Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, and Eltroipopag is the first oral TPO receptor agonist (TPO-RA) listed in China , Has been clinically used in foreign countries for ten years, has undergone many large-scale clinical trials, and has accumulated rich experience and data. In China, Eltrodopag has been widely used in patients with chronic ITP who have not been treated well in the past, but Eltrodopag is often considered to require long-term maintenance and patients cannot stop the drug. Recently, a phase II, multi-center, prospective study has explored this issue. MEDICONE specially invited Professor Yang Renchi from the Institute of Hematology, Chinese Academy of Medical Sciences combined with his own clinical diagnosis and treatment experience, on Atropo Talk about his views on Pa's early use, timing of stoppage reduction and predictive factors.
Professor Yang Renchi
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Chief physician and doctoral supervisor
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Hematology Hospital (Institute of Hematology) Chinese Academy of Medical Sciences Thrombus
li Member of the Steering Committee of the Hemophilia Working Group -
China Medical Education Association Hemostasis and Thrombosis Branch Deputy Director
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Standing Director of the Rare Disease Branch of the Chinese Association of Research Hospitals
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China Standing member of the Thrombosis and Hemostasis Professional Committee of the Hospital Association
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Member of the Hematology Branch of the Chinese Medical Association
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Deputy Leader of the Vascular Biology Group of the Experimental Hematology Professional Committee of the Chinese Pathophysiological Society
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Rare Blood in China Disease Working Group Leader
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National Hemophilia Collaboration Group Leader
Yimaitong: Itrobopar has been on the market in China for nearly 3 years.But it is mostly used for chronic ITP patients with poor previous treatment. So, is it feasible to use Eltrombopag earlier?
Professor Yang Renchi
It is definitely possible. Any of our medications, not just Eltrodippa, we use it in newly diagnosed or persistent ITP patients, which is definitely better than chronic or chronic ITP. Those patients with so-called refractory ITP, its remission rate is much higher, this is a common feature. In the past, hormones or gamma globulin were persisted in first-line or initial treatment because there were no better, faster, more effective, and safer drugs before TPO receptor agonists were on the market. For now, I personally still think that whether it is called first-line or initial treatment, it is hormones, but TPO receptor agonists represented by Eltroipopag should be used as soon as possible, and the hormones should be stopped as soon as possible to reduce the hormones. Side effects related to long-term use.
A recent prospective, multi-center phase II ESTIT study 1 included 52 newly diagnosed or persistent ITP patients who did not receive any other second-line treatment drugs and received second-line treatment with etrobopar for 24 weeks. It can be seen that compared to patients with chronic ITP in Europe and the United States, requires a lower drug dose , with a median dose of only 37mg/d at 24 weeks. Strong5strong 38% of the responders were able to maintain a sustained response 24 weeks after the drug was discontinued . The results of the ESTIT study also suggest the benefit of early treatment with Eltroipopag.
Yimaitong: What is the status of 's previous reports of sustained response (SROT) after withdrawal of Eltroipopag? Why can itrobopar induce SROT?
Professor Yang Renchi
In the past treatments, glucocorticoids or other broad-spectrum immunosuppressants were usually used.Inducing a part of ITP patients to obtain sustained response mainly refers to the ability to maintain platelets at a relatively safe level for half a year or longer after stopping the drug. So after our listing of Itrobopar, whether it is foreign research or domestic research led by myself, including our real-world research 2 , it has also proved that 30% patients can get a continuous response.
In terms of mechanism, on the one hand, Eltrodippa rapidly increases the number of platelets to activate a series of immune regulatory mechanisms to induce antigen tolerance. On the other hand, Eltroipopag itself also has an immunomodulatory effect 3 . After a long period of use, it can increase Treg activity directly or by increasing TGF-β levels, reducing APRIL levels to promote B cell maturation, and By regulating the balance of monocyte FcγR, the phagocytic ability of macrophages in patients with ITP can be corrected. All these are the potential immunomodulatory mechanisms of Eltroipopard inducing sustained response in patients with ITP after drug withdrawal.
Yimaitong: What kind of patients do you think can consider stopping Eltrobopar? What are the predictors of sustained response after drug withdrawal?
