Rituximab + Cyclosporine + Decadron

Hi. Long time lurker. I've ITP for 14 years. My problem is of destruction, so I generally respond to immune suppression. Sorry in advance for this being a long post.

This is a rundown on everything I've tried:
-IVIG (like most people, this has very short benefit)
-Prednisone (the first time I had it, I was in remission for at least a year--even after tapering off--but now it's only good for a short duration of time)
-Splenectomy x2 (a girl has to have her accessories and in my case it's spleens. Both times were not successful)
-Nplate (This was not a success. My counts would be low, so they would up the dose. The next week would be fine, so same dose. The week after they were low, so they would up it again. Lather, rinse, repeat)
-Promacta (Same as the nplate)
-Imuran (Kept me normal for over a year before I ended up in the hospital twice for fevers)
-Cellcept (My doctor switched me to this after Imuran, and it worked well at a pretty low dose until we decided to try cutting my dose in half)
-Rituximab x4 (I think I've gotten the regular dose each time. The very time, I think I only got 3/4 planned doses, but all the other times it was 4), I always have a reaction to the first infusion, no matter how premeditated I am BUT it keeps me normal (and slightly above) for 1-2 years, which I love and allows me to feel like a normal person for short period of time)

My last rituximab was in July of last year and it kept me in the 500s since. My counts went from 419 (8/5) to 90 (8/22) to 51 (8/26). I know those counts aren't bad (it's the target platelet count for many ITPers), but when my counts start going down, they will continue to do so until I hit 0 if I don't treat, so my hematologist started me on 20mg prednisone to hold me until I could see her on Monday.

Some of the ideas my hematologist threw out for me to consider with "vitamin r" such as low dose, maintenance every 6 months, or adding cyclophosporine and Decadron. I want to know if any one has tried the rituximab/cyclosoprine/Decadron ( www.ncbi.nlm.nih.gov/pubmed/25972158 ) and if they've had any success or if the side effects are worse than just rituximab. I don't want to just do single agent rituximab again because the duration of response decreases each time. I'm trying to figure out my next steps. It's kind of scary that I have exhausted all the standard ITP treatments when I'm not even 29 and I will be dealing with it for the rest of my life.

Sophie, I am glad you stopped lurking and decided to join in the fun. The more the merrier!

The rituximab/cyclosporine/dexamethasone study is only preliminary, with only 20 subjects. The response rate of 60% is not impressive (though those who do respond often get a nice long remission). What is significant in my opinion is that the 60% response rate was achieved in spite of the fact that 12 of 20 subjects had failed at least three other types of treatment. My biggest concern is that all three treatments are immunosuppressing to some degree, and I would like to see a larger study to feel okay about the risk of serious infection.

You wrote, "It's kind of scary that I have exhausted all the standard ITP treatments," but there are other, older treatments that you haven't tried, and you might want to review the PDSA literature. Some of the older treatments might not have quite as high a response rate, but for some, they may work while the newer treatments fail. One example is Dapsone, about which I have posted previously. It gets a 55-60% response rate, regardless of what other treatments have previously failed, and while it has its own side effect issues, immunosuppression is not among them.

Are you sure about your assumption that your platelets will keep falling if they fall to 20? How recently have your platelets dropped really low, and what were your symptoms? My wife, Ellen, achieved a partial remission after low-dose Rituxan, two years ago. She has dropped to around 20 a couple of times since, and has waited it out without treatment, only to have her platelets return to the 50s and 60s, which is a comfortable level for her. Her strategy would be to use a dexamethasone pulse only if she develops extreme bruising or mucosal bleeding.

Very few people die from bleeding, and each and every treatment has serious potential side effects. My thinking is the less treatment the better. To me, the Rituxan/Decadron/cyclosporine combination goes against that principle.

Sophie,

In the final stages of my numerous treatments I was given the Rituximab/Cyclosporine/Dexamethasone combination but it made no difference and I remained below 5.
After that I started on NPlate which put me into remission after a further 5 months.
I don't recall feeling any side-effects from taking the combination although, other than for the 4 days I had Dexamethasone, I was still on Prednisone and that drug over-ruled everything in terms of side-effects.

Rob16: I'll talk to my hematologist tomorrow about Daposone. It's not something I had heard about previously. Thanks! I thought I knew what the treatment options are, but I guess I have some gaps I knew there was some treatments that I never wanted to try (like the chemotherapies)

I think my platelet counts will continue to fall into low single digits because it's happened before (like 20+). The last time was a little more than a year ago, before rituximab round 4. They tried brief prednisone pulses, but it didn't work. I had bruises, blood blisters, petechiae, nose bleeds, heavy periods. I don't lead a particularly active life, but I have two large dogs (75 and 145 lbs!) and I'm clumsy. Even though I try to be careful, I inadvertently end up falling or hitting my head (like I'm the only one who should go under the desk and mess around with the plugs). I want to avoid prednisone (who doesn't) because it's affected my bones and I've had some breaks, one requiring surgery. If I knew my counts would hang out around 30-50, I would be okay with watchful waiting.

