Talking Telomeres

[Hopeful]

Hi StephM,

How are your brother's counts? Did he respond well to the ATG?

I had terrible joint pain when tapering cyclosporine, to the point where I thought I would never walk normally again. For me, the pain would go away after a few days or a couple of weeks (depending on how much I was tapering at the time). Whenever I lowered my dosage and felt the pain, I would have to remind myself that my knees were okay and that this too would pass.

The other time when I felt a lot of bone pain was when my blood counts were increasing.

Hopefully, it is just the cyclosporine taper for him as well! Make sure that the doctor is carefully watching his counts as he tapers so that he can catch any issues early!

[Greg H]

I'm writing this from a hotel a couple of blocks from the NIH campus in Bethesda, MD.

I'm back at NIH three months early for a bone marrow biopsy and some bloodwork. What won me the invitation for an early visit is avery gradual but persistent slide in hemoglobin levels since I stopped taking Danazol, culminating in an 8.8 on August 4.



That low reading may have been some sort of anomaly, since a second CBC a week later produced a friendlier 9.9. On the other hand, during the week prior to that 8.8, I had experienced many of the telltale signs of low HGB. I had blood pounding (or squishing) in my ears at night, I was sensitive to cold (in very hot summer weather), and fatigue had reached the point that I actually took a couple of brief afternoon naps. As I told my local oncology nurse, I felt "ragged."

I had, the week prior, packed up my younger daughter's second floor New York apartment, loaded it into a UHaul, drove it North Carolina, and unloaded it. It don't know that you can burn red blood cells, but, if that's possible, I had definitely lit the match to a bunch of them.

After I posted the 8.8, I fully expected that the CBC a week later would land me in the transfusion chair. But that was not the case, and I no longer have the blood pounding in my ears, nor am I in need of a nap in the middle of the afternoon.

I do, however, seem to be tiring more quickly than normal from strenuous physical activity, like brush cutting and other yard work.

So, I expect I will not be posting an 8.8 tomorrow, but I would be surprised if my HGB is an 11.

I glad to be having the biopsy, because I am just a interested as my NIH friends in understanding whether anything untoward is going on in my bone marrow.

I'll report back on what we find.

Take care!

Greg

[Cheryl C]

Good to hear from you again, though not for this reason! Hope your BMB results free you from these current concerns Greg.

[Birgitta-A]

Hi Greg!
Very interesting to read your story with Danazol . Positive that you don't have iron overload. Hope Danazol wii continue to have effect or if not you can restart the drug and that your HGB will increase!
Kind regards
Birgitta-A
75 yo, dx MDS Interm-1 2006, supportive therapy until 2010. Thalidomide 2010-2013. Now taking Revlimid since 2013. HGB increased to 14.5 April 2014 but is now decreasing.

[bailie]

This is a very interesting study. There is a link between short telomeres and MDS. There is an inverse correlation between age of MDS patients (increasing incidence with age) and length of telomeres (decreasing length with age). The graphs match up consistently. If they can come up with a drug that will increase the length of telomeres, I believe one of the solutions to MDS and AML will be solved. It is great that MD Anderson is exploring this link. I believe that the short telomeres are the primary reason for the "random acts of violence" in our bone marrow.


http://www.news-medical.net/news/201...n-and-MDS.aspx

[traceyn11]

Originally Posted by bailie

This is a very interesting study. There is a link between short telomeres and MDS. There is an inverse correlation between age of MDS patients (increasing incidence with age) and length of telomeres (decreasing length with age). The graphs match up consistently. If they can come up with a drug that will increase the length of telomeres, I believe one of the solutions to MDS and AML will be solved. It is great that MD Anderson is exploring this link. I believe that the short telomeres is the primary reason for the "random acts of violence" in our bone marrow.


http://www.news-medical.net/news/201...n-and-MDS.aspx

Very interesting study bailie! Thanks for sharing.

