Dropping counts, 4 years post-ATG

[Logain]

Hello,

A short prelude:

My wife has had SAA about 5 years ago, she's been treated with rATG&Cyclosporin (1 year taper) with excellent results.
She's been cyclo-independent for nearly 3 years now.

Even after stopping cyclosporin, her counts kept climbing (all 3 lines) steadily, with a peak of 180 plts in March/2015.

Two months later, her PLTs began dropping steadily, with an additional drop in hemoglobin in the past few months. A BMB affirmed a relapse.
Her current PLTs are 70, and hemoglobin is 11.

Now, we are faced with 3 options:

1. Another round of ATG. Our least desired option as - from what I've learned - one relapse will lead to another, and a second round also involves a much more significant risk of PNH and MDS. So this solution is basically just a short postponing of the disease for a later time, and with more dire consequences.

2. BMT. She has an unrelated donor that is 10/10. This is our current course, but the significant risks of GVHD caused us to try looking for other options.

3. Pray hard.

---
Now, to my questions:

1. What are your opinions of the information provided? Does anyone disagree with any of the aforementioned solutions or know of other solutions?

2. Has anyone had any experience with patients who relapsed, and had a full recovery afterwards?

Thank you so much, every bit of information would help immensely.

[bailie]

Welcome to the forum. There will be considerable information on this forum. I am sorry for your situation. My advice is if a transplant is in the future, it is important not to wait too long. It is best to have the transplant while feeling well.

What have the doctors suggested for future treatment?

[Neil Cuadra]

Logain,

Where did you get information that repeated ATG increases the risk of relapse, PNH, or MDS? Your choice to favor a transplant seems sound, but you want to make sure you've correctly assessed the tradeoffs.

Repeated ATG sometimes produces remission and sometimes doesn't. When it does, it can restore health temporarily or for the long-term. It's unfortunate that it takes guesswork to predict the outcome for each individual. Your wife's positive ATG response the previous time is a good sign, but you may dread another year or two of cyclosporin.

A transplant is riskier but offers the chance for a cure. I'm very glad to hear that a 10/10 match has been found. My wife had a successful unrelated-donor BMT after ATG, but her case differed because of her MDS diagnosis.

The "gotcha" is that if you're going to have a transplant, it's generally best to do it sooner rather than later. Sometimes the doctors try to get your counts up first, but at the same time they don't want you to have many more transfusions, or let more time elapse during which your counts might get worse or you might develop other health problems.

You didn't mention your wife's age or overall health status. Younger and healthier patients have the least transplant risk. Younger patients also have the longest lifetime ahead of them, so a cure is a clear goal, while seniors might favor a faster recovery and even short-term improvement.

Other choices include watch-and-wait, in case her condition improves on its own, growth factors to boost blood counts, or a drug trial. I assume that her hematologist is not recommending any of those.

You asked about relapsed patients who had a full recovery. One is Andrea Pecor, who was one of the first patients to join Marrowforums, and is doing fine after 5 rounds of ATG, the last of them 14 years ago.

[Logain]

Bailie - first of all, thanks. The doctors have suggested to try for cyclosporin once her counts hit the 50s, and if that doesn't work - to do a transplant.

Neil - thank you so much for the detailed and informative reply.
Regarding the risks of repeated ATG, my source is this study (done in 1998). "The probability of developing a late clonal disorder was 53 +/- 10% after multiple, as compared to 34 +/- 7% after single exposure (P = 0.15)."
My wife is 29, and is healthy overall with the exception of her AA. She's not so young that a transplant is almost a no-brainer, but she's definitely far from the more dangerous ages. That's precisely why we're in this dilemma.

On one hand, you're right. ATG could help her again for a year, two years, or even seven. Or it could not. Or it could cause her tiny PNH clone to take a leap forward and then we'll find ourselves in a bigger problem.
On the other hand, a transplant could cure her. Or not. Or cure her and cause her to suffer from cGVHD that would make her life miserable.
There's just no way to know which road is the right one to take, and that is why we're so torn. It's like there's no right answer.

Which is why I included option #3 - to pray hard, no matter which course we'll eventually take.

[bailie]

You have really identified the struggle all of us have had with these diseases/decisions. We can't tell the future. Even GVHD is difficult to guess ahead of time. I have had almost zero GVHD and has caused me no problems. Others have had a difficult time with GVHD. For me, the "cure" was the only choice. I wouldn't be living now without the transplant.

