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Greg H
Thu Sep 30, 2010, 07:49 PM
Here's a complicated question for you amateur hematologists:

In the MDS-IPSS lotto, you get extra points for multiple chromosomal abnormalities. But is one cell line with multiple badness better or worse than multiple cell lines with singular badness?

For example, I have two cell lines: A. The happy, well-adjusted normal cell line and B. The unstoppable Borg with their Duplication in the long arm of Chromosome 1 and their Trisomy 8 (with which they have lately been equipping all their scurrilous crew.) Both lines, A & B, are about equal in size -- i.e. half the cells in my cytogenetic analysis.

But it occurs to me that, were I not me but someone very like me, I might have 50% happy normal A cells, 25% evil Chromosome 1 dup cells, and a third expanding cadre of Trisomy 8 cells.

Does anyone in here have multiple bad cell lines, or is this just the wicked invention of my overactive imagination? If you have more than one bad line, do you think that's better or worse than one bad line with multiple badness?

Greg

Neil Cuadra
Thu Sep 30, 2010, 09:49 PM
Greg,

You have a wonderful way with words and analogies!

I understand your question but have read nothing that indicates the answer. I'd speculate that the answer depends on what treatment you get.

If you are trying to wipe out and replace all of your cells (radiation/chemo/transplant) then it may not matter how many lines with which problems you have. The goal is to wipe them out and replace them lock, stock, and barrel.

If you are taking a drug that has been found to work for a particular abnormality (Revlimid for 5q minus) then you'd hope to have no other abnormalities. But that's the exception. Even when other MDS drugs work, I don't know how they work, and I'm not sure that the researchers know either. They may have developed the drugs based on theories of our biology but it often seems that they rely on trial and error to find what's statistically beneficial to patients, no matter how it works. So knowing whether it targets one line vs. another may be beyond what we can determine without doing trials to find out.

As long as you're rolling the dice my instinct says to root for one cell line with multiple problems rather than splitting the problems up among cell lines. I think of the bad guys as the abnormal cells, not their individual problems, so the fewer bad guys the better.

Greg H
Thu Sep 30, 2010, 10:36 PM
Neil,

Your speculation is just along the lines of what I was thinking. Better one identifiable enemy with multiple weapons than several bands of rag-tag guerillas to fight. I'm going to ask my doc to weigh in on this next appointment.

I also like your point on the drug front. Reading abstracts and clinical trial descriptions, it sometimes seems a matter of "Well, Revlimid worked for this, let's recruit some folks with this other disease variant and see if it will work for that, too." I kind of gather that Vidaza and Dacogen are like this. That they work is pretty clear; how they work is a bit more speculative. (But thank god someone picked up those orphans, dusted them off, and got the FDA to approve them.)

The folks up at NIH working with Campath for younger MDS patients with Trisomy 8, HLA-DR15, etc. seem to be an exception. Talking with one of the principal investigators, I found he had a firm theory of why the therapy should work (which I could even understand, more or less). When I dug through some of their old research papers, I found they've been carefully working their way through the bits and pieces of the theory, testing it here and there. They've kind of carved out a piece of the MDS puzzle, figured out how to define it, begun to understand how it works, and now, based on that , are trying to figure out how to treat it.

That sort of careful work is definitely the kind of trial that I would be more interested in participating in, as opposed to the "let's throw this against the wall and see if it sticks" variety.

On the other hand, if it works, it works. I'm not going to turn down the Vidaza if I need it at some point!

Thanks for weighing in on my question; I'll be curious to see if anyone surfaces to brag about their five different abnormal cell lines.

Thanks!

Greg

Birgitta-A
Fri Oct 1, 2010, 02:49 PM
Hi Greg,
You do ask interesting questions! Is one cell line with multiple aberrations better or worse than multiple cell lines with an isolated aberration?

As far as I understand the important issue is how dangerous the chromosome aberrations are – will they take over rapidly so we soon only will have damaged cells.

In patients with CML where they have got much better treatment than for MDS, they are analyzing minimal residual disease (MRD) in the bone marrow after treatment with Gleevec, Tasigna, Sprycel and now Omapro. They control that quite often because if the MRD is too high in a patient treated with the first drug, Gleevec, the patient should try for example Tasigna instead.

In MDS they are examining new mutations - for example in the TET2 gene - and analyze how many % of the bone marrow cells that have this mutation:
http://www.nature.com/ng/journal/v41/n7/abs/ng.391.html

I am sure that you have read all about the prognosis for patients with your chromosome aberrations so I won’t refer to an article about that but there are many articles about how Vidaza and Dacogen may work.

Here is one about the two drugs that “lead to degradation of the main DNA methyltransferases, and continued replication results in passive demethylation that eventually results in reactivated gene expression. Activated gene expression, in turn, has effects on multiple different pathways, each of which could contribute to a clinical response.”http://clincancerres.aacrjournals.org/content/15/12/3938.full
Kind regards
Birgitta-A
71 yo, dx MDS Interm-1 May 2006, chromosome aberrations: del12p and -X, very severe fibrosis with pancytopenia, tx dependent since dx, Desferal and Exjade for iron overload, Neupogen 3 injections/week for low WBCs, Thalidomide and Prednisone for fibrosis, still asymptomatic

Greg H
Fri Oct 1, 2010, 11:03 PM
Hey Birgitta!

