11 yo - TPO-RAs don't seem to be working - Any experience with Azathioprine?

Hi, my name is Jose Luis, I'm from Spain and I'm the father of a 11 year old that has been recently diagnosed (June 2020) with ITP. I'm writing here because I cannot find an active community of ITP patients in my country and this seems a very active and friendly community.

I'm not going to write about all the despair, lows and highs (more lows than highs unfortunately) of these weeks and I'll try to be concise.

During these weeks the doctors have tried several treatments with some success, but no sustained response:

- Corticosteroids (dexamethasone and prednisone) have raised the platelets counts (never more than 60-80k), but as soon as they are tapered or suspended they go down immediately. The doctors don't want to apply this treatment on medium-long term and I understand it has lots of side effects.

- IGIVs have been applied several times and they rise the platelet count (the highest was 125k after a 2 day cycle), but as soon as the effect disappears the platelets go down again. This doesn't seem a viable treatment to maintain a good quality of life for him.

-TPO-RAs were my big hope, a treatment that could rise platelets to an acceptable level without causing too many dangerous side effects, but the results have been very disappointing so far. Eltrombopag (called Promacta in US I think) have been suspended after 1 month at maximum dose (75mg/day) without response (every week the platelet count was 10-15k at most). After that they have switched to Romiplostim (NPlate) (4mg/kg first week and now we are at 6mg/kg) but the results seem equally disappointing so far (9k last week count and this week I can see petechia everywhere so I guess it's going to be similar). To be honest, I cannot understand why these treatments are not working at all and it's causing me a lot of anxiety.

- The doctor has mentioned that he maybe will try next a treatment with Azathioprine, but I cannot find a lot of information about it. What I can find in the Updated international consensus report on the investigation and management of primary immune thrombocytopenia doesn't help a lot:

"Limited published data were found since 2010. A retrospective study assessing treatment patterns in ITP patients in Sri Lanka could not demonstrate a significant response to azathioprine (evidence level III). Azathioprine has less of a role in patients who could try a TPO-RA or rituximab"

Do you have any experience with Azathioprine? Do you know any other cases where Promacta and NPlate haven't worked and why? Any other advice?

Thanks a lot!

While I don't have any info on your question, I hope they find something that works. I'm newly diagnosed and still on initial Prednisone and seems to help, but drop when I taper so back up in dosage. I do get the patachia (sp?) no matter what at this point and my numbers were last 56k. I saw a couple days of over 100k when I didn't get it, but as they dropped down more I noticed it back. Good luck and I've seen many on here that will have more insight that I can. Praying for you and your family

Thanks, I also hope you will get better soon. As far as I know, 56k is a good number that would allow you to do a completely normal life.
I mentioned about petechia because for my kid, I only see them if platelets are lower than 20k or so, and they disappear quickly above those numbers. So in our case, they seem a good visual indicator that platelet level is becoming too low.

Hello Jose Luis
That's a lot of medication changes in a short space of time. Getting him off steroids was the right thing to do though.
Eltrombopag can take a while to achieve a response. Did they start him 50 mg then up it increase to 75mg? How long was he on each dose?
I am a stickler for following protocols but the one that says if no obvious rise in platelet counts after 2 weeks of a new dose is one I would ignore. I know from experience it takes longer. Fortunately I have a haemo who allows this sort of deviation from protocol.
Was he careful with his diet and mindful of what he could not have in his 'windows' before and after the Eltrombopag tablets? If not I would revert back to it and try again.
Azathioprine belongs to a group of drugs called thiopurines, if it is being considered he must have a TPMT (thiopurine s-methyltransferase) test before commencing it.
TPMT is an enzyme that helps the body eliminate thiopurines from the body. If he has none or low levels then Azathioprine must be given with extreme caution as he could reach toxic levels.
He must not have any live vaccines if taking Azathioprine or for 3 months after stopping it, nor be exposed to direct sunlight whenever possible and be plastered up in high factor sun cream and wear a hat all times when it is sunny.
It can also cause horrific diarrhoea (I've been there!!!)

Remember Azathioprine is an immunosuppressant medication leaving him more open to infections. Quite frankly with the Covid19 pandemic I would not consider suppressing my child's immune system at the moment. If Rituximab is mentioned I would not consider that either at the moment.

