Antibodies to Nplate, Loss of Effectiveness

Some patients treated for ITP with Nplate cease to respond to this treatment. For some percentage of them, this is due to development of antibodies to Nplate. So far, no cases of neutralizing antibodies against
Promacta (eltrombopag) have been reported.

In a case study evaluating 28 patients treated with Nplate, 8 (28.5%) lost response to treatment. 4 of these were tested for antibodies to Nplate, and 3 out of 4 tested positive to antibodies.

onlinelibrary.wiley.com/doi/10.1111/ejh.12733/abstract
Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series
Authors: Monica Carpenedo, Silvia Cantoni, Veronica Coccini, Enrico Maria Pogliani, Roberto Cairoli
First published: 4 February 2016 DOI: 10.1111/ejh.12733

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts resulting from both immune-mediated platelet destruction and inappropriate bone marrow platelet production. Therefore, in patients with ITP failing immunosuppressants/splenectomy, an alternative approach is to enhance platelet production stimulating thrombopoiesis. Studies on the development of recombinant thrombopoietins (rhTPO) were halted as a minority of patients developed an autoantibody that neutralized pegylated rhTPO and also cross-reacted with and neutralized endogenous TPO resulting in thrombocytopenia. Clinical use of romiplostim, a second-generation TPO-RAs, has shown that during long-term treatment, it may elicit the development of neutralizing antibodies to this agent resulting in acute thrombocytopenia. In our case series of 47 primary adult patients with ITP treated with romiplostim, 28 of 47 are evaluable for response loss. Among these, we observed eight patients who either progressively (3 of or abruptly (5 of lost response which accounts for a prevalence of 28.5%. Neutralizing antibody testing could be performed in 4 of 8 patients and 3 of 4 tested positive. These antibodies did not cross-react with endogenous TPO and retesting of 2 patients at 9 and 7 months yielded a negative result. At follow-up, 5 of 8 patients – including the 3 patients with neutralizing antibodies – went into long-term complete response when switched to a different therapy while 3 of 8 patients never regained a response on subsequent lines of therapy. Response loss does not seem to be so rare an event during romiplostim administration (28.5% in our series) and in a minority of patients, it can be associated with development of drug neutralizing antibodies. Although recognized by the manufacturer as a possible adverse event ensuing during romiplostim administration, development of neutralizing antibody in everyday clinical practice has so far not been specifically addressed in reports on romiplostim use outside controlled studies. Unfortunately, testing for these antibodies requires adhesion to strict procedures which is not easily accomplished in everyday clinical practice. This complexity represents a significant drawback in extending antibody testing to all patients who lose response to romiplostim.

Thank you Rob.

Be interesting to see if any more people on the forum comment on if the they too have lost response.

I was on Nplate for 2.5 yrs @ 100mg weekly self injecting.

Lost effectiveness - used to be over 50 - count now in single figures - IVIG weekly for the last six months.

rjsmyth,

Did you try switching to Promacta? If antibodies stopped Nplate from working, those antibodies won't affect Promacta.

Yes - tried Promacta (Eltrombopag here in the UK) did not work for me - then again nothing does.

Nplate worked very well for me for a long period although I used to get some side affects especially in the first few days after the injection such as being even more fatigued, wanting to bite peoples heads off (strange I know) and feeling shaky!

TBH I was hoping for remission but this never came. My platelets never rose to stratospheric levels - just gradually increased directly related to the dose.

I have had and are refactory to all the known treatments - Prednislone, Dexamethasone, Azathioprine, Mycophenolate Mofetil (MMF), Eltrombopag and Rituximab. Not tried Cyclophosphamide as I did not like the sound of the side effects.

I just missed getting onto the Fostamatinab trial but that has now failed its late stage study resulting in Rigel's shares tumbling. There is a trail going on in London for a new monoclonal antibody but unfortunately my work commitments don't allow me to attend two days a week.

I requested a Bone Marrow Aspiration to see whether Nplate had done any damage but thankfully this was normal - no increased reticulin.

Strangely even with IVIG my count just gets into double figures although with IVIG I have no symptoms. Leave it too long before my next infusion and I am in a bit of trouble.

Currently trying to stretch out IVIG (Privigen) to two weeks with one infusion of 100gramms in one day.

I still have my Spleen and I am reluctant to gamble of my future health without one. Consensus from the likes of Drew Provan is "don't do it". With antibiotics losing their effectiveness it seems like a bad idea to me.

Hello rjsmyth

You sound rather like me, also in the UK.

My spleen is perfectly healthy & doing its job. It's not going anywhere. My opinion is the risks of asplenia far outweigh any possible benefits.