[Neil Cuadra]

Originally Posted by Logain

Neil - thank you so much for the detailed and informative reply. Regarding the risks of repeated ATG, my source is this study (done in 1998). "The probability of developing a late clonal disorder was 53 +/- 10% after multiple, as compared to 34 +/- 7% after single exposure (P = 0.15)."

I'm not convinced that that study showed a causal connection. It could instead reflect the fact that patients who underwent multiple ALG treatments were less healthy all along or more likely to have had conditions other than aplastic anemia in the first place. Some cases of MDS are thought to be aplastic anemia because of the overlapping symptoms and because the chromosome problems characteristic of MDS go undetected in hypocellular marrow. The result for a patient could be repeated rounds of ATG, and then a diagnosis of MDS, but that doesn't mean that ATG caused the MDS. In fact, since ATG can improve precursor blood cell counts for MDS patients, ATG can make it easier to identify the MDS. I could be misinterpreting that study, since it refers to developing a clonal disorder, as opposed to being diagnosed with a clonal disorder, but I think it's worth asking your wife's doctor about your ATG concern.

By the way, the AA&MDSIF FAQ has a short answer to the question "How do I decide between antithymocyte globulin (ATG) and bone marrow transplant for treatment of aplastic anemia?"

[Hopeful]

Originally Posted by Logain

Bailie - first of all, thanks. The doctors have suggested to try for cyclosporin once her counts hit the 50s, and if that doesn't work - to do a transplant.

Neil - thank you so much for the detailed and informative reply.
Regarding the risks of repeated ATG, my source is this study (done in 1998). "The probability of developing a late clonal disorder was 53 +/- 10% after multiple, as compared to 34 +/- 7% after single exposure (P = 0.15)."
My wife is 29, and is healthy overall with the exception of her AA. She's not so young that a transplant is almost a no-brainer, but she's definitely far from the more dangerous ages. That's precisely why we're in this dilemma.

On one hand, you're right. ATG could help her again for a year, two years, or even seven. Or it could not. Or it could cause her tiny PNH clone to take a leap forward and then we'll find ourselves in a bigger problem.
On the other hand, a transplant could cure her. Or not. Or cure her and cause her to suffer from cGVHD that would make her life miserable.
There's just no way to know which road is the right one to take, and that is why we're so torn. It's like there's no right answer.

Which is why I included option #3 - to pray hard, no matter which course we'll eventually take.

Hi Logain,

I am sorry that your wife relapsed after such a good response to rATG.

I wouldn't put too much weight on that paper from 1998. A more recent paper comparing horse to rabbit ATG had the 3 year clonal evolution at 21% with horse and only 14% with rabbit. Even this seems high compared to other studies that I have seen pertaining to clonal evolution.

I also wouldn't worry too much at this point about the PNH clone expanding because of the ATG treatment. I was told that having a small PNH clone is a positive clue that an immune attack is going on that will likely respond to ATG.

I am not a big fan on the option to wait-until-platelets-hit-50k-and-then-start-Cyclosporine. It may be that a transplant will be your only option if you take this approach. The longer you wait with an immune attack occurring, the more potential damage to progenitor stem cells, which means the less chance for complete recovery to normal counts with IST. I see cyclosporine alone as a bandaid. It may stop her counts from falling further, but in my opinion, it is not a robust, long term solution for someone so young.

It is interesting that your wife had rATG as her first line of treatment and responded so well! I wonder if they would try hATG this time, if you went the IST route?? Your wife is young, responded to rATG, and has a small PNH clone. The odds are in her favor to respond to a second round of ATG. However, ATG is rarely a permanent cure. So she will likely have to deal with this disease again 5 or 10 or 20 years down the road. If you have little ones at home now, this may be the less risky option as she will likely be better, faster with ATG.

A transplant, on the other hand, can be a permanent cure. However, it will be harder and riskier in the short term.

There is an excellent paper from 2012 entitled "How I treat Aplastic Anemia" by Dr P. Scheinberg and Dr N. Young that I would encourage you to read:
http://www.bloodjournal.org/content/...hecked=true#T1
Here is a quote from the paper that may provide some encouragement:

"We do not usually recommend UD HSCT on first relapse in younger patients because most will respond to further immunosuppression. Relapse alone has not been correlated to worse survival in SAA."

I'd also encourage you to check out the videos at the AA&MDSIF website, if you haven't already. They reorganized their website, but you can find them here:
https://www.pathlms.com/aamdsif

I hope I didn't muddy things more for you! Good luck with your decision!