Thanks for the links. You are such a great resource for this forum. I find the more I know about the disease, the more comfortable I feel making decisions about the best course of therapy to pursue. Though, I must admit, sometimes I get in over my head reading journal articles.

Thanks,

Greg

mausmish
Sat Oct 2, 2010, 02:06 AM
I echo those thoughts on all counts.

Birgitta-A
Sat Oct 2, 2010, 06:58 AM
Hi Greg and Karen,
Yes, MDS is really very complicated partly because it isn't one disease but many that share some symptoms. If you look at clin trials gov you will find that there are 1057 clinical trials in MDS patients and then we have all other researchers looking at chromosomes and so on.

My doctor will defend his dissertation about Vidaza in MDS patients Nov 2010. In the Karolinska Institute, where I am a patient, they show the dissertations at internet so we will be able to read about MDS and Vidaza and learn more about Vidaza.
Kind regards
Birgitta-A

Greg H
Sat Oct 2, 2010, 11:05 PM
I echo those thoughts on all counts.

Hey Karen!

Looks like the Vidaza is really working for you. Are you planning a transplant down the road?

Oops! I need to remember to look around before I ask questions. I see you are going for transplant at Johns Hopkins. Hope you find a donor quickly and all goes well. Will they be doing a reduced intensity transplant or the big one?

Greg

Greg H
Sat Oct 2, 2010, 11:09 PM
Hi Greg and Karen,
Yes, MDS is really very complicated partly because it isn't one disease but many that share some symptoms.

Birgitta,
I am glad to hear you say this, given all the reading you have done on the subject, because this is exactly the impression that I have developed from my reading. I think that, ten years out, MDS will have splintered into a bunch of better defined diseases or diagnoses.
Take care!
Greg

mausmish
Sun Oct 3, 2010, 01:39 AM
Hi Greg,

I'm planning a bone marrow transplant as soon as a donor can be found. I'm having a great response to Vidaza but there's no way of knowing when it will quit working. I've had consultations with oncologists from several different centers. They disagree on some of the finer recommendations about pre-transplant conditioning and post-transplant treatments but they all agree vehemently that I need a transplant, the sooner the better. It took a few months for my husband and me to accept this but we are charging forward now. Interestingly, one of the points of disagreement among the doctors is whether to do a SCT or a BMT. One doctor said it is believed but unproven that stem cell transplants are more effective but my doctor at Johns Hopkins says they do only bone marrow for allogenic unrelated donor transplants because it reduces the incidence of gvhd. I'm having full myleoblative conditioning. Fortunately, my health (apart from the MDS) is quite good and the doctors are concerned about my high chance of relapse due to all the chromosome abnormalities and the number of blasts and pancytopenia when I was first diagnosed in January.

Next week is treatment cycle 10 with Vidaza. Hard to believe the time is flying by so quickly! Vidaza has been a real life saver for me. If you've read the research, you've seen that the way that it works is extremely interesting, as well.

I hope all goes well for you, too. I'm enjoying your forum posts.

Karen

Greg H
Sun Oct 3, 2010, 11:55 AM
Hey Karen!

The webcasts and podcasts I've listened to and the articles I have read give me the same impression: there's a real diversity of opinion about marrow vs. peripheral blood stem cells, as well as about the myeloablative vs. reduced intensity conditioning.

It seems like reduced intensity and peripheral blood stem cells kind of go together, because, with the reduced conditioning, they are actually depending on some GVHD to mop up the baddies in your marrow. With the full-blown conditioning, they are going to take care of that job with the chemo.

My transplant center (Wake Forest) is very RIC oriented, near as I can tell, though my doc did some training at Stanford, where they apparently use a tougher conditioning regimen for MDS than for some of the leukemias, because, as she says "The clone is stubborn." If I wanted to press it, I could probably get them to do a regular-intensity transplant for me, even though they usually cut those off at 50.

But the alphabet soup beside my cytogenetics is a little less impressive than yours, so I'm still INT-1 and looking hard at the NIH Campath trial, since I fit their profile. I've got a bunch of loose ends to tie up before I'm ready to devote the amount of time transplant takes, so I'm hoping I could use immunosuppression to buy a year or three. (My doc would turn five shades of purple and steam would come out of her ears if she read that sentence!)

From the reading, listening, and watching I've done, it seems like the guys and gals at Hopkins are real innovators, so I am sure you are going to be in very good hands there. Good luck on your donor search!

Greg

mausmish
Sun Oct 3, 2010, 01:08 PM
Hi Greg,

If I were in your position, I'd probably be doing exactly what you are. I was tempted to try to wait a year or three or even five with the Vidaza working so well but I started to get too nervous about the odds, especially when I don't have a matched donor waiting in the wings.

I had almost made up my mind to go for the radiolabeled antibody conditioning plus SCT in Seattle but then felt overwhelmed with the logistics of being 3000+ miles away from home when Johns Hopkins is a mere 29.3 miles from my doorstep.

Keep us posted with the research, please.

Karen