Decrease in Cyclosporine dose

[Nancy Brandston]

At what point do patients w/AA know that it is OK to decrease the cyclosporin? I was diagnosed w/AA in March 2007. I responded to 1 ATG treatment and continue today on cyclosporin drugs. My last red blood cell transfusion was August 2007. My blood test results have been relatively consistent (varying 1-2 points up and down) for the past 4 months. Last test results 2 weeks ago were hemoglobin 11.4, hematocrit 32, plateletets 138,000, neutrophils 1700, WBC 3.1 and RBC 2.8. I feel really well and exercise regularly. My last BMB was July 2007 with <10% celularity. Another BMB will be done in July 2008. My hematologist wants to begin a very slow reduction in cyclosporin by 25 mg per day (I'm currently taking 125 mg in a.m. and 125 mg in p.m.). She explains my blood levels may always be just a bit below normal. Although I'm thrilled to think I may begin the long road toward eliminating cyclosporin completely, I'm not sure I have all the information for making that decision. What are other AA patient experiences with criteria for deciding when to decrease cyclosporin?

Thank you.

[sandra]

Hi Nancy,

There are two acceptable approaches when starting to taper:

1. At least 6 mo after ATG, AND after platelets went over 100 or
2. After 6 to 12 mo after ATG, AND platelets stayed the same for like 3 - 4 mo, even if below 100.

Fro your description, you're good to go :-)

My hematologist wants to begin a very slow reduction in cyclosporin by 25 mg per day (I'm currently taking 125 mg in a.m. and 125 mg in p.m.). She explains my blood levels may always be just a bit below normal.

I think she meant 25 mg/mo, so the whole taper will be 10 mo. I think this is a very good idea. There is clear evidence that slow taper is the KEY for a solid remission with slim chances of relapse. The following article mentions a study that has done specifically on tapering CsA, although on a pediatric population:

http://asheducationbook.hematologyli...urcetype=HWCIT

This is the relevant part for you. My comments are in [square parenthesis].

"Current IST regimens including CsA call for a full CsA dose (5 mg/kg orally per day) for 6 months; after this time point, CsA is tapered, and it is unclear exactly (1) when and (2) how fast this should be done. In recent study, 42 children were divided into three groups: very slow tapering (<0.3 mg/kg/month) [16 mo], slow CsA tapering (0.4–0.7 mg/kg/month)[7 -12 mo] and rapid tapering (≥0.8 mg/kg/month)[less than 7 mo]. The cumulative incidence of relapse was 8% in the slow/very slow taper group and 60% in the rapid taper group.This study suggests that (1) it is safe to start taper CsA at 12 months of treatment (rather than 6 months) and (2) that taper should be very slow (less than 10% of the dose/month) for at least 1 year, to minimize the risk of relapse."

Your doctor is thinking about 10% per mo, which is in line with the research. However, if you are taking Neoral (liquid), it might be easier to go down 20 mg per month, due to the syringe gradations. This will bring the time to about 12 mo, quite acceptable. If you take pills, then 25 mg/mo is the dose.

Sandra

[Nancy Brandston]

Sandra, your response is so thorough and so welcome. I feel more confident my doctor is on the right track. Thank you immensely for your response. Nancy

[Nancy Brandston]

Hi again, Sandra,

I neglected to mention when attending the AAMDS Conference in LasVegas last year one of the physician presenters recommended CSA reduction at 25 mg every 3 months...the very slow reduction necessary to avoid relapse. I mentioned this dose reduction to my physician who is recommending 25 mg/month, which is consistent with your comments and the article. We may need to come to some understanding of reduction compromising reduction possibly at 2 month intervals. In any case, I again thank you immensely.
Nancy

[sandra]

Interesting, do you by any chance remember the name of that doctor?

I am a strong proponent of slow tapering, in particular for patients who took longer than usual to achieve partial remission. So I think anything between 12 to 18 mo is OK. Also, I know there are many doctors who not fully aknowledge this crucial part of the treatment.

Sandra

[Nancy Brandston]

Yes, Sandy, I remember the name of the physician who made the statement about reduction of CsA by 25 mg per day every 3 months. His name is Ronald L. Paquette, M.D., UCLA Jonsson Comprehensive Cancer Center. Now that you ask me, I wonder if completing a literature search in his name might produce some publication pointing to his references/research. I see my hematologist (Dr. Jane Liesveld) this afternoon and will advise her of this physician's name also. Depending upon how our conversation goes, I might ask Dr. Liesveld to contact Dr. Paquette...if Dr. Liesveld doesn't offer first.

At a reduction of 25 mg per day maintained for 3 months prior to further reduction, it will take 2-1/2 years for my reduction to be completed (starting at 250 mg per day, which is now at 225 mg per day). Do I infer from your comment below that in your opinion reductions should take 12-18 months. Why?

