Talking Telomeres

[Greg H]

Hi All!

I had my one-year followup for the Danazol trial at NIH in Bethesda in late November: chest x-rays, chest CAT scan, pulmonary function tests, a six-minute walk test, a bone marrow biopsy, and, of course, lots of tubes of blood for the lab.

I've been transfusion independent since early July, and my hemoglobin level is hanging in at roughly 11.5. Dr. Dumitriu and Dr. Young seemed very pleased with that result.

I'm very pleased as well. Back when I was having transfusions every other week, I felt that the time involved had very little impact on my life. But, now that I have a CBC only once a month, I find I have much more time to devote to other pursuits. And even more important, I have much less fatigue, so I feel like being more active and working on more projects.

The pathologist's report on my biopsy amounted to "same as it ever was," essentially no change since one year ago. I have dysplasia in all three lineages, meaning my blood factories for red cells, white cells, and platelets are all turning out some products that are defective. My platelet assembly line is the worst of the three, with lots of platelet precursors failing to divide up into tiny little platelet fragments, the way they are supposed to.

Last year, my cytogenetic report showed no chromosomal abnormalities, even though I have previously had defects in chromosome 1 and chromosome 8 in as much as 85% of my marrow stem cells.

This year's report shows the same duplication on the long arm of chromosome 1 and the same Trisomy 8 I have had in the past, with about 25% of cells affected. Dr. Dumitriu commented that "we have seen this pattern of on/off cytogenetic abnormalities in inherited bone marrow failure patients."
So, it's to be expected, and I'm resolved not to be overly concerned about it. Note that I now am considered an "inherited bone marrow failure" patient. It's that pesky TERT mutation that's causing the trouble. We are slowly working toward having testing on that front for my mother, brother, and daughters.

I asked how, exactly, taking Danazol -- androgen therapy -- helps correct the problem of too-short telomeres, when the problem is caused by a genetic mutation that, obviously, can't be fixed.

Though he assured me the exact explanation gets pretty complicated, Dr. Dumitriu gave me the simplified version. Genes like TERT (which has the job of building telomerase in order to lengthen telomeres), often don't work alone, but have promoter genes that can increase or suppress their activity. The Danazol works on one of these promoter genes to increase the output of the TERT I do have.

So here's hoping the promotion continues. I'm not due back in Bethesda 'til this time next year.

Take care!

Greg

[triumphe64]

Greg,
Glad to see you are doing so well.

My condition is different, but the Danazol has helped me tremendously.

[mausmish]

Excellent news, Greg! Very exciting that you've had no transfusions since July.

[tom30]

Greg, That is great news... congratulations...

[Sally C]

Greg,
That is truly great news - have been wondering about you. Maybe we'll run into you at NIH sometime.
Keep up the good work!
Sally

[Al's Wife]

Wonderful news, Greg. Thanks for sharing.

[Greg H]

Hi All!

I continue to be lazy about updating this thread; but that's mostly because nothing all that exciting is happening, and, in this case, no news is good news.
I am in the 18th month of the two-year NIH Danazol trial for folks with TERT and TERC mutations, and I continue to be transfusion independent -- since July 2012.

I had been taking Exjade for the iron overload that resulted from my every other week transfusions. But, in January, my platelets began to drop and my creatinine levels began to rise. My NIH doc, Dr. Bogdan Dumitriu, was concerned this could be related to the Exjade. In consultation with my local hematologist, Dr. James Wall, he recommended that we ditch the Exjade in favor of therapeutic phlebotomies.

So, now, instead of traveling every other week to my local medical center for a transfusion, I travel to the lab every other week for a bloodletting. The lab techs first take a little blood for a CBC. If my hemoglobin is above 10.4, they take a pint of blood.

Getting the blood out of me they use exactly the same procedure as for folks who are donating blood.

[IMG]
Untitled by hankins.greg, on Flickr[/IMG]

Just Kidding! They don't actually use leeches. instead, they use a very large gauge needle attached via a tube to a pint-sized plastic bag hanging from a little scale. They take 500 ml. I push blood pretty quickly, so it takes just a few minutes to get the pint out.

Since I have MDS, they can't save the red cells, platelets, or plasma to use in another patient. However, because I have several antibodies, the blood bank manager has them save my blood for use in type and crossmatch exercises with her students.

My HGB has managed to recover between every other week phlebotomies with only one exception. My platelets are hanging out in the 80s and 90s, which is below normal, but is typical for me. My neutrophils are regularly in normal range. And my lymphocytes are very, very slowly recovering from the Campath. Because they are still below normal, I continue to take Valtrex and Pentamidine to ward off infection.

