Hey Slip up!

Sorry for the slow response; I was out of town for a week.

The test that NIH did on my telomeres was on a peripheral blood sample -- not marrow aspirate. I think that's pretty much par for the course.

This telomere stuff is all pretty new, so don't be surprised if you get a quizzical look from your doc when you ask about it. It seems much more a hot topic in AA than in MDS, as well.

Take care!

Greg

telomeres
 

There is an interesting show on the smithsonian channel on telomeres. The title is Decoding Immortality. http://www.smithsonianchannel.com/si...do?show=137613

Hey Tom!

That's great! I'm going to watch it tonight.

Thanks!

Greg

Hi Greg,

Thanks for the lead on the test...we are still awaiting results from the last bmb. And have an appointment with Dr. Paquette at UCLA mid Nov. Will bring it up with him then.

Bruce is going for one more load of wood today -- colder weather is here and the geese, ducks, and blackbirds have all headed south.

Rehabbing a bathroom doesn't sound like a lot of fun, but spending time with your daughter does sound like a nice getaway.

Hugs

Happy Pills
 

I'm on the seventh day of my new therapy, taking 400 mg of Danazol -- a synthetic testosterone analogue -- twice a day. It's part of a small clinical trial at the National Heart Lung and Blood Institute of the National Institutes of Health in Bethesda, MD.

[IMG]
Danazol 200 mg by hankins.greg, on Flickr[/IMG]

I was up in Bethesda on Tuesday and Wednesday of last week for screening and, mostly, baseline testing. Though Danazol has been on the market since the 1970s, used primarily to treat endometriosis and fibrocystic breast disease in women, the trial I have entered represents a new use for the drug, with a high dose. Many of the tests seemed to be aimed at laying down a baseline, so that, two years from now, the researchers can determine whether Danazol has had any adverse effects, in addition to whatever help it has provided.

Along those lines, I had:

• Chest X-Ray.
• CT scan of the chest.
• Bone density measurement of the forearm, hip, and spine.
• Pulmonary function tests.
• Six minute walk test.
• Testicular ultrasound.

Why they would want this last test is obvious, given the fact that I'm going to be taking a high dose of sex hormones for two years. As to the details of the procedure, I'm going to let your imagination run its course. All I can say is it's the one instance I can recall when I felt there might be some advantage in having reproductive organs that were hid discretely inside the body.

Testosterone, and the estrogen into which the body sometimes converts it, have impacts on the amount of calcium retained in bones. That explains the bone density tests.

All the lung and pulmonary stuff is related to the genetic mutation that qualified me for the trial in the first place.

I am of interest to the NIH researchers because I have very, very short telomeres -- the caps on the end of chromosomes that protect them during cell division -- as well as a mutation in the TERT gene that is to blame for the telomere problem. Apparently, some folks who have this problem see no clinical symptoms as a result. Some develop aplastic anemia. Others develop pulmonary fibrosis -- hence the interest in lung function.

I also gave up 30 tubes of blood for various and sundry tests -- a full hormonal panel, as well as all sorts of serum chemistries, and the usual complete blood count.

Finally, I had a bone marrow biopsy that proved my best -- and most entertaining -- experience to date at NIH. The resident who performed the procedures was a stylishly-dressed, attractive young woman from Barcelona, equipped with those fashionable eyeglasses with the thick plastic rims.

Anyone who's had glasses like those knows well that, as the body heats up and the nose grows a bit slick with perspiration, the glasses start to slide down the beak. My young doctor had a ready solution. She asked the nurse for a piece of tape and strapped it across the bridge of the spectacles, with one end on her forehead and another on her nose.

It was truly hilarious. I only wish she had let me take a photo.

Taped glasses and all, my young doc proved very proficient at bone marrow biopsies, using ample lidocaine to ensure my comfort and drilling through my very hard bones to extract a nice marrow sample with minimal problems. I won't see the results until the end of this week or early next, of course.

