Question:      
Brief:
Moderate aplastic anemia progressed to severe aplastic anemia. Idiopathic. Evolved with trisomy 8 found later. Currently on Eltrombopag 75 mg daily and cyclosporine 50 mg twice per day.

Details
My niece (East Asian), now late teens, dx moderate AA early 2009;ATG in mid 2010 with limited response; RBC tx independent for one year then. Re-start cyclosporine alone in April 2013, then tx free for 9 months.
     Started Eltrombopag (Promacta) since Nov 2014, initially 25 mg daily for 1 month, then raised to 50 mg daily until end March 2015, then 75 mg daily until now, currently also on cyclosporine 50 mg x 2 times each day.
     Before starting Eltrombopag , platelets range 12k to 17k, ANC about 0.8 to 1.4. No noticeable improvement after starting Promacta

Our doctors here basically have no experience in using this new drug for treating SAA. We need expert advice from other places with more experience in using Promacta for treating AA or other bone marrow diseases, so that we can discuss with our doctors. I understand that Promacta has yielded success in clinical trial for AA patients and seems it is under trial for MDS patients. My questions –

1. We have started Promacta for more than 8 months and stayed on 75 mg daily for 4 months already since late March but no noticeable improvements. Her doctors are quite reluctant to further raise the dose beyond 75 mg, probably because they have not tried this new drug on AA patients, but only ITP patients for whom the maximum dosage is 75 mg for East Asians. For AA, what is the maximum dose for East Asians, 75 mg, 125 mg or 150 mg daily?
I read earlier from this article (re. section 5.2) that the maximum dose for East Asians is 125 mg/day. http://www.nejm.org/doi/suppl/10.1056/NEJMoa0000/suppl_file/nejmoa0000_protocol.pdf.
But according to this document (re. section 2.3), the maximum dosage for severe aplastic anemia for East Asians should also be 150 mg (only the initial dose different for East Asian and non-East Asian, 25 mg daily for former while 50 mg daily for latter).
http://www.pharma.us.novartis.com/product/pi/pdf/promacta.pdf
I am confused. Was there a subsequent change in the recommendation of maximum dose for East Asians?

2. Our doctor recently suggested stopping eltrombopag because no noticeable improvement is seen. According to your experience, Is 75 mg a dosage unlikely to yield noticeable improvements? What is the dosage at which signs of noticeable improvements can start to be seen? Is platelet usually the first line to improve?

3.      How long should we wait before we declare Promacta has no positive effects on my niece? My niece has stayed on 75 mg daily for 4+ months. Does it mean that Promacta has no effect on my niece? In your opinion, should my niece continue with eltrombopag? If so, at what dosage?

4. I recall that I have seen from articles/reports that chromosome changes were reported in some patients during clinical trial of Promacta for AA (some are more complex/serious chromosome 7 changes). What is the chance of chromosome changes? How does it relate to the duration and dosage of use of Promacta? We are concerned as my niece is on Promacta for more than 8 months already.

5. What are your suggested way forward and actions to be taken if you were in our place?

My niece is very very scared of BMT and refused this option. Promacta seems give us a light of hope, but results are so discouraging. Would appreciate your expert advice.

Best Regards,

Dear Dr XXXXXXX

Thanks for your prompt reply

You advised that the dose needs to be increased to 125 mg per day and assess response for 2-3 weeks more. Do you mean that if no noticeable improvement is seen at this dosage for 3 weeks, my niece should stop eltrombopag? Is 3 weeks sufficient? Shall we observe for a longer period? I learnt from a fellow patient in a western country that his blood counts remained stagnant for a few months while on 150 mg before seeing obvious improvements.

If we do not see noticeable improvements at 125mg, should my niece try 150 mg as per the medication guide of GSK? Is 150 mg excessive for East Asian patients?

Our doctors increased my niece’s dosage incrementally each time by 25 mg and observe for a few months before further increase by another 25 mg, rather than adjust the dose in 50-mg increments every 2 weeks according to the medication guide of XXXXXXX (http://www.pharma.us.novartis.com/product/pi/pdf/promacta.pdf). Does this affect the theuraptic effects ?


Best Regards,