If it were my child in the current situation I would go back to Eltrombopag with strict dietary control and give it a good few weeks to see if it has any effect.
I eat perfectly normally all day until about 6:30pm then avoid ingesting anything containing calcium, taking my Eltrombopag last thing at night 11pmish as I get into bed. I used to eat completely normally and set my alarm for 2am to take it but I soon got fed up of that routine.

He obviously has some response to steroids therefore it may be that he could try a small dose of Prednisolone say 5mg/day alongside the Eltrombopag and see if that helps. Or just bolus with Pred. say 15mg-20mg for 3-4 days if his count drops to symptomatic levels.

Doctors are concerned about counts, patients are concerned about symptoms. The aim of ITP treatment is not to normalise counts but to abate symptoms.
A count of 50 is quite acceptable. Treatment for ITP is rarely started for counts above 30 these days unless the patient has symptoms.

I hope this is of use to you. Do not let him be railroaded into something you are not comfortable with.

Thanks a lot for all this information and advice!

It confirms my concerns about Azathioprine. I don't feel it's the right moment to try that, at least for now. Luckily he hasn't experienced any bleeding until now, just bruising and petechia when platelets are below 20k approx.

About Eltrombopag, I think we were following dietary restrictions correctly. We woke him up at 6am (8 hours after dinner) to take the pills and then breakfast was 2.5 hours later, removing milk and dairies just in case. He started with 50mg for 2 weeks, and after that the count was 5k, so he received IVIG (went up to 125k) and changed to 75mg, but 2 weeks later was at 10k again. He was taking 75mg 1 month but the count was never higher than 10-15k, so the doctor decided to suspend it and try Romiplostim (Nplate). I wish it had worked, and I can suggest to try again taking it with a different pattern (at night for example as you mentioned) and maybe with low doses of prednisone to help.

If the counts were at least 20-30k I think we wouldn't try so hard with different treatments, but 10k and below seems dangerous to me (but I'm not an expert obviously) even if there are no bleeding symptoms for now.

Same with the romiplostim. You need to stick at it longer. The highest dose is 10mcg/kg and you should try that dose for at least 4 weeks before giving up. The doctors said this just this last weekend at the UK patient conference. They said that people give up too soon.

You beat me to it JJ. What did you think of having the conference virtually rather than physical attendance? Personally I preferred it

Thanks JJ and mrsb04!
Yes, I was there asking this kind of questions
For me, it has been an incredibly useful resource to learn about the latest developments and the possibility to ask these doctors directly. The virtual format has been ideal, physically attending to London would have been much more difficult and costly.

I will keep discussing with our hematologist about sticking with Romiplostim longer. Unfortunately, I don't feel he is convinced about trying much longer, but I will keep insisting.
Yesterday the count was 12k (I thought a little bit better than 9k last week, but they tell me it's basically the same) but with more bruising and petechia, so the doctor has put him on steroids (prednisone 1mg/kg) one week and increased the Romiplostim dose to 8micrograms/kg. Another thing than concerns me is that the idea of the doctor is replacing Romiplostim with an immunosuppressive agent (Azathioprine), but the advice of the doctors in the conference was trying the immunosuppressive alongside Romiplostim and maybe a different one (MMF for example instead of Azathioprine).

I just want him to consider all the options, but I guess each doctor has his own personal experience with treatments. I'm sad that we don't seem to agree on the best next steps... he is the doctor with all the knowledge and experience and I'm just a worried father that has been researching on the Internet for just a few weeks, but I don't like this feeling that we are not aligned.

jl
I saw a post by you at the convention. If you watched the final Q&A session it was me who submitted the question regarding the UK licensing Avatrombopag.
When you research the internet make sure the papers you read are both up to date and well referenced.
Have you seen the latest guidelines, lots about childhood ITP.? Link below is weird but it works.
ashpublications.org/bloodadvances/article/3/23/3829/429213/American-Society-of-Hematology-2019-guidelines-for

Hola José Luis. Te escribo en español. No hay una comunidad hispana en este tema pero no somos pocos los que lo padecemos ....
Quiero enviarte mucho animo. Yo vivo en España también y tu misma situación la vivieron mis padres conmigo. Me diagnosticaron purpura a los 11, en Venezuela donde viví hasta los 26. Hoy tengo 34 y sigo en esta lucha.