Dr. Bogdan Dumitriu took me through the consent; he'll be following me at NIH. I met Dr. Neal Young, Dr. Phillip Scheinberg, and Dr. Danielle Townsley, as well. Olga Rios is the research nurse on the trial

The Danazol capsules are a pretty standard size (and attractively-colored!). I've had no noticeable effects, so far, aside from a tendency to frequent headaches, which could, frankly, be related to seasonal allergies rather than Danazol. We'll see if it persists.

I'll return to NIH at 6, 12, and 24 months, repeating a lot of the same tests. Dr. Dumitriu explained that they will be saving up samples of my chromosomes until the end before running the tests -- all in the same run -- to see whether the Danazol has managed to lengthen my telomeres.

Other marrowforums folks are on the Danazol trial. You can read about their exploits here.

I've been on Danazol for over two years. It takes a few months to kick in. I'm jealous of all your tests except BMB. Everything we PRCA people do is off label. Danazol has the side effect of making red blood cells. That, and the sex hormone part, will keep you out of the Olympics and the baseball Hall of Fame. You might still be able to get into the Tour de France.:)

Longer telomeres slow down the aging process. So you can take longer between birthdays.;)

Interesting about the telomeres and the danazol Greg.

I am on a treatment that activates the VDR (vitamin D receptor) which is one of the main nuclear receptors involved in regulating the immune system. It affects over 900 genes that they know about. I had a look through supplemental data table 1 and searched for telomere (the link to the article & data tables is here: http://mend.endojournals.org/content...85.full#ref-24).

I found a gene that is called POT1 - protection of telomeres 1 homolog (S. pombe). It's supposed to be upregulated by a factor of 1.7 when the VDR is activated. Is this at all related to your TERT gene I wonder?

I can't pretend to understand everything about genes and stuff, but I find it interesting. My doctor wants me to try bio-identical hormone replacement, as they've recently discovered that estrogen affects about 25% of the human genome, which is pretty huge. It's interesting to hear of people trying the danazol. The estrogen receptor interacts with the VDR, same with the thyroid receptor.

Again, I can't pretend to understand it all, and I can't say my treatment has been a roaring success. But neither was ATG, tacrolimus, IVIG or cyclosporine. I do have some improvements on this experimental treatment, and my hematologist is monitoring me. I can't say I'm not frustrated but at least I'm not sick from drug side-effects.

I'm going to look at the articles you posted about telomeres. I always look up genes in that supplemental data table 1, but I have come to the conclusion that maybe they don't yet know all the genes involved in blood production in humans. I guess there's still a lot to learn.

Thanks for posting and good luck with your treatment.

Deb

Danazol
 

Hi Greg,
Thank you for the very interesting info about the Danazol trial :). We do hope it will help you and others that try that drug.
Kind regards
Birgitta-A

Hey Triumph!

The first person in this trial started in August and now has improvements in all three cell lines, so that fits well with your experience.

Given that Le Tour doesn't start until July, I should be in great shape in plenty of time.

Take Care!

Greg

Hey Deb!

All this gene stuff is way, way above my pay grade. I struggle to understand any of it.

What is particularly confusing is that TERT (and TERC and DK1) refer (near as I can tell) to two different things:

1. A particular protein that is part of an enzyme called telomerase, which is responsible for rebuilding the ends of telomeres after cell division.

2. The gene that "encodes" the TERT protein.

I hope that's right, anyway.

POT1 is a part of this story, another gene that encodes a protein. But instead of being a part of telomerase, the rebuilding enzyme, POT1 is one of six proteins that together make up a substance called "shelterin." Shelterin protects the ends of the telomeres, which in turn protect the end of the chromosomes.

Telomeres are nonsense, but they are nonsense that looks just like real, but defective, DNA. If they weren't protected, the cell's clean-up mechanisms would mistake them for a messed up chromosome, and probably crank up the process that puts the cell out of commission -- either through senescence or apoptosis (sleep or death, as I understand it).