You speak as if you have patients. Are you a physician?

Thank you for your continued interest.
Nancy

[sandra]

Hi!

Sorry for the delayed response, I was away for couple of days. Thanks for the name, I would certainly look up that doctor.

My 6 year old son was diagnosed with vSAA on Nov, 2006. He had ATG in Dec, 2006 and became transfusion independent on Feb, 2007. Thankfully, he is doing well, and now we are VERY SLOWLY tapering the cyclosporine. If everything goes as planned, the whole taper would last aprox. 18 mo.

Since my son's diagnosis I researched AA a LOT, mostly scientific articles, I have access to an online library, so I can download pretty much every article that catches my eye on a MEDLINE search. I also read both Marrowforums and Aplastic Central websites, and some caringbridges and carepages, mostly children.

The answer to your question is I cannot say 12 - 18 mo is the ideal time. First of all, the absolute numbers (e.g 25 mg at 3 mo) are less important than percentages (e.g. less than 10 % at a time). Some patients require more than the standard dose of 5mg/kg to achieve therapeutic levels, so they start the taper at higher absolute numbers. I can tell you for sure, the subject of tapering is barely tackled in scientific journals. The article I posted is one of the very few that makes a strong statement (something along the idea of issuing a medical guideline) about the length and duration of the taper. The way I feel about taper is that is like a retraining of the immune system, over time the T-lymphocytes become less aggressive or some clone populations simply die off (the ATG knocks off 99% of them, but T-cell expand primarily by clonal mechanisms, you cannot get rid of them entirely). So it stands to reason that a long enough retraining period gives the body a better chance to adapt. BUT, the way to achieve this is using CsA, an immunosuppressant. So you have to have a trade-off. The CsA has immediate side effects for some people, such as kidney toxicity, increased blood pressure, etc. You seem not to be the case, and most of the people tolerate it well. However, there is always the looming threat of long-term side effects, in particular the increase incidence in bad mutations that lead to cancer. Sometimes you cannot say for sure is because of CsA (e.g. MDS might be the natural course of AA evolving over time), but other times is certain, like in higher incidence of skin cancer for long term users of CsA (this has been establish for kidney transplant patients, who take CsA for prolonged periods of time, sometimes for life).

One other thing that I could say, is that I read the stories of a lot of patients, and your doctor is by far the most conservative I heard of regarding CsA taper. I read heartbreaking stories, patients with a good recovery whose doctors attempted the taper too fast (sometimes in as little as 2-3 mo), or too soon (platelets at 40K) and who inevitably relapse. I had to convince our doctor (articles in hand) that we think is better to do it slower, thankfully she was very agreeable. So it is impressive to me that your doctor wants to do it so slowly. Is it too slow? As I said, I don't know, but we felt that with the very good recovery our son has had, and based on the conclusions of that article, 18 mo might be enough.

Can I ask you where are you treated and who is your doctor? My son is treated at UMASS, Worcester and we also consulted with Dr. Shimamura at Children's Boston before she left for Seattle. I had also been in touch by e-mail with Dr. Nissen (she works with Monika Fuhrer who is the leading pediatric AA specialist in Europe). I remember very clearly, that was one of the first things she wrote to me ( we were still in the first months after ATG, waiting for a response) "Don't worry, he has great chances to recover well, but it is very important to do a very slow taper!" :-)

Sandra

[Nancy Brandston]

Sandra, I hope you will check for this communication. I have been well and just have not checked these threads in a month. You have been immensely helpful and I appreciate your efforts to communicate w/me. My hematologist is Dr. Jane Liesveld, at the James P. Wilmot Cancer Center, (a component of the University of Rochester Medical Center) in Rochester, NY. Dr. Liesveld is also head of the bone marrow transplant unit. I hope you son is doing well. Should you come upon any future publications regarding decrease of cSA, I would truly appreciate them. Many, Many thanks. Nancy Brandston, Rochester, NY

[Connie]

Hi Nancy, I am so glad to hear that you are doing so well. Sounds great to me! I can't remember how long my taper took, but I do know that it seemed to take a long time. I know many months. If I am right, it seems that perhaps one of my cell lines (reds?) had dropped at first. Also, this was my second time to taper on the Cyclosporine. The first time didn't work as well, so I went back up on my dose. Anyway, that was all quite some time ago. But it worked.
I enjoyed our visits at that conference.
Connie

[Kim2007]

I am still on 400 per day of cyclo. I have been on it since late Nov. after recieving atg. I am at 163 thousand platelets but my Dr. said that until my platelets stop going up they won't taper yet. Right now I am just kinda waiting it out to see what happens too.