Los datos están a favor de tu hijo, pues la purpura infantil remite en la mayoría de casos. También te aseguro, que si no remitiese, los pacientes de purpura tenemos la suerte de llevar una vida bastante normal salvo los vaivenes del contaje plaquetario y los cambios de tratamientos. Yo me gradué de ingeniería informatica, trabajo y nada me detiene. Tu niño, en el peor de los casos (que la purpura sea crónica) también va a tirar para adelante.

Yo estuve temporadas con azatriopina. Es un medicamento específico para trasplantados, pues reduce la actividad del sistema inmune y así se reduce la destrucción plaquetaria. Mi medico me mandaba vitamina C a la par de la azatrioprina porque me cogía bastantes mas catarros. No era ideal, pero servía para descansar de la predninsona por temporadas.

Eso de predninsona / azatrioprina fue a los inicios de mi periplo. Luego una hematologa me cambio a deflazacort. La verdad mucho mejor en cuanto a retención de líquidos y carita redonda...entre medias tuve un año de remisión espontánea. Y en otra ocasión la inmunoglobulina me dio otro año de descanso.
A los 22 opte por esplenectomia. Mis papas no querían pero yo era mayor de edad ya y quería empezar a trabajar en mi profesión, acababa d salir de la universidad y no quería ataduras. La esplenectomia me dio diez años de remisión...hasta los 32. Doy gracias porque fueron los años de emigrar y adaptarme a España ...
Ahora llevaba un buen tiempo con deflazacort y estoy en plena transición al romiplostim.

Esto es una condición, algo q nuestro cuerpo malinterpreto y nos cargamos las plaquetas. Pero no nos impide vivir , es un tedio, pero yo bailo, río, trabajo mucho, sigo estudiando. Tengo mis días grises, claro. Pero tu hijo, sea lo que sea (remisión o purpura crónica) hará su vida plena.

Ánimos

And the latest International and UK guidelines (2019) .

ashpublications.org/bloodadvances/article/3/22/3780/428877/Updated-international-consensus-report-on-the

I enjoyed the patient conference online but think I prefer it in person, but that maybe just because I'm not going out much and would welcome the break.

Muchas gracias, Juliandrea85!
Realmente me resultan muy reconfortantes vuestros ánimos, ayuda y experiencia. Tenemos mucho en común porque yo también soy ingeniero informático y a él le gusta mucho programar también.

Supongo que habrá sido duro volver a un tratamiento después de 10 años de remisión, ojalá el Romiplostim te funcione bien, los TPO-RAs parecen la mejor alternativa hoy en día en cuanto a calidad de vida y pocos efectos secundarios.

Muchas gracias de nuevo por tus palabras y espero que todo te vaya genial.

Thanks JJ for the guidelines, I think I have read them all but I'm not sure if our haematologist has read them. He seems more guided by his own personal experience than by international consensus, but we are in his hands and I need to believe that he knows what he is doing and what is best for our child.

Jose Luis
You are not in his hands, ask for his evidence base and if he is not following latest guidelines question him as to why he isn't.
You may find you want to find a new haematologist.

Colega de profesión entonces !

Y me encanta que le estes inculcando a tu hijo la pasión por programar!!