What seems so confusing about all this to me is that there's more than one way that TERT -- or any other gene -- can be messed up. Because a gene is basically a long strand of DNA, like an enormous word made up of various arrangements of four letters, misspellings can happen anyplace along the strand. So there's more than one kind of mutated TERT. At the moment, I don't know which mutation I have -- or even if it for sure makes a difference.

All this gene science is so vast and research on it is moving so fast that I only hope we're all around in 10-15 years to see what it looks like when the scientists figure it all out.

Do let me know if you turn up anything else interesting. One of the things I love about marrowforums is that folks ask such good questions, which forces me to question what I think I know, go read more stuff, and learn more and more.

I hope that your treatment brings you some success. I've read your posts, and, as bad as it is to have MDS, it's got to be so frustrating to have "we really don't know what you have."

Take care!

Greg

Thanks Greg. This was about the first time my treatment and conventional treatment sort of converged, so I thought it was interesting. But I agree - this is way above my pay grade too!

Deb

Wow, Greg, once again you managed to inform and entertain splendidly... And here is a very basic question -- is the hoped for result from the Danazol trial younger-looking telomeres?

Hey Catherine!

Sorry for the slow response. I was out of town for a few days.

Yes indeed, the thought is that the Danazol, an androgen, will improve the telomerase cycle -- the chemical process that repairs and lengthens telomeres. The TERT mutation that I have -- and the TERC mutation that some of our other friends have -- messes up this process.

The folks at NIH have used androgens in the test tube to improve the telomerase cycle in both bone marrow stem cells and white blood cells. They know that doctors in the field have had some success over the past 40 years treating aplastic anemia patients with androgens.

So this trial puts those two facts together in a trial to see if Danazol therapy can lengthen telomeres -- and if that lengthening will result in improved blood counts.

Danazol and other androgens can improve red blood cell counts another way: by increasing the release of EPO from the kidneys -- which has kind of the same effect as Aranesp. I would guess this would be of limited value to folks who are already churning out a lot of EPO, and I fall into that category.

A final interesting point: the test tube studies at NIH showed that the effect of androgens on blood cell telomeres was actually mediated through the aromatization process, which converts testosterone to estrogen. They theorized that it might be possible to use estrogen directly to stimulate the telomerase cycle, but, I suppose, went with a testosterone analog first because of the history of using those substances to treat AA.

Take care!

Greg

Greg,
I know that women don't like to take Danazol, and I would not like taking estrogen. It sound like both sexes can be happy and achieve the desired results.:p

Hey Greg,

Very interesting info about Danazol...and about the EPO connection too...and also wondering btw how your copper is faring...and if you think the wheatgrass is helping. So many questions but you're such a great answer guy. :)

Hey Catherine!

I'm not sure if they tested copper when I was up at NIH. I'm going to order the full set of labs, so I'll be able to find out in a week or so (or maybe sooner when Dr. Dumitriu calls with my cytogenetics report). If they didn't test it, I'll get my local doc to do so. I'll have to check my noted, but I think I've been doing the higher dose of 8mg of copper per day for about six months now. One would think that should be enough time to show some improvement.

I've only just gotten back on the wheatgrass, so it's too early to tell. I'll have ferritin tested locally in a couple of months, when we're sure the Danazol isn't messing with my liver. That would be the point to make a decision about chelation with Exjade or Desferal. I'm hoping those labs will show enough progress that I can stick to the wheatgrass alone, instead of some expensive drug. But we'll have to see.

Take care!

Greg

Thanks, Greg...Hope the copper supplements have worked for you, and the wheatgrass too!

Bruce saw the hematologist Tuesday and said he was ready to do a trial of Exjade. But right now, the jury's out whether that will happen, as Bruce's liver numbers are not where the hematologist would like them to be.

