Chances of AA turning onto MDS

[ccartbmw]

Hi Everyone,
I have had this disease for 3 years. My sister is a match for transplant but, I'm afraid to have it done. Does anyone have advise on AA turning into MDS? I have had ATG 3 years ago and came out of remission last May. My levels are 8.0 for Red and platelets 40 white 2.6. I feel extremely tired all of the time.
Help!!! Need some advise on what to do.

[Ruth Cuadra]

According to the AA&MDSIF, some studies that followed AA patients for 10-20 years have reported that 35-50% of patients develop MDS or AML. Other studies report only half those numbers.

Although it might seem like a large number of AA patient progress to MDS, it may be that those patients actually started out with hypoplastic MDS. Hypoplastic MDS can resemble aplastic anemia because the bone marrow is essentially empty. In fact, this may have been what happened to me when I was originally diagnosed with AA. One and a half years after ATG and immunosuppressive therapy, I was "re-diagnosed" with MDS. In fact, my disease was probably MDS from the beginning.

At the present time, the only absolute cure for AA or MDS is transplant, but that is not without considerable risks. You have the advantage of having a matched sibling donor available. Another consideration is that even though you might have fallen out of remission, another round of ATG/immunuosuppressives might help you get back into remission. You should take a look at the profile of Marrowforums member, Andrea Pecor, who has survived AA for many years with multiple rounds of ATG.

Hope this helps.

Ruth

[Dan2008]

The rate of conversion of AA into MDS is in single digits if the initial screening was done right (BM biopsy plus FISH for chromosomes 5, 7 and 8). Trisomy 8 does happen after ATG, and the clone serves as an ongoing irritant for the immune system which suppresses the marrow. Monosomy 7 carries a bad prognosis.

If concerned about MDS, you should talk to your doctor about repeating a BM biposy and cytogenetics. Unfortunately a Hgb of 8 will make an adult feel tired, irrespective of the cause. Procrit and Aranesp can give you a boost in Hgb, but are not a solution to low Hgb, but rather a short term fix.

Hope this helps.

Dan

[Lisa V]

Ruth, you say that some instances of apparent transformation from AA to MDS could have been based on a misdiagnosis to begin with, but whether it was AA or hypoplastic MDS, did your marrow suddenly go from being hypocellular to being hypercellular? I'm curious as to what would be involved in that process, and how common it is.

Dan, are you the same Dan from Aplastic Central? If so, we've talked about Trisomy 8 before, but I don't recall ever hearing a connection between it's onset and having had ATG. Could you elaborate on that?

Briefly, my husband did develop a Trisomy 8 mutation following his first ATG (or at least that's when they discovered it), which was considered enough to change his diagnosis from AA to hypoplastic MDS. I've often wondered if he was misdiagnosed to begin with, but aside from the name, his disease still acts like AA, so we still think of it as AA. His marrow is hypocellular, and he has responded to immunosuppressant treatment. ccartbmw, he had a second ATG following a relapse when his cyclosporine was tapered off. They gave him double the dose the second time, and he has shown a stronger response to it this time too. He continues having to take the cyclosporine, which apparently is usual in Trisomy 8 cases, but it's been a couple of years now and he's doing okay.

We are in the same position of having a sibling match but not wanting to risk a transplant. As long as the IST is working, there's no need to, but I'm just wondering what the odds are that his hypoplastic MDS might become hyperplastic, which would then not be likely to respond to ATG.

[Ruth Cuadra]

Originally Posted by Lisa V

Ruth, you say that some instances of apparent transformation from AA to MDS could have been based on a misdiagnosis to begin with, but whether it was AA or hypoplastic MDS, did your marrow suddenly go from being hypocellular to being hypercellular? I'm curious as to what would be involved in that process, and how common it is.

