Can Drugs/Transfusions interfer with BMT success?

[Lisa V]

The "safe" level for platelets depends on what type of activities you're talking about, as well as individual tolerances. Levels below 20k (and especially below 10k) can cause petichiae and bruising even if you're not doing anything particularly risky, but the more impact you're engaged in, the higher you want those levels to be. I'm used to hearing 50k as being a safe level for most normal daily activities, but if you're in a car crash or fall off a ladder, that's not going to be enough. Internal hemorhaging as well as external bleeding is a big concern.

When Ken was first diagnosed, his plts were 8k. The ER doctor looked me straight in the eye and said "DON'T let him fall down." Like I would have been able to stop him! We celebrated when his plts finally reached 100k. As his hem/onc said "You can do brain surgery at that level!"

As for why anemia puts a strain on the heart, it's because Hgb is what carries oxygen to the tissues (including the brain), and low Hgb means the heart has to pump a lot harder to deliver the same amount of oxygen. At least that's my understanding. Somebody may have a better explanation.

[Hopeful]

Marmab,

The safe level for biking is 60k or 70k. You have to be able to survive a bump to the head if you crash. I had a chart that listed the safe levels for various activities. I'll try to find it again. At levels below 20k (it varies person-to-person), you could be at risk for spontaneous bleeds. If your clotting factor isn't good, bumps can be a serious issue. So, you really want to be careful and avoid unnecessary risks.

I wish you could see an MDS/AA specialist sooner rather than later, because if your condition is immune mediated, there is a chance that cyclosporine alone could reverse everything rather than waiting for things to bottom out.

Lisa is right about the anemia. The heart has to work harder to get the oxygen to critical organs like the brain. If you are running, your legs need oxygen too. That's probably why they feel like lead when you are anemic. When I was severely anemic my heartrate got really erratic. At times it would exceed my max! It was also very easy at times to hit my max, sometimes even when I was walking. So, I really recommend wearing a heartrate monitor if you are exerting yourself so that you can pace yourself accordingly.

With regards to checking for CD4/CD8...When your doctor sent your BMB to pathology, he should have specified what condition he was suspecting. This would give the pathologists a heads up as to what to look for. Do you see anything mentioned on your BMB for "suspected diagnosis"? A lot depends on the expertise of the lab. That's why it is probably beneficial to have another BMB done at a Center of Excellence. It is not unusual to repeat a BMB when the first one looks suspicious. I had 3 or 4 before I finally got treatment.

As an aside, did your doctor run you through the gamut of tests (B12, folate, copper, AIDs, parovirus, etc.)? MDS/AA are diseases of exclusion, especially in the absence of cytogenetic abnormalities or blasts.

Hope this helps. Be careful out there!

[marmab]

Thanks so much for the clarifications re: platelets and the effects of anemia on the heart and body. I will email my doc to ask him why the Dx is MDS and not AA. Many people have asked this question, so I should get on it. In regard to what the doc was looking at in my blood and BMB, he did request, among other things, AIDS, parvovirus, Epstein-Barr; also Ferritin, Folate, B12, TRF, Hapto, and CalTIBC. Additionally, CD2, CD3, CD5 CD7, CD10, CD19, CD20, CD45, HLA-DR, FMC-7, Iron St, IPT, Kappa, Lambda. I know what some of these mean, but not many. I did not see Copper anywhere (would it be abbreviated Cu?).

If you can find the chart about what the safe level of Plts is for various activities, that would be great.

When you mention cyclosporine alone, does that mean without ATG first? And is it true that sometimes ATG is tried alone (no cyclosporine afterwards)? Not sure if I have that right.

I am, as always, grateful to have the benefit of your combined knowledge and interest in sharing it! The downside, of course, is that it comes from your first-hand experiences with these diseases. But I guess that is how life goes -- until we are personally affected by these things, we are often blissfully unaware. Thanks again.

marmab

[Lisa V]

Originally Posted by marmab

When you mention cyclosporine alone, does that mean without ATG first? And is it true that sometimes ATG is tried alone (no cyclosporine afterwards)? Not sure if I have that right.