Professor Yang Renchi
I personally think that so far, there is no indicator that can accurately predict whether the drug will continue to respond after stopping the drug. If the cost of treatment is not considered, it is recommended that patients use it for a long time. Clinical observations in the world for more than ten years have proved that the long-term use of Eltrombopag has a long-lasting, reliable and safe effect. 4 . There are no bone marrow fibrosis, thrombosis and other problems that previous clinicians have been concerned about. Relatively minor.
But combined with the actual situation in China, if you want to reduce the stop of Eltrombopag due to economic restrictions, it is generally believed that the platelet meter should be stabilized at 50-100×10 9 /L for at least 3-6 months ,Then consider reducing stops. In the ESTIT study, the duration of etrobopar administration was 24 weeks, and after the end of the 24-week treatment period (PT), the average platelet count ≥30×10 9 /L, which was at least twice the baseline count and no bleeding Symptomatic patients can gradually reduce the dose and stop the drug. 38% of the responders can achieve a sustained response after stopping the drug. However, it is worth noting that in patients with reaching _strong6 CR _strong6 50% can maintain a sustained response after stopping the drug after the end of the 24-week observation period, and the SROT rate of patients who reach the R not reaching CR is 25% Although there was no statistical difference between the two groups (P=0.1151), the SROT rate of patients with CR was significantly higher in numerical value, suggesting that patients with newly diagnosed/persistent ITP may have a response to treatment with Eltropopag above CR. Higher downtime reduction will have a strong guiding significance for clinical practice.
Patients with different reactions maintain sustained response after stopping the drug after the end of the 24-week observation period
Yimaitong: What should a patient do if he wants to try to stop etropopag and maintain a sustained response?
Professor Yang Renchi
If the patient needs to reduce or stop etrobopar, it must be controlled under close monitoring to reduce and stop the drug , it is not possible for the patient to reduce the dose or stop suddenly, it is easy Causes rapid fluctuations in platelet counts. The recommended stopping method is still inconclusive. In the design of the clinical trial of Eltrodippa, a half-dose reduction was specified. For example, the patient's dose was 50 mg, two tablets, and directly reduced to 25 mg one tablet. However, patients were found in clinical practice. If the dose is reduced by half, the platelet decline will be faster.Foreign scholars have explored the method to extend the interval between medications and reduce the frequency without reducing the dose 5 . For example, if you use 50 mg a day, you can stop one day a week, for example, stop one day on Wednesday and use six days a week. If the effect is still good, we will stop for two days a week, but do not stop these two days continuously, such as Wednesday and Saturday. If it can still be maintained, stop for one more day a week, pay attention to the number of days of withdrawal, so as to gradually reduce The interval between medications is lengthened, and the corresponding daily dose is also reduced.
In the ESTIT study, the patients continued to take Eltrodopag for 6 months, and the Eltrodopag was completely discontinued within 2 months relatively quickly. The method was adopted to reduce the dose first and then extend the interval between medications. It can be seen that under this scheme, there are still 38% of responders who continue to respond after stopping the drug after the end of the 24-week observation period. The results of the study also suggest that must regularly monitor bleeding symptoms and platelet count during the reduction and stopping process to ensure that it is maintained within a safe range, especially in the initial stage of the reduction. It can be seen from the curve that recurrence mostly occurs within 2-3 months from the beginning of the reduction and stoppage. During this period, close follow-up should be performed, and the longest period should not exceed 1-2 weeks. After 12 weeks, the curve is relatively stable, and the follow-up interval can be gradually extended . If the patient's platelet drops below a safe level after reducing the dose of Eltropopag, the treatment should be restarted in time.
References:
1. Lucchini E, et al. Br J Haematol. 2021 Feb 22. doi: 10.1111/bjh.17334.
2. Huang Yueting, Liu Xiaofan, Fu Rongfeng, et al. Treatment with Itrobopar Clinical analysis of adult primary immune thrombocytopenia[J].Journal of Clinical Hematology,2019,32(1):16-19,23. DOI:10.13201/j.issn.1004-2806.2019.01.005.
3 . Scheinberg P. Blood Adv. 2018 Nov 13;2(21):3054-3062.
4. Ghanima W, et al.Haematologica. 2019 Jun;104(6):1112-1123.
5. Al- Samkari H, Kuter DJ. Br J Clin Pharmacol. 2018 Nov;84(11):2673-2677.
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