[Logain]

Hopeful,

First - thank you for your reply, it was a very interesting read.

I've read so many studies done on the topic, and from all I've learned there's only one constant: The longer you survive, the better your odds at being cured, since research is constantly moving forward.
The study you quoted had me flustered before, as there was no definition for what he referred to as "younger" patients. Younger as in 5-7? Or younger as in 20-30?

The latest studies speak of ways to restore telomere lengths, improving the bone marrow's ability to generate new cells and fight off the disease. Others speak of having identified new unique characteristics in patients with AA (CH8+ chromosome, if I recall correctly). And there are more underway.

So basically my choice is between having to fight off AA again in the future, and (probably) having to fight off cGvHD in the future. The long-term prognosis for cGvHD seems better (as there are far more people who suffer from it, therefore a greater motivation to cure), but the better immediate treatment seems to be IST (as there's no chance of dying from that, as opposed to SCT).
Does that make sense?

[Margaret W]

I had ATG in 1987, when it was experimental and given for 16 days. I had a partial response and since then, I've floated between platelet counts of zero to 5K and almost normal, and HGBs of 5 or so to 14. At present, my platelets hover between 16K and 30K; hemoglobin runs 7-10; RBCs are 2 mil. or thereabouts; only counts that are normal are WBCs. At present, I'm not being treated and no treatment is in my foreseeable future due to hemolytic reactions to all blood products from even carefully matched donors (way too many antibodies). I see a hematologist infrequently, but I get CBCs run once a month via a standing order. There's no drama; I have odd bruising and get petechiae, but I just roll with it.

This is part of what is so exasperating about aplastic anemia. I was diagnosed in 1972, when there was no treatment for it except for steroids and most people who had SAA, such as I, perished from it. AA causes panic, but often (usually?), that panic is followed by rising counts and an "all is well for now" state. And every case of AA is so individual and particular to each patient.

I hope that what I've said can give some hope rather than lead to further despair and is not misleading. It's anecdotal, of course - but that's the nature of AA.

[Hopeful]

Hi Logain,

I didn't mean to scare you with that quote. It was meant to inspire you I think those under 30 are considered young in the AA world. The 30's are still young-ish. Whereas those of us over 40 are considered old for AA. So, the likelihood of your wife responding again to hATG or rATG is probably pretty good, which is why the paper recommends it for relapsed young AA patients without a matched sibling donor.

I would strongly encourage you and your wife to watch this video by Dr. R. Tiu, entitled "Aplastic Anemia: Current Thinking on the Disease, Diagnosis, and Non-Transplant Treatment":
https://www.pathlms.com/aamdsif/courses/776

Dr Tiu is an excellent speaker and a very compassionate doctor. The video will touch on many of the issues that you are debating. Be sure to watch the Q&A session at the end. There is an inspiring 25 year hATG survivor who is now approaching 80. There is a woman who speaks of her daughter who survived a BMT and is now at year 15. There also is a person who had rabbit and then hATG. It is just a very relevant video for you.

There is also a very timely live webinar coming up on May 12th that you may consider viewing, depending on your time zone. It is called "Aplastic Anemia: Why Treatments Work and Why They Don't". It will be discussing the tradeoffs between BMT and IST for the treatment of AA. The great things about the live video is that you can ask questions that the speaker will address at the end.
https://www.pathlms.com/aamdsif/webinars/920

[Logain]

Margaret,

Thank for sharing your personal story. It does indeed give some hope as I was always certain that once the counts start dropping, it means the rogue T-cells that attack the marrow survived the IST and started multiplying, thus you will eventually get to a state where your marrow is gone and you can't survive.
Reading your personal experience has shown me otherwise, which - despite making life more difficult for us - gives hope.

Hopeful,
Thanks for all the info (again!), I'll be sure to watch the vid and that webinar is definitely on time
Hopefully, we'll be wiser come May 13th.

