Prednisone versus high-dose dexamethasone

Response was faster and response rate was better for high dose dexamethasone.

www.ncbi.nlm.nih.gov/pubmed/23686644
J Thromb Thrombolysis. 2013 May 18. [Epub ahead of print]
Prednisone versus high-dose dexamethasone for untreated primary immune thrombocytopenia. A retrospective study of the Japan Hematology & Oncology Clinical Study Group.
Sakamoto K, Nakasone H, Tsurumi S, Sasaki K, Mitani K, Kida M, Hangaishi A, Usuki K, Kobayashi A, Sato K, Karasawa-Yamaguchi M, Izutsu K, Okoshi Y, Chiba S, Kanda Y.
Author information: Division of Hematology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma-cho, Omiya-ku, Saitama, Saitama, 330-8503, Japan.

Abstract:
High-dose dexamethasone (HDD) has been shown to be an effective initial treatment for immune thrombocytopenia (ITP), but it is not clear whether HDD offers any advantages over conventional-dose prednisone (PSL). We retrospectively compared the efficacy and toxicity of HDD and PSL for newly diagnosed ITP. The response was evaluated according to the International Working Group (IWG) criteria. We analyzed data from 31 and 69 patients in the HDD and PSL groups, respectively. There were no significant differences in patient characteristics between the two groups except for the incidence of the eradication of Helicobacter pylori. The response rate was better in the HDD group (42.7 vs. 28.4 %), and this difference was statistically significant when adjusted for other factors including the eradication of H. pylori. In the HDD group, a response was achieved earlier (28 vs. 152 days in median) and steroids were more frequently discontinued at 6 months (64.5 vs. 37.7 %). Among patients who achieved a response, there was no significant difference in the incidence of loss of response. There were no significant differences in the rate of adverse events, transition to chronic ITP, and splenectomy. In conclusion, HDD might enable the early cessation of steroids without a loss of response.

PMID: 23686644 [PubMed - as supplied by publisher]

High-dose dexamethasone can work when prednisone won't:

www.ncbi.nlm.nih.gov/pubmed/1961352
Effect of high-dose dexamethasone in prednisone-resistant autoimmune thrombocytopenic purpura (ITP).
Neth J Med 1991 Aug;39(1-2):6-10 P Dubbeld, C van der Heul, H F Hillen

This study investigated whether high-dose dexamethasone pulse therapy could bring about a remission in adult chronic idiopathic thrombocytopenic purpura (ITP) patients who had not achieved a remission on the usual prednisone therapy. Newly diagnosed patients with ITP received the usual prednisone therapy, 1 mg/kg/day, for 3 weeks, after which period the dosage was tapered off. If after 6 weeks of treatment the platelets were less than 50 x 10(9)/l the prednisone therapy was considered a failure and 200 mg dexamethasone i.v. was given on 3 consecutive days. Six of the twenty-five patients with newly diagnosed ITP treated according to this protocol achieved a sufficient response with prednisone therapy. Nineteen patients were resistant to or relapsed during prednisone therapy and were treated with high-dose dexamethasone. Four of these nineteen patients showed a sufficient response. Three are still in remission. As no serious adverse effects were observed, high-dose dexamethasone therapy can be considered before splenectomy in prednisone- resistant ITP patients.
Affiliation
Department of Internal Medicine, Sint Elisabeth Hospital, Tilburg, The Netherlands.

Seems like a pretty low success rate with either Prednisone or Dex.

I agree, Emily. But 3 out of 25 had a durable response. Steroids are tremendously cheaper and safer than other treatments. That is why they are tried first.

This study suggests that even if prednisone doesn't work, switching to high dose dexamethasone might be worth trying.

Note that it is an older study.

The following paper from 2007 reflects two trials where multiple cycles of HD-DXM were given.
In one of these trials, multiple cycles of HD-DXM gave relapse free survival of 90% at 15 months and long term response rate of 67.6%. The second trial showed similar results.

Relapse was defined as a platelet count decrease less than or equal to 20K (monocenter study) or less than or equal to 30K (multicenter study), or the presence of bleeding symptoms due to thrombocytopenia. In other words, relapse free meant treatment free.

