
Stamp "Read the original" and we will make progress together