[TASHMAC]

I was diagnosed with AA in November 2012 and at the time had a 16 month old and another daughter who had just turned 3. Due to the risks associated with a BMT (and with no sibling match) I opted for horseATG and had this in November 2012 and responded very well, my counts recovered to completely normal within about 3 months!! I remained on cyclosporine and my doctors implemented a slow taper. My life pretty much returned to normal and I acted like I had beaten AA throwing myself back into work etc etc. By January 2015 I was down to taking 100mg of cyclosporine per day but unfortunately I had been noticing a downward trend with my platelets. My doctors were hopeful that the counts would not all fall and that things would stabilise. Unfortunately by March/April 2015 all 3 blood lines were falling. My doctors decided to increase cyclosporine and it did not work all it did was cost us time really as we had to give the increased cyclosporine about 6 weeks before we could determine whether it worked but honestly I think we had to give it a go. So in May of 2015 I decided to opt for a second round of ATG this time rabbit. For me, with 2 children aged just 4 and 5 at the time, I found the thought of a BMT still too risky (I am currently 39 so still not considered old for AA but not necessarily young). I met with the BMT team and they were very frank with me. They suggested that I would respond to the second round of ATG but that my response may not be as good as it was the first time round but the very fact that I responded well the first time was a good indicator that I would respond well again so with mortality risks of about 20 to 30% with a BMT we all agreed that I should try the ATG again. So how did I respond to the second round ...... very very very slowly. It was tough because I had the first round of ATG to compare it to so while my counts improved quickly post the sound round of ATG such that I did not require transfusions ..... they really only responded to a level that just had me above the level where transfusions are needed. So I read and I read about response times ..... most papers suggest if you don't see a response in 3 to 6 months then you are unlikely to see a response .... but some do suggest you give it longer. I then stumbled upon someone who had not responded until 9 months post and this gave me hope as this person was actually requiring transfusions for the full 9 months and then suddenly started to respond. So in many ways I was a lucky person as my levels were "safe" in the sense that I did not need transfusions they just weren't getting any higher. Around 8 months post completing the second round of ATG I started to see a more positive trend with my counts and right now (almost 12 months to the date that I started rabbit ATG) my platelets are nearly normal!!! my haemoglobin is OK, it is around 11 but my WBC is still low at around 2 .... so yes that does worry me.

SO what about PNH ..... well like your wife I started this journey with a very small PNH clone .... less than 1% ...... and my doctors were like it is so small that if we tested everyone in the population we could find that a large percentage of people have a clone of a similar size so I tried not to let the PNH concern me. They told me it was a "positive sign" as typically people with a PNH clone respond well to IST ..... and I guess i have proven that to be the case ..... however the question you are probably wanting to really know the answer to is has my PNH clone increased in size and unfortunately the answer is YES. Post my first round of ATG my PNH clone increased in size (to about 3.5%) but then it reduced in size when things were going well and around the time I relapsed it started increasing in size again so I was not too concerned as the doctors still considered it very small. BUT post my second round of ATG my PNH has really worried me ... so having been less than 1% when this all kicked off it increased to around 15%.... we were checking it every month post ATG and every month we were seeing a real increase. It has not been checked for about 6 months now so I am hoping that given I have started to respond that it is also decreasing in size. I have read a number of papers and the majority of papers I have read suggest that in about 1 in 8 cases ATG can cause PNH to increase in size but typically the increase is for it to only double in size ..... but clearly in my case it more than doubled. These papers however do suggest that in the majority of cases where the PNH does increase in size that with time the increase does slow and then reverse but potentially not back to the levels it was..... so I agree that you should have some reservations about the way the PNH clone may respond but whether this is reason enough to avoid a second round of IST I don't know. Clearly in my case I decided the risks associated with un-related BMT were too high. Whether I have made the right decision I can only hope that I have. I just continue to tell myself that for every year I remain alive and reasonably healthy is another year that modern medicine has to learn more about the disease and improve the means in which they treat the disease. I have tried to surround myself with positive stories and it does seem that there are a number of people out there who simply needed a second round of IST to beat this "bloody" disease and I hope that I am one of those people who has now beaten this disease. I do however believe that I will be taking cyclosporine for a very long time but hopefully the dose will be able to be reduced over time.

I wish you and your wife all the very best and if you have any questions please let me know.

[TASHMAC]

Just another quick thought ..... don't wait around to start the cyclosporine .... the cyclosporine should be implemented as soon as possible. Once my doctors realised the counts were falling they immediately started to increase cyclosporine .... my platelets were about 100 when they started increasing the cyclosporine. And don't mess around with the dose either I would recommend going high from the start.

[Logain]

Originally Posted by TASHMAC

I just continue to tell myself that for every year I remain alive and reasonably healthy is another year that modern medicine has to learn more about the disease and improve the means in which they treat the disease. I have tried to surround myself with positive stories and it does seem that there are a number of people out there who simply needed a second round of IST to beat this "bloody" disease and I hope that I am one of those people who has now beaten this disease. I do however believe that I will be taking cyclosporine for a very long time but hopefully the dose will be able to be reduced over time.