My ITP is refractory to Azathioprine, MMF, Fostamatininb, and now N Plate. Which I'm not too bothered about as getting very twitchy after reading this post www.pdsa.org/forum-sp-534/6-general-itp-discussion/29301-apb-to-all-nplate-users-micro-clot-side-effects.html#55431

I was planned to taper off N Plate post minor surgery, which by the way was cancelled due to a count of 6 the day before scheduled op and 2 days after injection.

The only thing I have had a response to is Prednisiolone at the start but counts dropped as it was tapered. Currently only on Prednisolone but needing 20mg a day to keep count at 20. I do not want to stay on this dose much longer as already have osteoporosis. During washout for Fostamatinib trial 18 months ago I maintained counts above 15 on 5mg a day so it looks like I'm losing response to that too.

Currently researching Dapsone and Danazol as not keen on Cyslophos and Rituximab doesn't seem to be a sensible route at present what with small grandchildren catching all sorts of nasties whilst building up their immune systems.

Last summer 2015 I seemed to lose responsiveness to Promacta, only getting to 10 on 50 mg daily. Romiplostin was no better after 3 months and was discontinued after a month on max dose as per the protocol. Rituximab was next but while waiting to start and during the 4 weeks infusions I dropped to1. At Xmas 2015 I begged to go back on Promacta as I had bleeding gums and we agreed that it was worth it to keep me above bleeding level. I was put on 75 mg daily and gradually rose to 10 again and then each month for 10 months I have kept on rising till now at 59 we are planning to lower the dose if my count rises further. ITP is indeed a very unpredictable condition and our drug responsiveness is very unpredictable too so it seems worthwhile revisiting previous meds and persevering for longer at higher doses despite low counts than some protocols suggest in order to achieve improvements.

Margaret, unfortunately Azathioprine gave me horrendous diarrhoea, the longer I took MMF the lower my mood became, lifting remarkably within 3 weeks of stopping it.

As for N plate:- after a full set of investigations for chest & shoulder pain my GP concluded it was probably the cause. Interestingly since I stopped taking it those symptoms are diminishing to almost none .

I find the most annoying thing about having ITP is side effects of medications.

I've never had any serious bleeding with a count as low as 5 but the oral blood blisters are annoying to say the least. They only kick in below a count of 10. Under 20 I'm frozen stiff and covered in bruises but I've learnt to live with that.

All I want is a count of >20 minus any horrid side effect of drugs. . Not too much to hope for surely

I agree - if my count was twenty or more I would possibly not need any medication. I could put up with the fatigue. I would just have to be careful not to get into any dangerous situations. I stopped motorcycling as a hobby last year when the Nplate stopped working!

In my experience there are varying degrees of side effects from these drugs and they can all be pretty unpleasant in their own sweet ways.

Unfortunately IVIG is my only option at the moment - a long way from ideal - but I am still here!

rjsmyth, is your baseline count now higher / lower / the same as your baseline count before starting Nplate?

Margaret k wrote: Last summer 2015 I seemed to lose responsiveness to Promacta, only getting to 10 on 50 mg daily. Romiplostin was no better after 3 months and was discontinued after a month on max dose as per the protocol. Rituximab was next but while waiting to start and during the 4 weeks infusions I dropped to1. At Xmas 2015 I begged to go back on Promacta as I had bleeding gums and we agreed that it was worth it to keep me above bleeding level. I was put on 75 mg daily and gradually rose to 10 again and then each month for 10 months I have kept on rising till now at 59 we are planning to lower the dose if my count rises further. ITP is indeed a very unpredictable condition and our drug responsiveness is very unpredictable too so it seems worthwhile revisiting previous meds and persevering for longer at higher doses despite low counts than some protocols suggest in order to achieve improvements.

Great story with a very good point!

Hal9000 wrote: rjsmyth, is your baseline count now higher / lower / the same as your baseline count before starting Nplate?

Yes - definitely lower - without IVIG I will be in single figures. My current plan is to lose weight and cut out alcohol completely (boring and easier said than done) to see then if my condition improves.

Cutting out alcohol had absolutely no effect on my count at all thank goodness. I enjoy a pint of decent ale.

Thank for sharing your stories. I was wondering if any of you feel that your platelets might have done better if you were never on N-Plate or Promacta? Was just wondering. I was considering Promacta if my platelets fall again--though the cost in the USA is $100,000 a year (you pay $8,000 out of pocket for Medicare).

We were on a cruise just recently and I got sick while on the cruise. I ended up taking 5-hour naps; have been really concerned about my platelets and will do a test real soon. I started out this way the first time my platelets fell. Little by little I am feeling better. I do well with IVIG--as long as the doctor will give it to me.