So wheatgrass may turn out to be the best option here too.

I found this article. I don't think it's been posted here.

http://abstracts.hematologylibrary.o...d-34d4ec5dab4f

Normal. 46XY
 

I have news, friends and neighbors, very interesting news.

Though I don't have the actual report in hand, today I got the top line results from my recent bone marrow biopsy at NIH, courtesy of Dr. Bogdan Dumitriu.

The report on the marrow and aspirate (blood pulled from the marrow) were not all that newsy. I still have dysplasia (messed up blood production) in all three cell lines (reds, whites, and platelets). Blasts (immature white blood cells) are "around five percent." That's higher than they have been, but Dr. Dumitriu doesn't seem concerned.

I'll know more about all that when I get the full printed report from the Medical Legal Department at NIH.

But the big news was in the cytogenetic report, where we look for chromosomal abnormalities.

And the news was . . . normal. 46xy. No abnormalities. Bupkis.

What makes that remarkable is that previous BMBs have found abnormalities in as many as 16 of the 20 cells analyzed (80%).

Here's the track record:
From 80% of cells with messed up chromosomes to 0% in six months. What gives?

Here's the story I'm telling myself . . .

At some point, my marrow started churning out defective hematopoietic (blood producing) stem cells and progenitor cells. Some of those had broken copies of Chromosome 1. My immune system responded by developing a set of T-cells primed to attack those defective marrow cells. But the attack backfired, and the cells with the Chromosome 1 defect began to acquire another defect in Chromosome 8.

Last November, I received Campath at NIH. That knocked my T-cells flat, stopping the immune war in my marrow. It began to recover, showing improvement in my red cells, neutrophils, and platelets. Improving reticulocyte numbers showed I was making baby red blood cells. But then something stopped the improvement in my red cells: the too-short telomeres in my stem cells began making too many progenitor cells that just aren't viable; they die off before making red cells.

So the improvement in my counts stopped. But my marrow, despite the short telomeres, continued to heal. Relieved from the T-cell attack, the Chromosome 8 mutation subsided. Now the Chromosome 1 mutation is gone. I'm still not making enough red blood cells, but the threat that a mutant clone poses has lessened for now.

That's the story I'm telling myself, but what do the docs think?

Dr. Matt Olnes, formerly of NIH, told me "I think you are right on as far as your assessment of what may be happening with your marrow. I also think that the Danazol is a logical next step to improve your red cell transfusion requirements."

Dr. Bogdan Dumitriu, my doc on the Danazol trial, was a bit more reserved. It could simply be that the 20 cells cultured for the cytogenetic analysis happened to be normal. On the other hand, he suggested, the results certainly suggest that "things are stable (which is what we want) or even improving (cautious)."

Either way, that's my story, and I'm sticking to it. Now we just need the Danazol to kick in and give my poor stem cells a little more telomere to work with, so they can make more viable red blood cells and I need less frequent transfusions.

Wow Greg!
That is great news! I figure any bone marrow is merely a snapshot as to what is going on that day/week and who knows? It's the big picture and things can always change..we weren't born with MDS so maybe stuff can reverse itself. You just never know, but I'm so happy for you, whatever the reason!

I have been on Danazol (100 mg, 2xday) for a few months now and my last platelets were up to 88k!!!!! I haven't seen that since April 2010, post chemo, when shortly thereafter, they started to decline. I'm hoping with that and the Revlimid, I can become more transfusion independent....

Hey Cheri!

Go 88K! That is outstanding -- and a better number than I get half the time. I do hope it holds.

What dose of Danazol and Revlimid are you taking?

I hope you have an excellent Christmas and New Year!

Greg

That's fantastic news Greg! What a great Christmas present :)

Wonderful news, Greg. Bupkis is worth celebrating!

Excellent news, Greg! Merry Christmas!

BMB
 

Congratulations Greg!
Kind regards
Birgitta-A