These rates are extremely high.
I am eager to hear what others think of this!

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience
www.bloodjournal.org/content/109/4/1401.full?sso-checked=true

In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%)

.

In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (< 18 years, 36 of 42 = 85.7%; ≥ 18 years, 41 of 48 = 85.4%, P = not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P = .018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%)

I do not know why we are not hearing more about the use of multiple treatments with high dose dexamethasone.

Can anyone shed some light on this?!?!?

Do you mean combo treatments such as Dex and Rituxan?

Rob, I did the Dex pulses first in 2006. At that time, I was with Kaiser and they only did the one 4-day pulse. I was in remission for 4 years.

Then in 2010, I again did the Dex pulses (along with IVIG as a precation). I had the one where they did it 4 times (3 or 4 days of pulses--then waited 14 days--then did it again). I've had a 4 1/2 year remission. Of course, you never really know if it was actually the pulses or because I had stopped taking Sinequan (on the list of meds that lower your platelets). My platelets actually started going back up once I stopped the Sinequan--so I would say I'm not 100% sure which it was at the time. I had the IVIG over a 24-hour period (it was my 5th IVIG). My doctor at the time thought that I was becoming refractory and told me so. He was amazed when my platelets went back to normal; never really knew the true reason. At that time they were at "0".

I also could have been in the category where they would have went back up on their own eventually; you just never know for sure. Or I could have an underlying problem.

They also say that the pulses work best if you've never had Rituxan or any TPO's.

DeeDee:

I'll have to remember this. You are the only person I know of (ever on the PDSA), that reacted so well to Dex. For some reason, that snuck by me!

Sandi wrote: Do you mean combo treatments such as Dex and Rituxan?

No, just dex. Repeated 4 day X 40 mg high-dose dexamethasone pulses over multiple weeks.

You posted this same article in Sept. 2013, in a conversation primarily with Luca:
pdsa.org/forum-sp-534/7-treatment-general/27296-intermittent-prednisone-treatment.html#36414

Both trials showed very high remission rates when the HD-DXM pulses were repeated multiple times. The article is a little tricky to read because it discusses two separate trials that were conducted differently, but got similar results. Apparently, multiple courses of HD-DXM can be very effective for a good many people. I thought I was reading the results wrong, they were so surprising.

Sandi, when you get a chance, you might want to revisit the studies in that thread. Not everyone has such a horrible time on the HD-DXM pulse - DeeDee (successfully), Luca (who had to stop "because my doc poo-pooed the Dex route"), and Ellen for example. Ellen has had several treatments, and each time her platelets jump up then slowly decline. She dislikes the treatments, but there is no taper and negligible weight gain or moon face, and the negatives don't last for long. Ellen has had a much easier time of it than what I have heard from a lot of people on prednisone. Ellen hasn't gotten a durable response, but it has been a great rescue treatment for her. The studies show some pretty promising results for a lot of people, though.

As I commented at the time, there is no major pharmo company willing to pay for a lot of research on something they cannot patent.

From what I have read and what I have observed, I would try 4 courses of HD-DXM before ANY other treatment, unless the side effects proved unbearable. I have seen what IVIG can do. YOU have seen what Rituxan can do. We have all seen what prednisone can do. We have all heard what WinRho can do. Okay, Promacta, but the insurers aren't going to pay for it except as a last resort.

It seems to me that a series of HD-DXM pulses is the "least-worst" way to start treatment, and can often work even after prednisone was unsuccessful.

The problem isn't really doing Dex once or twice, it's when they try to follow the entire six month protocol that people have problems. It seems like the side effects get worse with each monthly pulse and that's when it becomes intolerable, although some people react the first or second time. I'd have to re-read the studies to see if they followed the six month course. If a person is happy with the length of time that counts stay up afterwards, it would be worth subsequent treatments, but that generally doesn't happen (except for the few that you listed).

I thought about Dex too and it would have been my next treatment if I hadn't had remission. You're right though, we don't see a lot of people here being treated with the Dex protocol.