Dee Dee

DeeDee Marie wrote: I was wondering if any of you feel that your platelets might have done better if you were never on N-Plate or Promacta?
Dee Dee

For me Nplate was good for a considerable period although as with all ITP medications it is not without side effects. I certainly would not rule out taking it especially if you react as some do and can maintain counts over 50 (the target) by taking small doses. There is of course always the possibility of remission which is well documented.

Unfortunately for me my Immune System laughs in the face of all attempts by medications to suppress its function and in the case of Nplate (stimulating the over production of platelets) it seems to have won that battle as well.

IVIG just about kids my Immune System into thinking my platelets are not mine but only for a brief period. Although my count is still very low the quality of the platelets must be better because I have no bleeding symptoms as long as I don't try to push the time between infusions out too far.

I had another 100gms of IVIG yesterday in one hit and it made me feel a bit rotten yesterday evening and this morning. The fortnightly double dose visit seems to have worked as my count was 7 before the infusion. This will give me a better quality of life until something better comes along (not holding my breath for that one).

rjsmyth, take a look at this article and notice how 'anti-idiotypic antibodies' are thought to work in IVIG.

www.nufactor.com/FA-IG_004.aspx

Then take a look at what that type of antibodies are and that vaccines are being created.

en.wikipedia.org/wiki/Anti-idiotypic_vaccine

What do you think?

mAb therapy has been around for quite a while. Just checked Uptodate,British National Formulary and medicines.org no mention of Racaotumomab on any of them.

Hal9000 wrote: rjsmyth, take a look at this article and notice how 'anti-idiotypic antibodies' are thought to work in IVIG.

www.nufactor.com/FA-IG_004.aspx

Then take a look at what that type of antibodies are and that vaccines are being created.

en.wikipedia.org/wiki/Anti-idiotypic_vaccine

What do you think?

Made interesting reading - thanks. Although I do not pretend to understand it all.

I dunno rjsmyth, seems like immune system and Ig understanding is really primitive. Totally non tailored treatment to various illnesses right now. With better understanding, have to wonder if vaccines (guided immune learning?) based on Ig components might one day be useful.

You mentioned a new monoclonal antibody being developed. Have any more on that?

Extracts briefly:

It is a "multicenter, open-label, multi-dose study to evaluate the safety, tolerability and efficacy of UCB7665 in subjects with primary ITP".

"The study is initiated, managed, and financed by UCB Biopharma SPRL who is the sponsor of the study".

"The study medication is an antibody (type of protein) that aims to lower levels of Immunoglobulin G directed against your platelets. In this way the study medication can limit the destruction of platelets"

"......30 participants across approximately 25 centres throughout Europe and Australia"

Thanks for that rjsmyth. For the record, the best description I could find on the study was here:

www.hra.nhs.uk/news/research-summaries/a-multicentre-open-label-randomised-itp-study/

In reading through the 'research summary' I didn't see anything that would set this drug apart from Rituxin. Perhaps others see something ?

I can only hope that the constructed proteins in the new drug are better targeted to ITP than Rituxin.

Deedee, I was looking through some old threads. With your multiple successes with Dex in the past, are you like the 'poster child' for high dose Dex treatment? LOL

Curious. Do you recall how your counts would progress? Would they always jump up the week after the pulse? Always go up even higher on second week after? Then only stay up sometimes after the two weeks?

Hal, I'm so sorry I never got back to you. We were on a two-week vacation then I got sick with a sinus infection--so I missed your question. I think you are right about my reaction to Dex pulses. I seem to have had a very good reaction to these pulses (even my doctor has noticed this).

My feelings are is that my platelets fall to some kind of "trigger" in the first place. 1st time was due to one of the following: Out patient surgery (2006) a reaction to the medication they gave me at the time during surgery. I felt like I was going to have a heart attack; developed a lot of blood blisters in my mouth. Also, doing too much in the way of work, working out and running 6 days a week, and maybe stress. The second time they fell in 2010, I was again doing a lot of extra volunteer work, still running quite a bit, and stress again. I also think I became allergic to Sinequan (a mediation I had taken for a while--but when I went off it, my platelets started going up). Additionally, the day my platelets fell, I was bit by a bug (possibly a West Nile mosquito).

So, I think my body was really run down when I got bit by a bug (and West Nile can be bad). The IVIG and the pulses helped to get my body to heal again--that's what I think. I did go for a month with platelets near 0. My platelets went up slowly and not all at once. The Dex pulses didn't make them jump up--nor did the IVIG. It was a slow process--but they stayed up (after falling back down one time). I also believe because I didn't take any other harsh medications, I was able to heal a little faster. It took a lot of patience and not giving in to take other harsher medications. I also tried to eat healthy during this time. I hope this helps explain my theory. I would give this a try again if they fall back down. Once we have ITP, we are always more vulnerable for them to fall again--it just takes a "tigger". Hope this helps explain my theory.