Take care!

Greg

[Birgitta-A]

Hi Greg,
Very interesting with your positive response to danazol! Congratulations!
Kind regards
Birgitta-A

[cathybee1]

Oh, Greg, this is such great news that your hgb continues to hold. Boring news is good news in this crowd.

Also glad you're on phlebotimies now. Bruce discontinued Exjade as well, but not from side effects. Because his ferritin level got down to the mid 300's while taking a relatively low dose. Our doctor at UCLA said he's never seen anyone respond quite that positively to Exjade, given Bruce is still transfusion dependent.

So glad you checked in.

[Sally C]

Hi Greg,
I was recently wondering how you were doing as it has been a while since you posted. This is wonderful news!
Don continues to be transfusion independent going on 2 years now. This after he stopped taking Promacta in July, 2012. NIH works miracles don't they?
Keep up the great work.
God Bless,
Sally

[tytd]

Hello Greg,
It is marvelous to hear that you are doing so well. You have to have patience and perserverance to get thru this disease as so many on this forum have. You and Sally's husband successes are tributes to NIH and clinical trials. I wish you all continued good luck. tytd

[Greg H]

Hi y'all!

Thanks for the good wishes. I wish I had Bruce's response to Exjade. My Ferritin is very stubborn. But I don't really mind the phlebotomies. It gives me a chance to visit with all my friends in the lab.

Don's response to Promacta is also amazing. I definitely remember when you all couldn't even travel because of frequent transfusion needs.

This is a very mysterious disease and I think we will know much, much more about it a decade from now. Hopefully, our participation in research trials will contribute to that increase in knowledge and make the road a bit easier for future MDS patients.

Take Care! It is seriously soggy down here in NC as tropical storm Andrea passes by. I'll bet it's none too dry in Richmond either, Sally.

Greg

[Sally C]

Hi Greg,
You are so right in saying you remember when we couldn't travel. But Promacta has changed things dramatically. We just got back from the Houston area. We drove about 3,300 miles, ate our way up and down the state of Louisiana - and Don didn't miss a beat. Last check his platelets were 123,000. Truly amazing. And he has been off Promacta since July, 2012. Currently on no MDS drugs at all.
It has been pretty soggy in the Richmond area and is still raining. But having lived on a lake for 12 years - about 10 of which the lake almost dried up - we'll take any rain we can get to keep it full.
Again, so good to hear from you and so wonderful to know you're doing so well. Wish we could run into each other at NIH sometime. We'll be there again on July 9.
Take care and stay well!
Sally

[tom30]

I never considered BPA in receipts - at end of article...

http://www.thestar.com/life/health_w...sy_steps.html#

At last, we’ve got solid proof: You can renew and revitalize the DNA embedded in your cells to make improvements in your own health and live a longer and healthier life. And you don’t have to take questionable supplements (some good ones are mentioned later) or make a late-night agreement with someone who smells like sulfur to get it done. By adopting a handful of beneficial lifestyle habits, you’ll actually be practicing cutting-edge gene therapy!

So let us introduce you to telomeres...

[Greg H]

Near as I can make out, the NIH Danazol clinical trial has been pretty much an unqualified success, at least in my case.

I was up at The National Institutes of Health early in December for the final visit associated with the Danazol trial.

I gave up twenty-two tubes of blood and had various parts of my insides examined with various technologies, including chest X-Ray and CT scan, ultrasound of the liver, ultrasound of the testicles, pulmonary function test, six-minute walk test, and bone density scan.

Aside from the seriously cool gingerbread house competition in the lobby and getting to visit with members of the staff that I have come to regard as friends, the only thing remarkable about my visit is that it ended my daily doses of Danazol.

This visit marked the end of the 24 month clinical trial, so I am now off Danazol.

I was signed up for a new protocol that allows the folks at NIH to continue to follow my progress; I'll return next December for a BMB and such.

The theory for why we would stop taking a drug that has worked so well has two storylines:

1. Back when Danazol was regularly used for folks with bone marrow problems (mostly AA rather than MDS) only a small percentage responded. But, among those who did respond, once they had a good, healthy, prolonged response, it was possible to stop the drug yet have HGB stay high. So, based on experience, it should be possible to stop it without causing me problems, and, as Dr. Dumitriu said, "This drug we are giving you isn't water," i.e., there are potential side effects, some of them quite serious. Back in the old days, if folks did relapse after withdrawal of the drug, the docs found that restarting almost always resulted in resumption of the positive effect.