Oye, tu niño no esta solo, ni es el único. Se lo tienes que decir, por favor. Lo que yo mas recuerdo de mis inicios en esto con la edad de tu peque, y lo que mas me fastidiaba, eran los efectos secundarios. Físicamente yo me sentía bien aunque un análisis me saliese en 5k plaquetas pero la predninsona me hacia doler las rodillas y engordar. Te imaginarás eso en una preadolescente. También me fastidiaba mucho explicar mi condición al resto de niños o incluso profesores porque nadie de mi cole había oído hablar de la purpura. Y la sobre protección de mis padres también me limitaba muchas actividades y diversión de una niña de esa edad, por ejemplo, temían que fuese a la piscina con mis amigas porque tenían miedo que me diese un golpe o un corte...
Los primeros años tuve un doctor que iba muy a la antigua, era mayorcete y seguía la pauta de hace años, quería conteos de plaquetas de 150k y las dosis de predninsona que me daban eran innecesariamente altas, alternado unas veces con la azatrioprina como te conté. Mis padres fueron a pedir otra opinión a una médico que me quería extirpar el bazo como única opción que daba y obviamente de esa consulta salimos pitando...
A los 17 o así, fuimos a ver a otra doctora que nos gustó mucho y tuvo la consideración de mantener las dosis al mínimo y sustituir predninsona por deflazacort que es menos agresivo, cero dolor de articulaciones, menos retención de líquido. Además con ella probé la inmunoglobulina con la que remiti un año, y fue mi médico hasta la remisión posterior a la esplenectomia en el 2008.
En mi época no había romiplostim ni el resto de tratamientos de ese estilo y los médicos querían >150k o nada...y ahora los médicos en la decisión de iniciar tratamientos son mas conservadores.
En mi recaída a los 32, hace dos años, lo que hicieron fue observación los primeros dos meses, no fue hasta q llegué a menos de 30k que discutimos las opciones, y me sorprendió. Me di cuenta q algo no iba bien porque tuve una menstruación excesiva y en una mujer con purpura eso es ya una señal de alerta así que me plante en urxencias...
Pues como el deflazacort había sido una opción en el pasado, mi hematologo de aquí me inicio tratamiento con deflazacort. Me sorprendió que la dosis fuese mucho mas baja q lo que tomaba en Venezuela diez años atrás y me explicó que por ejemplo 80k plaquetas es una cantidad mas que buena.
Te digo que si no te convence azatrioprina para tu niño por el tema covid, como comentaste en otro post, pues le dices al hematólogo que no.
Hay algo que se aprende de todo esto y es que los pacientes sí que tenemos algo que decir y que también hay derecho a "negociar " los tratamientos que nos convencen o no...
Pide otra opinión, o hablale de otras medicaciones. Ahora tu niño es menor y debéis evaluar como padres, pero teneis que hablar todo en familia.

También creo como te dijeron por ahi, que lleva poquitas dosis de romi para ser tajantes diciendo que no responde.
A mi el romi me va bien, llevo poco con el pero parece que respondo. Las primeras dos semanas bien, las siguientes dos tuve una bajada a 40k porque me rebajaron el deflazacort. Volvieron a subirmelo y 120k...y me lo bajaron y aguanté sobre 100k en los análisis posteriores. El jueves recien tuve mi primera analítica luego d una semana sin defla y solo con romi: 118k
Esto es paciencia, y no le quitemos importancia porque es un tema que debemos controlar de seguido, pero seamos conscientes de que podemos hacer vida prácticamente normal apartando q visitamos al medico mas d lo q nos gustaría

Espero que salga todo bien y me quedo atenta a noticias vuestras te repito que tu niño va a tirar para adelante.
Un placer escribiros, colegas informáticos!

Thanks for your advice. The haematologist was decided to start with Azathioprine today, but after our conversation (and also due to a huge bump in platelets) he has decided to keep giving Romiplostim another opportunity.

I knew the count was going to be higher because all the petechia and bruising had disappeared, but I wasn't expecting 290k! (I had never seen it so high in these months). I guess the combined action of Prednisone avoiding mass destruction + Romiplostim increasing production is the reason of this change in just one week. Now it's time to see if Romiplostim alone is able to keep a decent level.

Again, thanks all for your help and advice, this is being like a rollercoaster and the days we are low is really comforting to know that we are not alone.

Hola Juliandrea85, (to the rest of users, please forgive that we are doing a parallel thread in Spanish because it's easier for both of us, but I'll keep updating the main thread in English also)

De nuevo muchas gracias por compartir con tanto detalle tu experiencia y por todos tus ánimos. Estoy seguro de que mi hijo se siente muy identificado con muchas de las cosas que describes y yo no puedo evitar sentirme también identificado con tus padres. Él es muy valiente como tú y nos está dando una lección a todos, pero creo los padres no podemos evitar intentar proteger a los hijos a toda costa, aunque a veces quizá lleguemos a ser sobreprotectores. De verdad que es difícil gestionar el sentimiento de impotencia que se produce al ver que hay muy poco que esté en nuestra mano para poder curar la enfermedad, así que cuando de pronto ves algo en lo que parece que sí puedes ayudar (como evitar que se de un golpe) lo llevamos quizá hasta el extremo. Pero intentaré no perder de vista cómo se siente él (y más ahora que entra en una edad difícil) y no protegerlo en exceso

Como comentaba en la respuesta anterior, hoy ha sido un día bueno porque las plaquetas habían subido un montón y hemos conseguido retrasar el tratamiento con inmunosupresores y darle al Romiplostim un poco más de tiempo. A ver qué tal se comporta esta semana sin Prednisona y si puede mantener unos niveles suficientes solo con el Romi.