Lisa,

My marrow remained hypocellular even when the diagnosis shifted from AA to MDS. It was in the first BMB after my ATG treatment that chromosome abnormalities showed up. They either weren't there before the ATG or just weren't detected. Over the course of the next year, my BMBs showed various kinds of abnormal chromosomes in that each test produced different results. A couple of times we saw the very uncommon Trisomy 15. According to my doctor, the presence of any abnormality at all was the basis for changing my diagnosis to MDS.

It seems to me that bone marrow that moves from hypocellular to hypercellular is likely on its way to AML, but that wasn't the case for me.

Regards,
Ruth

[Dan2008]

Hi Lisa,

I usually don't post here, but I was browsing to see if anybody knows why Bruce's site is down (it still is). I lost my collection of AA articles because my computer crashed, but from memory, Trisomy 8 is the most common cytogenetic abnormality developed post ATG. The clone itself is the target of the immune system. The immune system tries to attack the clone, and it suppresses the normal marrow too, via collateral damage. As you are suppress the immune system with ATG + CsA, the clone is allowed to expand and it becomes more visible.The conclusion of the articles was that ATG does NOT create Trisomy 8, and patients with Trisomy 8 usually require maintenance CsA, because of the ongoing "irritation" which the clone produces. Without CsA the marrow is suppressed again, and the patient returns to severe pancytopenia and transfusion dependence.

One third of the MDS patients repond to IST (ATG + CsA) and Trisomy 8 patients belong to this group, because the pathogenesis of their pancytopenia is immune-mediated.

It is possible that some patients have a small clone under the level of detection at diagnosis, and the clone expands with the rest of the marrow. In some other patients the clone might evolve during the period of severe pancytopenia due to the stress of the Stem Cell Compartment (few stem cells are forced in overdrive, and don't have time to correct mutations).

Hope this helps.


Dan

[Lisa V]

Thanks, Ruth. I wonder if we should be on the lookout for other mutations? At this point the doctor doesn't feel the need to do any more BMBs unless his symptoms start to change. His rationale is that it's not going to make a difference in his treatment, so why go through it? As far as the Trisomy 8 is concerned, that's probably true, and the last BMB showed the clone had shrunk, but with such a small sampling it's hard to know how accurate that is. On the other hand, if he develops a Monosomy 7 or something, then we'd have to start looking at transplant. Did you have any change in symptoms when you started developing your mutations?

Dan, if you do find the article that that info came from, I'd like to print it out and share it with our doctor. You can send me a PM on this forum if you don't want to post it.

Thanks, and I didn't mean to hijack the thread!

[Ruth Cuadra]

Hi, Lisa.

I didn't mean to hijack the thread!

Don't worry -- it's just the nature of conversations, and this has been a very useful one especially with Dan's interesting input. Thanks, Dan!

I never experienced any changes in symptoms from the time my BMBs showed no abnormalities to when they first showed up after ATG. I remember the shock of the news that I had bad stuff--as opposed to no stuff--happening in my marrow.

I think I'd agree with your husband's doctor that doing another BMB in the absence of any changes probably isn't worth it.

Regards,
Ruth

[Lisa V]

Yes, Dan has a wealth of knowledge and always has useful input!

Ruth, I'm confused now. You didn't experience any changes in symptoms, and yet something made you decide it was time for a transplant. How would you have known that without a BMB?

Not that I'm anxious to volunteer Ken for a BMB, I'm just wondering how we know where he stands otherwise, or does it matter as long as his CBCs are decent?

In other words: what actually changes when a transformation takes place, and when is it time to act on it?

[Dan2008]

1. Genomic instability in bone marrow failure syndromes

http://www3.interscience.wiley.com/c...TRY=1&SRETRY=0

FISH more sensitive than conventional cytogenetics, Monosomy 7 carries poor prognosis, Trisomy 8 good prognosis. Trisomy 8 which develops in AA patients (start as AA and evolve into MDS after Trisomy 8 is discovered) has a better prognosis than primary MDS with Trisomy 8

Patient # 13 evolved from normal cytogenetics to 50% Trisomy 8, but the initial marrow was analysed only with conventional cytogenetics

2. Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults.

http://pt.wkhealth.com/pt/re/bjha/ab...195628!8091!-1

3. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia

http://bloodjournal.hematologylibrar...full/99/9/3129

full text available online

Trisomy 8 is found in more advanced FAB subtypes, often included in the intermediate-risk group with average survival of 2.4 years (17.2 months in an analysis of 115 patients with trisomy)8,26 and time to evolution of AML of 1.6 years.18 The sharp contrast of this observation with the clinical course and prognosis of trisomy 8 evolving from AA suggests a different biology for an apparently identical cytogenetic abnormality in late AA and in primary MDS.