2. The other storyline is a bit more theoretical (and complicated, so this is definitely the layman's version that my small brain could comprehend). I have a mutation in a telomerase-linked gene (TERT) which is giving me too-short telomeres (about like someone 100 years old) and messing up my blood production. Theoretically, the Danazol is kick-starting the telomerase process, building my telomeres back up to where they should be at my age. If that worked, then my telomeres should now be long enough to do the job on their own without the drug. In other words, Danazol therapy for folks with short telomeres is not about stimulating the red cell production process more directly, like with synthetic EPO, where, if you stop the drug, the effect vanishes. Instead, we've hopefully lengthened my telomeres. As Dr. Dumitriu put it, "It took 50 years for your TERT mutation to create this problem. If we've given you another fifty years . . . " My post-Danazol telomeres will be measured, but Dr. Dumitriu hasn't completed that part of the analysis as of this writing.

Since December, I have had a half-dozen CBCs. The results look like this:

12/03 - 12.0 (at NIH)
12/17 - 11.1
12/31 - 10.7
01/15 - 10.6
01/28 - 10.1
02/11 - 11.4

That was looking a little dicey until that last one, no?

But, during most of this period I was not only having fortnightly CBCs, but therapeutic phlebotomies, as well, to reduce my iron overload. The target for that was a ferritin count under 400, and we hit 255 with the 1/28 CBC. So, no more phlebotomies. I get to keep that blood and the HGB it contains; and the result looks promising, with a reading of 11.4 in the latest CBC.

My other numbers are fine. Platelets are going through one of their stints of hanging out in the 80s or 90s, which is subpar, but par for the course for me. Neutrophils are totally normal, and lymphocytes continue to slowly recover.

I still have MDS. My marrow is still a mess, with plenty of dysplasia in all the cell lines. I still have trisomy 8 and a broken Chromosome 1 -- both on 60% of my cells in the last biopsy. But that broken marrow is still making some functional blood cells.

The bottom line is that, four years ago next week, I walked into an appointment with my family doctor to discover that my hemoglobin was sitting at 6.2. I didn't even know what hemoglobin was. He shipped me over to Same Day Surgery for my first ever transfusion.

A month later, I had an MDS diagnosis, a hematologist telling me I had maybe eight or ten years, and a transplant doc ready to nuke my bone marrow.

Did we panic? Yes, we panicked.

But then we started reading and studying. I found marrowforums. I found NIH and Barbara Weinstein, and Dr. Matt Olnes, and Campath.

And Campath didn't work for me. But, in the process, I found Dr. Bogdan Dumitriu, who checked my telomeres and enrolled me in the Danazol trial. And now, after taking in 79 units of packed red blood cells, I haven't had a transfusion in 19 months.

I have new chickens in the coops; we have new kittens; Marcy & I just celebrated our 40th Wedding Anniversary; and I've taken up melodeon (button accordion) and anglo concertina. Like Steve Martin says of the banjo, if I play it every day, in 20 years, I might get good at it.

I'm a lucky guy.

[maggiemag]

Hi Greg,

I find your story just fascinating! I think I asked my honc about a year ago about the telemere thing, but don't remember what she said. I am wondering if there is a standard lab test for the shortened telemeres, or is it found on BMA? Is it only done under study circumstances? In other words, can I have it done? I have an assemblage of weird medical stuff, and maybe I fit that mold? Certainly is cutting edge research!
Mags

[Birgitta-A]

Hi Greg,
Very interesting ! Hope your HGB will hold!
Kind regards
Birgitta-A
Positive response to Revlimid.

[Greg H]

Originally Posted by maggiemag

Hi Greg,

I find your story just fascinating! I think I asked my honc about a year ago about the telemere thing, but don't remember what she said. I am wondering if there is a standard lab test for the shortened telemeres, or is it found on BMA? Is it only done under study circumstances? In other words, can I have it done? I have an assemblage of weird medical stuff, and maybe I fit that mold? Certainly is cutting edge research!
Mags

Hey Mags!

There's a lot of research being done on telomeres at present, though a lot of it is focused on the role that over-active telomerase plays in promoting the uncontrolled growth of solid tumors.

The test for telomere length is not yet a standard item, but it is definitely available. Repeat Diagnostics is one lab that was in it early on and there's another one called Spectracell Labs. I have no idea of the cost, but you'd probably want to work through your doc to get it done.