Just to clarify:

One trial had 4-day pulses spaced 28 days apart for 6 cycles (24 total doses over 21 weeks).
The second trial had 4-day pulses spaced 14 days apart for 4 cycles (16 total doses over 8 weeks).
The two trials got similar results.

They indicated that they were planning a 3 cycle trial, but I cannot find it.

In either case, it is INTERMITTENT treatment over 4 or 6 cycles, NOT CONTINUOUS high dose treatment.

What they found was that counts stayed up LONGER if multiple cycles were used.

Again thanks for the citations. Good ammo for next visit. Have been wanting to try.

Rob16 wrote: In either case, it is INTERMITTENT treatment over 4 or 6 cycles, NOT CONTINUOUS high dose treatment.

What they found was that counts stayed up LONGER if multiple cycles were used.

Right, those studies have been going on for years. We don't see much of Dex being used around here though.

I think I heard at one of the conferences (been to two), that once they have given you Rituxan and TPO's, you don't always respond to the Dex pulses as well. They did mention how they were trying to use Dex with Rituxan and other meds. Just thought I'd mention this.

For me this treatment is good because I've had family members who've had complete bone failure illnesses. Dr. Brussles had told me that I need to be careful with my treatment choices. He even wanted to refer me to some specialist in Texas to look me over.

You wonder why Dex isn't used before Prednisone in the newly diagnosed based on study results? That might be a good question to add to my list.

Sandi - The protocol at Emory seems to be HD-DXM. Ellen has never had prednisone from her hematologist.

DeeDee - My guess is that they are finding that if Rituxan and TPOs don't work then dex won't either, although I would be surprised if it applied to both Rituxan and TPOs since the mechanism is different.
Regarding dex in combo with other drugs, there is some good research that HD-DXM enhances the effectiveness of Rituxan. What hasn't been determined is whether the effect is additive of synergistic.
DeeDee, did I understand you correctly that HD-DXM pulse results in less bone loss than with prednisone?

Rob, I'm not sure about that. I did take prednisone for 3 months in 2006 after my first Dex pulse (through Kaiser). I didn't do well taking prednisone and couldn't wait to get off of it. I do have a lot of bone loss, but it started before the ITP--so I was heading that way. This would be another good questions for the doctors.

Hi DeeDee,
I see you had a good response to Dex. My doctor is considering this for my next line of treatment, but I am nervous about the side effects. How was your overall experience? did you see a lot of side effects? I have been on pred for 6 months and it is no longer working. I have not really had a bad experience with the pred tho

I tolerated the side affects very well. I did a total of 4 pulses spread out two weeks in-between each pulse. You might only need 3 pulses--depending on how your doctor feels. You do feel a little bad when you get to the 4th day (tired from the Decadron). But, overall, you sort of know that they are not going to damage you as much as some as the other medications. I think you will do just fine. For some reason, I tolerated the dexamethasone better than the Prednisone. If I relapse, This will be my first line of choice--especially since Dr. Brussels mentioned that I shouldn't do some of the other treatments due to bone marrow problems in my family.

Since my platelets were at "0" off and on for about 6 weeks, I had to be patient. But, after the last IVIG I had over a 24-hour period, my "stubborn" platelets started going up and stayed up. Since you did so well on the pred, you probably will be able to tolerate the dexamethasone.

Good luck to you!

...and the winner is:

"High-dose dexamethasone is a preferred strategy to conventional prednisone as first-line management of newly diagnosed adult primary ITP."... and better tolerated, too!

High-dose dexamethasone versus prednisone for treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial

Yu Wei1, Xue-bin Ji1, Ya-wen Wang1, Jing-xia Wang2, En-qin Yang3, Zheng-cheng Wang4, Yu-qi Sang5, Zuo-mu Bi6, Cui-ai Ren7, Fang Zhou8, Guo-qiang Liu9, Jun Peng1, and Ming Hou1,*

Key Points

High-dose dexamethasone is a preferred strategy to conventional prednisone as first-line management of newly diagnosed adult primary ITP.