Robert1959: Thanks for sharing your experience. Had you tried Rituximab before or was the combo your first exposure? I'm glad you found success with NPlate!

Hi Sophie! I'm glad you joined in.

I have a different thought than the others after reading your story. I noticed that when you used the TPO's, the doses were adjusted according to your counts, up and down. That is a common error when dosing N-Plate or Promacta and will cause counts that jump around too much. I wouldn't say it wasn't successful for you; I would say the dosing schedule wasn't successful. You could revisit those with a proper dosing and see what happens.

Either of those should be started at a certain dose and maintained for a while. You can't start too high or you'll shoot the counts up which can be dangerous. You start low or mid-range and keep it there for several weeks, then begin to adjust based on counts. Adjusting should be done slowly or you'll have the yo-yo affect.

You've been given several ideas....the ball is yours!

Sophie,

I had already had 3 doses of Rituximab and was about to receive my 4th dose when I had a count of zero and so they decided to do the 3 treatments combined. I was down to 75mg of Prednisone and also on 100mg Dapsone and Tranexamic Acid which they stopped and I was then given 4 days of 40mg Dexamethasone and 400mg of Cyclosporine (which was gradually reduced over the next 2 months while I started on the NPLate).
The Dapsone was also a non-event for me.
I also experienced the NPlate roller coaster until one day my system just went back to normal and has stayed there since.

Hi Sandi, Thanks for your advice! I went back to my records, because the NPlate/Promacta was a long time ago and I think I misremembered.

Nplate: This was started after failed 2nd splenectomy in 2010
6/1/: Plt 9 / 1 mcg/kg NPlate
6/8: Plt 98 / 1 mcg/kg NPlate
6/15: Plt 9 / 2 mcg/kg NPlate
6/22: Plt 31 / 3 mcg/kg NPlate
6/29: Plt 315 / 2 mcg/kg NPlate
7/5: Plt 57 / 2 mcg/kg NPlate
7/13: Plt 14 / 3 mcg/kg NPlate
7/20: Plt 73 / 3 mcg/kg NPlate
7/27: Plt 146 / 3 mcg/kg NPlate
8/3: Plt 16 / 4 mcg/kg NPlate
8/10: Plt 152 / 4 mcg/kg NPlate
8/17: Plt 95 / 4 mc/kg NPlate
8/23: Plt 8 / 5 mcg/kg NPlate
8/31: Plt 222/ 5 mcg/kg NPlate
9/7: Plt 65 / 5 mcg/kg NPlate
9/14: Plt 3 / 6 mcg/kg NPlate / 60mg Prednisone started
9/20: Plt 925 / NPlate stopped / Prednisone stopped / moved forward with Rituximab #3 (and stayed in remission until January 2012)

Promacta: Started at 50mg on 1/31/12. I was also tapering off steroids at the same time. My counts were 474 on 2/6/12 so promacta was held until 3/6/12 when my counts went back to 91. Plt was 52 on 3/12 and 7 on 3/20, so Promacta was upped to 75mg. 3/23 was 6 so Prednisone was started and was 27, 137, 267, 451, 170, 235 while steroids were tapered off. Without Prednisone, Plt counts were 202, 50-150 (there was clumping) for two weeks. On 5/14 count was 4 so decision was made to switch to Imuran since Promacta wasn't maintaining my counts without steroids (This was the same time I broke my foot and was desperate to stop steroids so I could heal).

Based on that information, should I consider giving Promacta/Nplate another go? I've always written them off. I'm sure there was another reason for stopping the NPlate but I just can't remember. I used to be better at keeping all this straight... :S

Sophie,

I am going to go WAY out on a limb, so take this with a grain of salt. In looking at your Nplate series, it appears to me that as your platelet levels increase, so does your autoimmunity also increase, but gradually over one to two weeks. For example, you increased your Nplate to 5 mcg/kg, your platelets increased nicely, then fell again over the next two weeks, even though your dosage remained the same. This would be different than what Sandi called the yo-yo effect, where platelets drop because of an excessive or unjustified drop in dosage.