There is also a ton of hokum about telomeres out there on the web, so take what you read with a grain of salt and stick to reliable sources.

The folks at NIH have linked the short telomeres caused by a genetic abnormality like mine to bone marrow failure, pulmonary disease, and liver disease. Another research group has linked it to the likelihood that Barrett's esophagus will morph into esophageal cancer.

Take care!

Greg

[mausmish]

Greg,

That is amazing news! Congratulations!!!

Karen

[tom30]

Hi Greg, This is really interesting news, I hope your numbers continue to stay where you want them to. Thank you for all your posts they were very helpful to me. Congratulations on your 40 year anniversary!

[Sally C]

Hi Greg,
I had been wondering about you. This is such great news - NIH is such a blessing!
Don also remains transfusion independent going on 2 1/2 years now - and has been on no MDS meds since July, 2012. Promacta really performed a miracle!
We still go every 3 months - Don is like NIH's "ET". He is the only patient who has maintained his counts without being on the med. A wonderfully strange case for them to research.
Congratulations on your 40th anniversary. From one Tar Heel to another!
God Bless and keep up the great work!
Sally

[StephM]

Originally Posted by Greg H

Hey Mags!

The test for telomere length is not yet a standard item, but it is definitely available. Repeat Diagnostics is one lab that was in it early on and there's another one called Spectracell Labs. I have no idea of the cost, but you'd probably want to work through your doc to get it done.


The folks at NIH have linked the short telomeres caused by a genetic abnormality like mine to bone marrow failure, pulmonary disease, and liver disease.

Greg

Hi!
Thanks for the information. My brother's hematologist told us the test was not available here in France. I talked about it during our last appointment because there is something disturbing in my brother's story. Not only did he get SAA out of the blue but his father died 10 years ago of a liver disease.
There may be a link, like a genetic abnormality.
I could try to find a way to have the test done but would it change anything in his treatment? It would just tell us that he has a high chance to relapse after the tapering of cyclosporin is completed.
Which is better not knowing... Am I wrong?

[Greg H]

Hey Steph!

The coincidence of liver disease and SAA in the family could be random, or it could in fact be linked to a TERC or TERT mutation. The family trees that I have seen at NIH (with the names obscured, of course) show a mix of Aplastic Anemia, pulmonary disease, and liver disease. So it would definitely be work checking out.

You could contact the folks at NIH directly to discuss options. I think the last person I referred to them found that they wanted your local doctor to do the telomere screen and the tests for the mutations. But it still might be worth talking with or emailing Barbara Weinstein, the research nurse on the trial (301-594-4180; weinsbar@nhlbi.nih.gov). NIH treats plenty of international patients in their trials, though the travel expense might be prohibitive for you. I think they might be interested in talking with you based on the family history. It's worth am email, for sure.

If your brother has short telomeres and/or a TERT or TERC mutation, that would definitely have implications for treatment. It could indeed be that relapse would be more likely. The lead doc on my Campath trial at NIH (Campath being an alternative immunosuppressive treatment, like ATG/Cyclosporine) told me that they have found folks with short telomeres are more likely to relapse. In fact, he believes I showed a brief response to Campath, but quickly relapsed.

It would also mean that it would be worth trying Danazol therapy. Most of the folks in the Danazol trial are AA patients, not MDS. And I gather it has been very successful. One option, of course, would be, if he relapses, to try the Danazol without all the testing. Synthetic androgens used to be standard treatment for AA decades ago.

If you'd like, I can email you some articles to share with your brother and his doctor. Just private message me your email address.

Good luck to you and your brother!

Greg

[Greg H]

Thanks, Sally, Tom, Birgitta, and Karen for your well wishes. I'm afraid I have become more of a lurker than contributor here, but I do drop in from time to time to check on your progress -- and others as well.

I really think that the experience that I and others have had with Danazol and Don's success with eltrombopag should convince anyone that clinical trials can be a very viable treatment option.

Take care!

Greg

[StephM]

Thank you Greg for all those details. I think I will try to contact the NHI. It's worth trying.
My brother is starting to taper cyclosporin next month and he is really scared. Knowing that there might be a cause for relapse and that solutions exist would be a tiny bit comforting.
For the moment, the most difficult thing to handle is the pain in the joints. He hasn't been able to work since September last year and he can hardly walk. The doctors told him it might not be caused by cyclosporin but rather by the ATG treatment and that the pain may never go away.
He is so depressed...
It might be worth asking them at the NIH about that too.

Thanks again