Interview with big coffee | Professor Yang Renchi: Clinical management practice of ITP patients with drug withdrawal

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disease.
As the first oral TPO receptor agonist (TPO-RA) marketed in China, Eltroipopag has been clinically in foreign countries.
After ten years of application, after many large-scale clinical trials, we have 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 explored this issue.
Yimaitong specially invited Professor Yang Renchi from the Institute of Hematology of the Chinese Academy of Medical Sciences to combine his own clinical diagnosis and treatment experience to discuss the early use and reduction of Eltrombopag.
Stop timing and predictive factors to talk about his views.

Professor Yang Renchi Chief Physician and Doctoral Supervisor Director of Thrombosis and Hemostasis Diagnosis and Treatment Center, Chinese Academy of Medical Sciences Hematology Hospital (Institute of Hematology) Director of the Asia-Pacific Hemophilia Working Group Steering Committee Member of China Medical Education Association Hemostasis and Thrombosis Branch Deputy Director China Research Hospital Standing member of the Chinese Society for Rare Diseases, Standing Committee of the Thrombosis and Hemostasis Professional Committee of the Chinese Research Hospital Society, Member of the Hematology Branch of the Chinese Medical Association, Deputy Leader of the Vascular Biology Group of the Experimental Hematology Professional Committee of the Chinese Pathophysiology Society Leader of the Chinese Rare Blood Disease Working Group National Yi Maitong, leader of the Hemophilia Collaboration Group: 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 is definitely possible.
Any of our medications, not just Eltrodipam, we use in newly diagnosed or persistent ITP patients, it is definitely better than chronic or those with so-called refractory ITP.
Its remission rate is much higher, which is a common feature.

In the past, we insisted on using hormones or gamma globulin for 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.
However, TPO receptor agonists such as Eltroipopag should be used as soon as possible.
At the same time, the hormone should be stopped as soon as possible to reduce the long-term hormones.
Use-related side effects.

A recent prospective, multi-center phase II ESTIT study1 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 with patients with chronic ITP in Europe and the United States, the required drug dose is lower, and the median dose of the patient at 24 weeks is only 37 mg/d.

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 the previous reports of sustained response (SROT) after withdrawal of Eltroipopag? Why can itrobopar induce SROT? In the past treatment by Professor Yang Renchi, glucocorticoids or other broad-spectrum immunosuppressive agents were usually used to induce sustained responses in some patients with ITP.
This mainly refers to the ability to maintain platelets at a relatively safe level for half a year or after stopping the drug.
Longer time.

So after our Atrobopar is on the market, whether it is a foreign study or a domestic study led by myself, including our real-world study 2, it has also proved that about 30% of patients can get a sustained response.

In terms of mechanism, on the one hand, Eltroipopag 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.
After a long period of use, it can increase Treg activity directly or by increasing the level of TGF-β, reducing the level of APRIL to promote B cell maturation, and through regulation.
The balance of monocyte FcγR can correct the phagocytic ability of macrophages in patients with ITP.

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 the drug is stopped.
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 Eltrodopag has long-lasting and reliable efficacy and good safety.
4.
The long-term use of Eltrodopax does not have the problems of bone marrow fibrosis and thrombosis that have been concerned by previous clinicians, and other side effects are relatively minor.
.

However, based on 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 above 50-100×109/L for at least 3-6 months, and then consider reducing the stop.
.

In the ESTIT study, the duration of administration of Eltropopag was 24 weeks, and after the end of the 24-week treatment period (PT), the average platelet count was ≥30×109/L, which was at least a two-fold increase from the baseline count and patients with no bleeding symptoms could gradually decrease Measure and discontinue the drug.

38% of the responders can achieve a sustained response after stopping the drug.

However, it is worth noting that 50% of patients who achieve CR 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 achieve R below CR is 25%, although there is no statistical difference between the two groups.
(P=0.
1151), but the SROT rate of patients with CR is significantly higher in value, suggesting that patients with newly diagnosed/persistent ITP may have a higher reduction in downtime when the response to treatment with Eltropopag reaches CR or higher.
Strong guiding significance.

Patients with different reactions maintain a sustained response after stopping the drug after the 24-week observation period is over.
Yimaitong: What should a patient do if he wants to try to stop etrobopar and maintain a sustained response? Professor Yang Renchi, if the patient has the need to reduce or stop the drug, must be controlled under close monitoring to reduce or stop the drug.
It is not allowed for the patient to reduce the dose or stop suddenly, which may easily cause rapid fluctuations in the platelet count.

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 ways to lengthen the interval between medications and reduce the frequency without reducing the dose.
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 it six days a week.
If the effect is still good , We stop two days a week, but don’t stop these two days, such as Wednesday and Saturday, if it can still be maintained, stop one more day a week, pay attention to the number of days to stop the drug do not continue, so that the interval between medications will be gradually extended.
The corresponding daily dose is also reduced.

In the ESTIT study, patients continued to use Eltrodopax for 6 months, and relatively quickly stopped Eltradipal within 2 months.
The method was adopted to reduce the dose first and then to extend the interval between medications.
It can be seen that under this scheme, 38% of the responders still maintained a continuous response after stopping the drug after the end of the 24-week observation period.

The research results also suggest that bleeding symptoms and platelet counts must be monitored regularly during the reduction and stopping process to ensure that they are 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 carried out, 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.

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Treatment of adult primary immune thrombocytopenia Clinical analysis of [J].
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Scheinberg P.
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