The combination of ATG and cyclosporine has a greater success rate than either alone, Marmab. Somebody once explained to me why this is, but I've forgotten the details. They are both immune suppressants, but they apparently act in somewhat different ways and reinforce each other.

There may be times when one or the other will do the trick, however, particularly if the situation is not too severe. Our own experience with cyclo alone at relapse was unsatisfactory, but others have turned it around this way. I don't know as much about using it as a first line treatment for either AA or MDS, but it might be worth a conversation with your doctor.

The only case I can recall hearing of ATG used without cyclosporine (or some other follow-up immune suppressant like Prograf [tacrolimus] or Cellcept [Mycophenolate mofetil]) is this one:

http://www.marrowforums.org/profiles/Andrea_Pecor.html

I don't know why they did it that way, but her first ATG was about 30 years ago, so maybe the protocol hadn't been refined yet?

[Greg H]

Hi All!

Great conversation we are having introducing Marmab to our suite of peculiar diseases! I'm amazed at the collective knowledge of the subject.

Here's an abstract of a 2008 NIH study that looked back at folks with MDS who received ATG, Cyclosporine, or both.

The full range of MDSers were included -- various ages and risk levels, etc. -- though the bulk were INT-1.

30% of all patients responded to IST. Of those they found that only 8% responded to CSA alone (1 out of 13 patients), versus 24% to ATG alone (18 of 74 patients), and 48% (20 of 42) to ATG plus CSA.

This is looking back at folks that they had already decided to treat with IST, so it's not a random trial, but includes folks that the docs figured, for whatever reason, might respond. In other words, you can't read this data and figure that nearly half of MDSers are going to respond to IST. You can read it to say that ATG alone is about three times as effective as CSA alone, and ATG plus CSA is twice as good as ATG alone.

Of course, 8% did respond to just CSA. They didn't speculate on why the combo is better than either drug alone, though, given their rationale for Campath, one can surmise they think the combo knocks down the offending T-cells more completely and for a longer time than either drug alone.

Take care!

Greg

Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy
Elaine M. Sloand, Colin O. Wu, Peter Greenberg, Neal Young, and John Barrett
ABSTRACT

Purpose
Marrow failure in some patients with myelodysplastic syndrome (MDS) responds to immunosup- pressive treatment (IST), but long-term outcome after IST has not been described. We evaluated patients with MDS treated with IST at our institution to determine their clinical course compared with a comparable supportive care only group.

Patients and Methods
One hundred twenty-nine patients with MDS received IST with a median follow-up of 3.0 years (range, 0.03 to 11.3 years), using antithymocyte globulin (ATG) or cyclosporine (CsA) in combina- tion or singly. Variables affecting response and survival were studied and outcomes were compared with those of 816 patients with MDS reported to the International Myelodysplasia Risk Analysis Workshop (IMRAW) who received only supportive care.

Results
Thirty-nine (30%) of 129 patients receiving IST responded either completely or partially: 18 (24%) of 74 patients responded to ATG, 20 (48%) of 42 patients responded to ATG plus CsA, and one (8%) of 13 patients responded to CsA. Thirty-one percent (12 of 39) of the responses were complete, resulting in transfusion independence and near-normal blood counts. In multivariate analysis, younger age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus CsA treatment (P 􏰀 .001 and P 􏰀 .048, respectively). In multivariate analysis of the combined IMRAW and IST cohorts, younger age, treatment with IST, and intermediate or low International Prognostic Scoring System score significantly favored survival.

Conclusion

IST produced significant improvement in the pancytopenia of a substantial proportion of patients with MDS and was associated with improved overall and progression-free survival, especially in younger individuals with lower-risk disease.