We have at least one forum member, with the handle drbean7218, who uses a combination of Promacta and cyclosporin A with great success. In theory, the Promacta increases production of platelets, while at the same time the cyclosporin A suppresses the destruction. Here is his thread:
pdsa.org/forum-sp-534/6-general-itp-discussion/27398-18-jun-2016-my-platelet-count-is-224.html?start=180#47543
It seems drbean's dose of Promacta is kept constant at a low level of 25 mg, while the Cyclosporin A is adjusted up and down to increase or decrease his platelet levels. Perhaps by combining these treatments, the required dosage of each is decreased, resulting in fewer side effects overall.

... and here is an interesting but technical article about the use of various combination therapies for ITP:
onlinelibrary.wiley.com/doi/10.1111/jcpt.12421/full

Hmmm. That's a tough call. Some people have a tough time getting stabilized on N-Plate and tend to drop low right before the next dose. You might be one who has a difficult time with that drug. Promacta might be worth another shot, but you'd need to give counts time to level without changing the dose. Some people have taken a dose in between 25 and 50 which worked nicely for them. The thing is to ride it out when counts drop instead of raising the dose.

Robert1959: Thanks for the extra information!

Rob16: That's what my hematologist was thinking about with the NPlate. We even sent some of my blood to Amgen to see if I anti-NPlate antibodies (I didn't).

Rob16/Sandi: I could be totally wrong, but feel like my problem is not so much producing platelets but tricking my wacky immune system. In general, when I'm on immunosuppressives, my counts respond (it's just a matter of how long). This last year (post rituximab), my monthly counts were very stable in the 520s. My counts were normal on 25 mg of Imuran for a year and 250 mg bid of Cellcept for 2.5. Prednisone works too, but the side effects! Is there any way to know for sure?

I guess I have way more research to do for tomorrow...

Sophie,

On further research, dapsone does not work as well on splenectomized patients. A recent article from this January reports the results of nine studies with 328 patients combined. Overall, 52% of the patients responded positively to dapsone: 56% of the non-splenectomized and roughly 30% of the splenectomized.

The article is an analysis of older line treatments including dapsone, danazol, hydroxychloroquine and vinca-alkaloids.

www.sciencedirect.com/science/article/pii/S0248866315006293
Is there still a place for “old therapies” in the management of immune thrombocytopenia?
Conclusions
The use of new treatments such as RTX and TPO-RA in ITP has led to a major improvement in patient management. However, old molecules should not be forgotten and are still useful in specific conditions (Table 4), particularly because their efficacy and tolerance are well-known, and also because of their low cost. We thus suggest using dapsone as soon as possible in evolving ITP because of its safety and efficacy, which is assessed after 3–6 weeks. The prospective study being conducted in France will describe the efficacy of and tolerance to the molecule more precisely. When ineffective, and in ITP patients with positive ANA (> 1/160), hydroxychloroquine is an interesting alternative with a good response rate, which is often delayed (3 months), in half of the cases. Due to its virilizing effects and the potential risk of liver cancer, danazol will be used in elderly patients (> 65 years) only after ruling out prostate cancer or a previous history of thrombosis, and with a careful surveillance of liver enzymes. As the time to a response with hydroxychloroquine and danazol is long (around 2–3 months), a concomitant treatment should be transiently used particularly in patients with bleeding events or when the platelet count is below 20 G/L. Vinca-alkaloids can be used in patients who do not respond to IVIg or as an alternative treatment to IVIG before surgery, notably splenectomy. Vinblastine will be used preferentially because of its lower risk of neuropathy compared with vincristine, particularly in the elderly. However, the prolonged use of vinca-alkaloids is not recommended.

Table 4.
Treatment propositions.
Drugs Indications
Dapsone 2nd line therapy after corticosteroids
Rule out G6PD deficiency particularly in men
Non-splenectomized patients (less effective after splenectomy)
Not contraindicated during pregnancy
Danazol Patients>65years
Non-splenectomized or splenectomized patients
When thrombocytopenia due to myelodysplastic syndrome is not completely excluded
Hydroxychloroquine ITP secondary to lupus
Primary ITP with antinuclear antibodies (>1/160)
Not contraindicated during pregnancy and breastfeeding
Vinca-alkaloids Non-responders to IVIg and corticosteroids
To increase platelet count before splenectomy
G6PD: glucose-6-phosphate-deshydrogenase; ITP: immune thrombocytopenia; IVIg: intravenous immunoglobulins.

As a renal nurse I would be wary of cyclosporine. It is a known cause of kidney failure

Sophie - it is entirely possible that you have a problem with destruction, but research has shown that most patients have problems with both destruction and production. There is no way to know for sure. All you can do is try the treatments and see which ones you respond to.