Monosomy 7 should continue to be regarded as itself a dire event, but for trisomy 8, the cytogenetic abnormality does not alter the desirability of an aggressive immunologic approach to improve the function of an empty BM.

4. Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

http://www.pubmedcentral.nih.gov/art...?artid=1895154

full text online

IST improves bone marrow function in selected patients with MDS, though it does not generally eliminate the cytogenetically abnormal clone.37 Patients who are younger, are HLA DR15 positive, and have more recent onset of disease have a high response rate.22 This high-responder group includes most patients with trisomy 8 (E.M.S., unpublished data, 2005).

In our experiments, clonally expanded CD8 cells showed apparent cytotoxicity specifically for autologous trisomy 8 hematopoietic progenitors. MDS with 5q– and monosomy 7 have neither skewing of the T-cell repertoire nor T-cell effector cytotoxicity for karyotypically abnormal progenitors. Intrinsic sensitivity of trisomy 8 cells to lymphocytes of their cytokine products, while not rigorously excluded, seems unlikely because of the following: (1) alloactivated T lymphocytes do not produce the same effect as autologous T cells; (2) adding interferon-γ (IFN-γ) to cell culture did not decrease the proportion of trisomy 8 cells (data not shown); (3) Fas antagonist did not preferentially conserve trisomy 8 cells in CD3-depleted marrow; (4) lymphocytes from patients on CsA therapy did not diminish the proportion of trisomy 8 cells; and (5) there was a reciprocal relationship between trisomy 8 clone expansion after IST and trisomy 8–specific T-cell reduction.

An immunologic description of the pathophysiology of trisomy 8 MDS must also explain the myelosuppression encountered in this condition. During the immune response to trisomy 8 cells, normal hematopoietic cells could be damaged as “bystanders,” leading to generalized hematopoietic cell destruction and pancytopenia. Such a bystander effect has been described in a mouse model of immune-mediated marrow failure46: donor lymphocytes, activated in response to H2 differences in an F1 hybrid recipient, were cytotoxic to hematopoietic stem cells genetically matched at H2 to the effector cells. Bystander killing may result from cytokines released by activated T cells47 or by the cross-recognition of targets through molecular mimicry or epitope spreading.48-50


Dan

[Ruth Cuadra]

Originally Posted by Lisa V

Ruth, I'm confused now. You didn't experience any changes in symptoms, and yet something made you decide it was time for a transplant. How would you have known that without a BMB?

Lisa,

It's correct that I didn't experience any change in symptoms. I had BMBs at regular intervals following my ATG treatment. After about 15 months, a BMB came back showing chromosomal changes and the Dx shifted to MDS. I continued taking immunosuppressants but we started serious discussions about going to transplant. Neil and I got second and third opinions that concurred with my doctor's view that whatever the underlying disease might actually be, my bone marrow was unstable and only likely to get worse. In fact, I had two more BMBs before I actually got to transplant that showed various, different abnormalities each time. So it was the BMBs that told us it was time for transplant but those tests were done as part of the followup/aftercare from the ATG and not in response to any changes I could detect.

Hope this makes it a little clearer.

Regards,
Ruth

[ccartbmw]

Hi Every One,
Had my first injection on Friday. Had a blood draw, today (Wednesday). My blood dropped to 7.6 it was 8.5,3 weeks ago. Is this normal for the cells to drop before they go up?Any information will help.

Thanks
ccartbmw