J Clin Oncol 26:2505-2511. © 2008 by American Society of Clinical Oncology

[Lisa V]

Originally Posted by Greg H

This is looking back at folks that they had already decided to treat with IST, so it's not a random trial, but includes folks that the docs figured, for whatever reason, might respond. In other words, you can't read this data and figure that nearly half of MDSers are going to respond to IST. You can read it to say that ATG alone is about three times as effective as CSA alone, and ATG plus CSA is twice as good as ATG alone.

You bring up a good point, Greg. First, you have to keep in mind that the number of patients in a particular study may be quite small (the ones I've read so far have had 20 or fewer participants). If they say "10% showed..." and there were only 10 participants, that's one person. Second, often there has already been some screening as to who would be considered a likely candidate. People with hypoplastic MDS seem to show the best rate of response to ATG/cyclo, followed by those with RA. Trials involving people with RARS, RAEB or RAEB-t have not shown good results, so you have to look at the breakdown of who participated in the trial.

[Hopeful]

I'm not a doctor nor do I work for the pharmaceutical industry, but I do think there is a role for cyclosporine alone for the treatment of MAA (which perhaps you have). However, it does need to be started early before the T-cell destruction gets out of control. MAA does not have as high a success rate with IST as SAA, and I believe this is because of the long watch-and-wait time between treatment and diagnosis.

In developing countries that don't have ATG, cyclosporine alone is used and has been proven to be effective for the treatment of even SAA. The success rate isn't as great as ATG, but if you are in watch-and-wait mode and things are slowly going downhill for you, it seems like a reasonable alternative to try. Here's an article about its success rate in developing countries:

http://www.ncbi.nlm.nih.gov/pubmed/16270758

The other reason why I believe that cyclosporine alone could work is that many of us need to stay on it for years to increase/maintain are counts. This is long after ATG has run its course. Cyclosporine may not be able to knock the big punch that ATG can do in the beginning. However, if you catch the disease early enough, perhaps you won't need that.

[marmab]

As Greg said, great conversation here! I know I've said it several times, but I feel so fortunate to have found you folks -- your collected wisdom and knowledge is impressive (and your willingness to share it). And although I have come to appreciate just how weirdly individual this disease(s) is/are, there is ALWAYS useful information to glean.

So...that said, I am a bit confused about where to go in the future. Watch and wait at the moment, yes. But if I am headed in the direction of IST, and it seems that I might be (whether my Dx is ultimately hypoplastic MDS or AA), should I consider the "traditional" mix of ATG first, then CsA? Or just one of them? And should I completely forget about doing Epogen or transfusions (unless absolutely needed). The statistics, albeit with the caveats you mention, seem to show that ATG/CsA together STILL yields the best response rate. I'm also a bit confused about proceeding to IST sooner rather than later. My counts are not wicked low, but someone (Hopeful or Lisa? I don't remember at the moment) implied that there is no advantage to waiting; that it's better to treat before counts bottom out.

What to do, what to do....? Blood test tomorrow, anyway. Maybe that will tell me something.

Thanks very much, again, for keeping this conversation going.

marmab

[Hopeful]

Sorry to confuse you further.

ATG/CyA is the standard first treatment for older patients with SAA.
MAA usually gets a watch-and-wait approach, unless things start changing or the patient becomes increasingly transfusion dependent. This is because the marrow can sometimes spontaeously recover on its own. Also, it could be because the diagnosis of AA is based on elimination of every other possible diagnosis. So, first the doctors like to make sure that you really have SAA before they give you toxic drugs to treat it! Your counts aren't that bad (in the AA/MDS world). I was on watch-and-wait for a while with lower counts than yours.

I was just theorizing that Cyclosporine alone may have a place in the treatment of this disease for people with MAA. It was tried at one point for me, but I had gone too far past "the point of no return". Had it been tried earlier, I wonder if I could have avoided ATG and the MDS evolution.

Good luck with your blood test!