Abstract

This study compared the efficacy and safety of high-dose dexamethasone (HD-DXM) and conventional prednisone (PDN) on the largest cohort to date as first-line strategies for newly diagnosed adult primary immune thrombocytopenia (ITP). Patients enrolled were randomized to receive dexamethasone 40 mg/d for four days (n = 95, non-responders received an additional four-day course of dexamethasone), or prednisone 1.0 mg/kg daily for four weeks and then tapered (n = 97). One or two courses of HD-DXM resulted in a higher incidence of overall initial response (82.1% vs. 67.4%, P = 0.044) and complete response (50.5% vs. 26.8%, P = 0.001) compared to prednisone. Time to response was shorter in the HD-DXM arm (P < 0.001), and a baseline bleeding score ≥ 8 was associated with a decreased likelihood of initial response. Sustained response was achieved by 40.0% of patients in the HD-DXM arm and 41.2% in the PDN arm (P = 0.884). Initial complete response was a positive indicator of sustained response, whereas presence of anti-platelet autoantibodies was a negative indicator. High-dose dexamethasone was generally tolerated better. We concluded that high-dose dexamethasone could be a preferred corticosteroid strategy for first-line management of adult primary ITP. This study is registered at clinicaltrials.gov as NCT01356511.

Submitted July 22, 2015.
Accepted October 13, 2015.

Might be worth considering....but I don't know about the 'well tolerated' part!

Hi Rob,
I'm still around (though, have been busy). I would try the pulses again if I need to. I'm almost in a 5 1/2 year remission presently. You do have to be patient while doing the treatment; that's why my doctor gave me the IVIG while my platelets were near "0" at the time. What frightens me is the way our medications are raising so fast. I just read that one medication went up 6,000% overnight!! And, yet in Canada, they are not going up so fast.

Dee Dee

Sandi,
......less poorly tolerated?

I do think that there seem to be huge individual differences in how different people are affected by different steroids.

hopefully I will never need high dose steroids again, but I would try anything other than prednisolone.

@Rob - I agree, but I think about 80% hated Dex.

I just figured out something about dexamethasone. It has a very long half-life of 36-54 hours, which means that even though one typically takes it for four days, it remains effective for two weeks or more. What many people complain about as the "WITHDRAWAL" of dexamethasone may actually be the continued high levels of steroid. Because of its long half-life, dexamethasone is somewhat self-weaning.

Example, assuming 48 hour half-life (2 days) and 40 mg dexamethasone is equivalent to 267 mg prednisone.
Days 1-4: 267 mg equivalent doses
Day 6: 133 mg (equivalent blood level)
Day 8: 67
Day 10: 33
Day 12: 16
Day 14: 8 mg.
Thus, steroid levels in the blood remain elevated roughly 2 weeks, gradually declining over that timeframe.
I am curious whether others have experiences consistent with this. For example, at what point does insomnia end, and when does fatigue begin?

Rob,

For some reason, I didn't get the insomnia from the Dex pulses. I would do the 4-day pulse, then on the 5th day, I would be dragging myself out of bed. I have more problems with Prednisone. I actually think that I am allergic to prednisone and this is why I have a problem with it. The pulses made me more tired than anything else--and I mean really tired. And, that was almost 6 years ago that I had them. I would still do them again since they did work for me and I am highly allergic to a lot of the other treatments (or I'm fairly sure I would be since this is how my body reacts.) I'm sure I would end up with RA or Lupus.

Rob16 wrote: I just figured out something about dexamethasone. It has a very long half-life of 36-54 hours, which means that even though one typically takes it for four days, it remains effective for two weeks or more. What many people complain about as the "WITHDRAWAL" of dexamethasone may actually be the continued high levels of steroid. Because of its long half-life, dexamethasone is somewhat self-weaning.

It may be, but you still have withdrawal because you are hitting your body with 40 mg's for four days straight and then complete stop. The side effects mentioned after stopping have been extreme fatigue, muscle pain and feeling flu-like, which is more like withdrawal.

Sandy,
You described it just like it is. Extreme fatigue and flu-like symptoms.