I wish you and your wife all the very best and if you have any questions please let me know.

Tashmac, thank you for the long, detailed reply and for sharing your personal story. It was a very interesting read!

I completely agree and relate to your thinking, that as each year passes, medicine makes progress and that improves our odds. That's what gives me hope.
Hope alone, though, is not good enough for me - so I keep digging and trying to find new research, studies and whatnot, to try and push it forward faster

I believe that in some ways the decision was more clear to you, as you had two young children to take care of and any immediate chance of mortality was out of the question, disregarding long-term effects.
I'm very happy it worked out for you, and hope you remain in remission for an infinite amount of time (or until they finally develop a real cure!).

One of the reasons that have me worried is that my wife really wants children and I am reluctant to even think of a scenario in which a second round of IST is followed by having a child, then closely followed by a relapse. That would be a disaster.

My wife's doctors insist on starting cyclosporine at 50 PLTs, and whether it helps or not we'll find out later. The kidney-related effects of cyclosporine can be very serious if it's taken for a prolonged period, so we're trying to consider that as the doctors' main, logical reason for not starting her on it sooner.

BMT outcomes are steadily and significantly improving over the years, to the point in which - in recent years - MUD results are very very similar to MSD results, so this encourages us.

[Margaret W]

Logain,

I've been struggling lately with feeling horrible physically and with the emotional effects of other people who are still - after nearly 44 years! - thinking and accusing me of being a hypochondriac. Platelet count is still under 30K; RBCs low; HCT at 27.

On to my point... There are many women besides myself who have had children after their AA diagnosis and before they had a serious mitigation of their disease. I've heard of them and met them at conferences over the years. I could have only one child, but he is perfectly healthy and has always been so. He's one of the cheeriest people I've ever met and I don't know where I would be without him, in so many ways. When I got pregnant with him, I had a platelet count of 18K and they told me I would not be able to carry for more than a few weeks. I carried for just short of 42 weeks (he weighed nearly 8 pounds and was born with long fingernails, even!) and although it was a bit scary, we went home healthy and happy after 3 weeks in the hospital. This was back in 1974. I required no transfusions during the pregnancy except at the very end and my counts even went up a bit; I don't know if this was due to testosterone crossing the placental barrier, as I was carrying a male infant, or what...

Please never give up on miracles. They happen all the time. Many blessings to you and your wife.

[Logain]

Thank you Margaret, there's no chance that I'll give up

Anyways, an interesting development...her BMB results show 60%-70% cellularity in her bone marrow, which is normal for her age.

Could this still be a relapse of AA, or could her dropping PLTs (58 now) and HGB (10.8) mean something else?

[Margaret W]

Wow, Logain, I don't know... It's undoubtedly best to run that by her hematologists. It's a very interesting development. Maybe your wife is on her way towards going into a total remission!

I went from bone marrow cellularity of 0-2% on various bone marrow pathology reports since 1974, to cellularity of 5% last fall. My records had been sent to Phillip Scheinberg when he was at the NIH and also to Neal Young, at the same place, at various times, and Dr. Scheinberg (who, I understand, is back in South America) recommended that nothing be done at present. In January of this year, due to the increased cellularity, my local hematologist discharged me from his care with the recommendation that I go to the NIH. But I'm too tired to make the trip from SE Michigan to Baltimore, and so I opted for the University of Michigan instead. Their recommendation? "Watch and wait..." Back to Square One, IOW.

Dr. Scheinberg sent an e-mail to my then-treater (who is now struggling with a cancer diagnosis himself), which I was allowed to read, and said that he would not rely so much on bone marrow biopsy reports as he would on the counts themselves. If I'm functioning, have no active bleeding, etc., then it would be best to do nothing for the time being, he said. I guess I'm okay with that, but I'd surely feel better with a better HGB, RBC count and a platelet count over 50K, which I'm a long way from right now. I haven't had a platelet count over 50K for a couple of years now.

I've been dealing with this for my whole life... In 1978, I went back to the doctor who'd treated me when I was a baby. Because he had all my records in front of him, I asked him what my platelet count was in 1951. He looked at the records, said, "It was well below normal!" and slammed my chart shut. I think for most of us, aplastic anemia is a chronic problem. There are always going to be crises here and there, and there's an ongoing one when you can't take transfusions anymore, which is where I am now. But I count my blessings - and there are so many of them!

I'm very happy to read that your wife has normal cellularity in her bone marrow, and that her platelet count is above what's considered "dangerously low." Good signs, indeed!!!