Purpura thrombop nique Immunologique : Les recommandations th rapeutiques r centes

2. Published (PubMed) guidelines for ITP

3. ITP phases For Internal Use Only. Amgen Confidential.

4. International consensus: Overview of management options This slide summarizes the main conclusions of the international consensus. As we will see, the steroids remain the first line treatment for ITP. In constrast, the second line treatments were a subject of a considerable debate and it was impossible to give a clear, unique and consensual therapeutic strategy between splenectomy and the different possible second line treatments. So, theses treatments were given according to alphabetical order. For refractory ITP which is defined in the IWG terminology as a patient with severe and symptomatic ITP who failed to respond to second line treatments including splenectomy, TPO-r agonists are clearly the only treatment with strong proof of efficacyThis slide summarizes the main conclusions of the international consensus. As we will see, the steroids remain the first line treatment for ITP. In constrast, the second line treatments were a subject of a considerable debate and it was impossible to give a clear, unique and consensual therapeutic strategy between splenectomy and the different possible second line treatments. So, theses treatments were given according to alphabetical order. For refractory ITP which is defined in the IWG terminology as a patient with severe and symptomatic ITP who failed to respond to second line treatments including splenectomy, TPO-r agonists are clearly the only treatment with strong proof of efficacy

5. International consensus: First line treatments No revolution for the first line treatment and unsurprisingly, steroids remain the first line treatment. It’s important to highlight that steroids should be administered on a short period to avoid severe side-effects associated with prolonged steroids administration and it’s also important to remind that steroids probably do not influence the natural history of the disease. International consensus considered that to date, there is no evidence that dexamethasone could be superior toprednisolone of prednisone. No revolution for the first line treatment and unsurprisingly, steroids remain the first line treatment. It’s important to highlight that steroids should be administered on a short period to avoid severe side-effects associated with prolonged steroids administration and it’s also important to remind that steroids probably do not influence the natural history of the disease. International consensus considered that to date, there is no evidence that dexamethasone could be superior toprednisolone of prednisone.

6. International consensus: Emergency treatment For emergency treatment, it’s logical to propose a combination of first line treatments using high dose of steroids, IVIg and in this situation platelet transfusion. For emergency treatment, it’s logical to propose a combination of first line treatments using high dose of steroids, IVIg and in this situation platelet transfusion.

7. International consensus: Second line treatments « …subject of a considerable debate… » For immunosuppressive treatments, there is a grade B for cyclosporin only. However, the committee considered that azathioprine, cyclophosphamide and MMF remain an option. It’s however clear that these treatments are associated with a risk of severe side effects. A large review of the litterature conducted by Arnold and Kelton’s group showed that short term response is observed in about 50% of cases. However, the long term response frequency is lower than 30% and the optimal dose and long term safety remain unknown For immunosuppressive treatments, there is a grade B for cyclosporin only. However, the committee considered that azathioprine, cyclophosphamide and MMF remain an option. It’s however clear that these treatments are associated with a risk of severe side effects. A large review of the litterature conducted by Arnold and Kelton’s group showed that short term response is observed in about 50% of cases. However, the long term response frequency is lower than 30% and the optimal dose and long term safety remain unknown

8. International consensus: Second line treatments As you know, we have robust data and level A of evidence concerning the efficacy of TPO mimetics with several controlled randomized studies. The response is very good in splenectomized and not splenectomized patients. We have a license for romiplostim and eltrombopag. However, the cost of the treatment is high, these treatments are only suspensive and the committee remind that with have no firm data concerning the very long term safety with a potential risk of reticulin deposit in the bone marrow. As you know, we have robust data and level A of evidence concerning the efficacy of TPO mimetics with several controlled randomized studies. The response is very good in splenectomized and not splenectomized patients. We have a license for romiplostim and eltrombopag. However, the cost of the treatment is high, these treatments are only suspensive and the committee remind that with have no firm data concerning the very long term safety with a potential risk of reticulin deposit in the bone marrow.