[Lisa V]

My take on why IST isn't used much for MAA is that success would be harder to quantify. For SAA or VSAA patients who have undergone ATG/cyclo, if their counts improve to the point of no longer needing transfusions, that is considered a good response. That doesn't necessarily mean full recovery of counts. For some, it has essentially just thrown them from SAA back to into MAA. If being MAA falls within the criteria for success, from a doctor's point of view there may not me much of an incentive to subject someone who is already there to a potentially toxic treatment. It's all relative. The same counts that are so worrisome to someone who is watching them slowly decline would be greeted by cheering by someone who is working their way up from the bottom.

For me, the most important factor is "are you transfusion-independent?" If the answer is yes, then watch and wait seems appropriate. The point I was trying to make earlier about there being no advantage to waiting was based on your saying you might start transfusing, Marmab. Once you start having to do that, I see no point in putting off IST. It seems unlikely to me that it would just turn itself around at that point, so it would be better to treat it quickly and try to minimize the amount of transfusions you need to have. That's the whole point of doing it, so that you won't have to rely on blood products. Of course you will undoubtedly have to have some during the process, but the fewer the better is the goal.

On the other hand, as Hopeful suggests, there may be an advantage to trying cyclo alone at this point, just to see if it can turn things around enough to keep you off the transfusion train altogether. It may or may not be effective, but at least it won't interfere with ATG treatment if that's what you end up doing.

Before you put together a plan of action, however, it's important to have a dialog with your doctor. He or she may have other ideas. It's good to be proactive and go in with as much information as you can pull together, but I can recall several times when I went to Ken's appointments armed with the lastest tidbits I'd gleaned off the web, only to have many of them shot down. If that happens, try to find out what their reasoning is. Bottom line, they have far more training than we do and are usually looking at a bigger picture. If you have a good doctor, they will welcome dialog and active participation, but in the end, they are the ones responsible for deciding what type of treatment is appropriate.

[marmab]

Hopeful and Lisa,

Your clarifications and explanations are excellent. It is quite illuminating to hear from those who have "been there and done that". I do see the reasoning behind waiting as long as possible to do anything if I absolutely don't have to, and then choosing the most efficacious and least toxic option for the particular case. Your point was well taken about blood counts, i.e. the viewpoint when you're on the decline vs. coming back up from the bottom.

AND. last but not least, I am holding out hope that my counts will bottom out sooner rather than later (lower), or maybe even begin to recover on their own. I am seeing a pattern where my whites and reds are declining s..l..o..w..l..y; it's my platelets that are going down more quickly. Not sure why.

Thanks, always, for your intelligent and well-informed input.

marmab

[freedom99]

Hi Janice;
Thanks for your email;
I will give you information as best as I can.
Greg H is in a similar ball park as you are and he has a lot of research sources available.
To sort it all out takes time and that's important for you to take your time and try and sort things out, especially with the stage of MDS you are at.
My Doctor in Windsor gave the offer of a BMT for my wife but indicated that the level she was at and her age presented major risks but more importantly that the BMT would not be the cureall. She said that after the BMT there would be still a dysfunctionality left that would result in the bone marrow starting to act in the same way as before. She said it was like killing weeds. Kill the weeds but they still come back. This could be because of the 5qminus.
Maybe Greg H can enlighten me and the doctor on this.
At the same time I would weigh positively on the side of the doctors who say you are a good candidate for a BMT.
I too was concerned with the Vidazza treatment somehow altering the bone marrow to make it worse. The doctor didn't give me an answer except to say we were running out of options.
Be well informed about the drugs suggested to know the action of the drugs etc.
My wife took Vidazza with no side effects at all but had no effect of the MDS. Although she only took it for 3 months whereas the recommended time is 5-6 months. Then there are some who have such side effects the first week they give up. The doctor says one should work through those first number of treaments.
MDS is an evolving disease making it difficult to anylize, diagnose, treat and understand.
These forums especially this one gives a lot of info pro, con, back and forth, up and down and in the end making us more informed. Being more informed helps us to make decisions.