Again, sorry for being so late Dee Dee

Deedee, a bit of an unexpected story about count response. Let me try to clarify. When you say they didn't jump up with either steroids and IVIG could it be that your counts would rise about 30 per day? So after say day 2 of treatment your count might be around 60? Three days around 90?

About the triggers. Sounds like they have been 1) surgery medication and 2) Sinequan or West Nile virus. Would it be fair to say that the removal of these triggers allowed your immune system to recover to normal?

Similarly, if one had ITP triggered from an allergy antigen exposure, removal of that allergy antigen could allow one's immune system to recover to normal?

How does any of that sound?

Yes, Hal, I would say that was true for me. They went up slowly, but stayed up as long as I rested and keep the "triggers" away. Actually, on one day in particular in August of 2010, I was just out of the hospital for a couple of weeks, had my blood taken in the morning (was @ 12,00), then I went to USC to be part of a trial for a new drug. While I was waiting for the doctor to take me in to examine me, I was relaxing and eat a couple of cookies. I got examined by the doctor (3 hours later) and was told not to take any more of my Dex and that I qualified for the Trial. I then was on my way home and it was about 5 p.m. I got a call from the doctor's assistant and she wanted to know if I had taken my Dex. I said "no" and she said my platelets had gone up to 33,00 (from 12,000 earlier to 33,000 that day) and that I know was not longer qualified to be in the trial (they had to be 30,000 or under). She said to call me in a few days after I had my blood drawn again to see if they were under 30,000. From that point on, they kept going up. I think the next blood draw they were at about 90,000. So, you just never know! I kept doing my dex pulses and as my own doctor had asked and finished them up.

They've stayed up since. I usually don't worry too much unless I am really tired. Sometimes that is a signal for me that they could be dropping. That's when I try to rest a little more.

Hope this helps you.

I do feel for me, that these triggers do set me off. And, I do have a lot of problems with certain medications, too. So, I try not to take too much medication. They usually give me a tightness in the chest--like I can't catch my breath.

Hal, hope this helps you--feel free to ask me any questions you might have as we are all different.
Dee Dee

DeeDee, you are very lucky in your ITP trials and tribulations. It's almost like your immune system learns bad things differently than most others. Do you have allergies to foods or things in your environment?

LOL, I'm going to get a bag of cookies on my next trip to the store. Who knew

Hal, I think it was sitting in the waiting room and just resting that made my platelets go up!! The cookies were good and made me feel better! I do have some allergies to foods and always seem to get hay fever. I think this goes along with my ITP. When I was a little girl, I was allergic to milk and chocolate and would break out all the time. As I got older, it was quite as bad--but I did continue with the eczema. I think it's all related to our immune system.

I'm also highly allergic to feathers. I am a little different from others with ITP; but, when my platelets do go down, they hardly want to budge. They stay at "0" for a long time and this really frustrated my doctor. This is where the patience comes in--I try to be brave and really take care of myself

Ahh, strong allergic reactions, including skin reactions. Allergies to both foods and airborne allergens. Would it make sense that you are/were allergic to those drugs that triggered your ITP episodes?

As I understand, allergic responses are not learned in the immune system, while immune responses to viruses are - and they are adaptive responses. Hmmm, perhaps there is some small amount of learning in allergic responses.

Normal count or 0 count, with little in between. Gosh, that is almost exactly like John describes his counts with treatments.

Do you try to avoid yearly flu vaccines, or, vaccines in general?

Yes, I avoid the yearly flu vaccine and any other vaccines in general. I was actually in the doctor's office the last time my platelets were low--the doctor gave me three vaccines--and immediately, my platelets went from about 65 to around 12. And, I do believe I am allergic to many drugs; also believe that when you are allergic to drugs, you might end up with Lupus as a side effect.

I, too, believe that I could be given some of the popular treatments (except for the Dex) and they might actually make me worse instead of better. Is this what John said too? So, that's why I do try to take care of myself; otherwise, I might end up with platelets stuck at 0 again. When they are that low, you need a very good hemo doctor who doesn't freak out. Most doctors not familiar with ITP do freak out. Even when my platelets were at 0, after a couple of weeks of watching what I ate, resting, and taking care of myself, my symptoms started to subside. All the blood blisters disappeared too. But, by then my platelets had gone up to about 12-15 when this happened.