9. International consensus: Second line treatments Splenectomy remains a good option but the committee recommend to wait at least 6 mths before proposing splenectomy. The committee also proposed to perform isotopic platelet scanning if available.Splenectomy remains a good option but the committee recommend to wait at least 6 mths before proposing splenectomy. The committee also proposed to perform isotopic platelet scanning if available.

10. ASH 2011: Evidence-based practice guidelines for ITP Second line treatments We recommend: Splenectomy (Grade 1B) TPO-R agonists for patients at risk of bleeding who relapse after splenectomy or who have a contraindication to splenectomy and who have failed at least one other therapy (Grade1B) We suggest: Eltrombopag and romiplostim may be considered for patients at risk of bleeding who have failed one line of therapy such as corticosteroids or IVIg and who have not had splenectomy (Grade 2C) Rituximab may be considered for patients at risk of bleeding who have failed one line of therapy such as corticosteroids, IVIg or splenectomy (Grade 2C) The ASH guideline is more direct. The authors recommend and do not suggest that splenectomy should be the second line treatment after failure of first line treatment. The authors however suggest and not recommend that TPO-r and RTX may be considered before splenectomy for some patients. The ASH guideline is more direct. The authors recommend and do not suggest that splenectomy should be the second line treatment after failure of first line treatment. The authors however suggest and not recommend that TPO-r and RTX may be considered before splenectomy for some patients.

11. Treatment should be personalised This slide highlight an important point from ASH guideline and international consensus: even if there are some differences between ASH guideline and International consensus, these two articles clearly stated that the treatment must be personalized This slide highlight an important point from ASH guideline and international consensus: even if there are some differences between ASH guideline and International consensus, these two articles clearly stated that the treatment must be personalized

12. Chronology of treatments The question is the chronology of these treatments and particularly splenectomy, anti CD20 and TPO-mimetics. However, litterature does not give an answer concerning this important question and it’s impossible to give a consensual and universal strategy. So, the international consensus did not give an order for these treatments and mainly recalled that the general rule is that treatment should always be tailored to the individual patient The question is the chronology of these treatments and particularly splenectomy, anti CD20 and TPO-mimetics. However, litterature does not give an answer concerning this important question and it’s impossible to give a consensual and universal strategy. So, the international consensus did not give an order for these treatments and mainly recalled that the general rule is that treatment should always be tailored to the individual patient

13. Splenectomy, TPO-R agonists or anti-CD20: How can we choose? Evidence based medicine (EBM)? Patient’s preference? License and policy level? Cost-effectiveness study? Personalised treatment Co-morbidities Age Pattern of response to short course of steroids

14. Treatment of Chronic ITP:What strategy?

15. Treatment of Chronic ITP:What strategy?

16. Treatment of Chronic ITP:What strategy?

17. Elderly Contra-indication to splenectomy Duration of ITP <1 year Liver sequestration on isotopic study? Patient reluctant? Young patients Duration of ITP >1 year Splenic or hepato/splenic sequestration on isotopic study Don’t forget splenectomy To conclude, splenectomy is still a good strategy for chronic severe ITP. the developpment of new treatments such as TPO-r is a very good news but we must not forget old treatments. For developping countries, the cost of new treatments is to high and surgery remains a valuable treatments. Medical treatments appear also interesting for old patients or patients with severe co-morbidity in whom we can hesitate to propose surgery. In contrast, in young patients with severe ITP and who failed to respond to first line medical treatments and rituximab, splenectomy remains indicated, particularly if isotopic study shows splenic sequestration.To conclude, splenectomy is still a good strategy for chronic severe ITP. the developpment of new treatments such as TPO-r is a very good news but we must not forget old treatments. For developping countries, the cost of new treatments is to high and surgery remains a valuable treatments. Medical treatments appear also interesting for old patients or patients with severe co-morbidity in whom we can hesitate to propose surgery. In contrast, in young patients with severe ITP and who failed to respond to first line medical treatments and rituximab, splenectomy remains indicated, particularly if isotopic study shows splenic sequestration.