Un abrazo y os seguiré contando la evolución (espero que con buenas noticias)!

Good news! Yes it's easier for me to write in spanish because it was a long story to tell. I'm not used to write in english about ITP and it's hard to translate all words related to our condition.

De verdad me alegro muchísimo estaba atenta al foro para saber de vosotros.
Ánimo y un abrazo

Second week with a very high platelet count (250k) and this time with no steroids at all (only Romiplostim). Keeping my fingers crossed for next week.

Nice to know about you and happy about the good news!

Today I've got my Romi too.

Next week you will have good news, you'll see!

Another week, another chapter in this roller-coaster.

Today's count was completely off the chart (1.126.000) so Romiplostim has been paused for a couple of weeks.

I feel a bit stupid because the hematologist didn't seem to think it was a big deal and I was so surprised that I wasn't able to ask anything else. I took for granted that they were great news but now I'm a bit worried that such a high number could also be a risk. It seems surreal that today I'm worried about him having too many platelets.

I know that a count above 400.000 is a signal to stop or decrease the dose, but do you think above 1.000.000 could pose a significant risk of thrombosis?

Thanks

Hola José
Yes, 1.000.000 and above is very high. My highest count that i remember was around 600k just after splenectomy, but few days later they went down to 400-500k

Don't be afraid, just pay attention. Can you afford private lab analytics? If yes, try to make counts during this week. I remember i made analytics every two days when at my lowest levels and it was a "frotis" with just a few drops of blood from my finger but it was in Venezuela. Dont know if that kind of test are usual here..but anyway, even a normal analyis (blood from the vein) is worth. I would do it every two days, at my own, in a private lab.

You will see if that peak of 1.000.000 starts to low

Saludos y abrazos.

Gracias como siempre Julia Andrea!

Yes, probably I will try to schedule a platelet count earlier. The hematologist didn't seem worried, in fact they have been monitoring his platelets weekly and now he has decided to wait 2 weeks, but I will feel better with a check sooner.

My guess is they have been trying to find the Romiplostim dose a bit 'aggressively' after the lack of response to Eltrombopag and at some point it started to work "too much". The recommendation I have read is to start at 1mcg/kg, then increase 1mcg/kg every week until count > 50k or decrease 1mcg/kg if count > 200k for 2 weeks (and stop one week if count > 400k)
- They started directly at 4mcg/kg, with no response -> 9k platelet count
- Next week 6mcg/kg, no or low response -> 12k platelet count
- Next week 8mcg/kg AND prednisone -> 290k platelet count, but they thought it was mainly due to steroids
- Next week 8mcg/kg without prednisone -> 250k platelet count
- Next week 8mcg/kg without prednisone -> platelet count > 1M
- Next 2 weeks NO treatment -> ?

I once had a count of half that while on romiplostim and had to do a week of anticoagulant injections.

Just to give you a quick update, everything seems fine for now. 2 weeks after pausing Romiplostim treatment (due to >1M platelets) they are back to normal levels (and I mean "normal pre-itp": 200k).

Doctors were in doubt:

• Wait and see if the levels hold up without treatment
• Start with Romiplostim again at lower doses

Finally they decided to keep Romiplostim at a lower dose and see next week. I guess they don't want to take the risk of platelet level dropping too much because last time it took a while until it recovered.

Will they test to see what his count is before starting the lower dose? Would they treat if your son's count is in the normal range?? A count of over 1 million would scare the heck out of me!!

I know what you mean Mel. Over 100 puts me on edge

Hi Mel, mrsb04,

They did test yesterday, and the count was 200k. They decided to treat him with a lower dose instead of no dose at all and see what happens because they think if they stop the treatment completely the levels will go down again dramatically (just five weeks ago the count was around 10k every week and we weren't getting any response to the treatment with TPOs). I was expecting with 200k they would wait a bit more without treatment and watch the trend, but I also was scared to go back to the previous situation so I didn't push too hard when they decided that the best option was keeping the treatment at a lower dose.

When the platelets raised to over 1M, I checked with two different doctors because I was also very worried, but they told me the risks were very low because the condition was temporary and he was an active kid with no other health problems.

Now I cannot stop thinking that maybe something has changed in his body and he is not destroying platelets anymore (or at least not at the same rate than before) and Romiplostim could be doing more harm than good. Definitively, if next week is >100k again, I'll ask to keep reducing the dose.

Thanks.