[Faye R]

Hi Greg
My brother has ben nagging me about Telomeres, he his a health nut not me have good food but not to the extent that he goes to, he has even gone to the point where he would like to be self sufficient. I'm on Vidaza, Danazol seems to be a less invasive option, but I wonder how it would affect you say down the tract if you want a SCT. would you be able to do so. I also wonder if Danazol will be more affective on the male verses the female.
Best of luck for November
Faye R
DX RCMD now DX RAEB-2

[bailie]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237881/

IM (Gleevec), the first selective tyrosine kinase inhibitors (TKI), is reported to cause a dose-dependent inhibition of telomerase activity in various leukemia cell lines, including BCR-ABL negative cell lines [86]–[88]. IM regulates telomerase activity by decreasing the expression of hTERT and increasing the expression of telomerase inhibitor protein phosphatase 2A (PP2A) [87]. Following treatment with IM, the expression levels of TRF1, TRF2 and PinX1 are markedly reduced. The second-generation TKIs nilotinib and dasatinib, which have higher potency than imatinib against BCR-ABL (reviewed by Wei et al.), are more effective in reducing telomerase activity [89],[90].

Patients who received autologous or allogeneic HSCT (auto-HSCT or allo-HSCT) experienced more severe erosion of telomere length in their blood cells under massive differentiation pressure compared with their donors. Akiyama et al. reported that the telomeres of transplanted cells became shortened by up to 1.9 kb in auto-HSCT recipients over an observation period of 5.3 years, the same frequency of telomere erosion as would occur over 15–20 years in normal individuals. Telomere erosions of up to 2.1 kb were observed in patients who received allo-HSCT [60]. Baerlocher et al. evaluated 44 long-term survivors after allo-HSCT with a median follow-up of 17.5 years. Significantly shortened telomere length was observed in all blood cells lineages, including granulocytes, naïve/memory T cells, B cells and natural killer/natural killer T cells in the recipients compared with that in their donors [61]. The rate of telomere shortening in recipients is highest in the first year after HSCT and then slows down to a rate similar to that of their donor and of healthy controls [62]. Telomere shortening in patients who received allo-HSCT seems to be more sensitive to the influence of ageing than auto-HSCT. A correlation between donor age and telomere shortening rate has been found in allo-HSCT but not in auto-HSCT recipients [60].

The telomere length of hematopoietic cells in the recipient before HSCT, which represents the inner environment of host, is another factor impacting the outcome of transplantation. Peffault et al. reported that treatment-related mortality was inversely correlated with age-adjusted recipients’ pre-transplantation telomere length in their lymphocytes (hazard ratio, 0.4) in patients who received allo-HSCT, especially in patients with advanced stage disease [69].

Conclusions
Telomeres are essential for the maintenance of chromosome stability in mammalian cells. Accelerated telomere shortening leads to activation of telomerase in stem cells and in the majority of tumor cells. In patients with hematologic malignancies, shortened telomeres and increased telomerase activity are usually observed and are associated with disease progression. In patients who have received HSCT the telomere length of engrafted stem cells is closely related to the outcomes of HSCT. Consequently the telomere characteristics should be taken into consideration during donor selection. It is also necessary to evaluate the effect of chemotherapy and conditioning courses on telomere length. Many promising telomerase targeting therapies have been confirmed to be tolerable and efficient to induce immune responeses in patients with hematological malignancies. However optimized strategies are still required to ensure their clinical efficiency. Further work will be needed to elucidate the complete story of telomere biology and to explore efficient telomerase-targeting therapies in hematologic malignances.

[Neil Cuadra]

The September 28 issue of TIME Magazine has an article named Why It's Tough to Survive a Year in Space, accompanied by a diagram that shows problems that occur when you spend many months in space.

One of the problems they illustrate is that telomeres shorten more rapidly in space than on the Earth. They are currently studying this expected effect, to see how the combination of radiation, weightlessness, changes in diet, and other factors make telomeres shorten.

That certainly tells us that MDS patients shouldn't volunteer to be long-term astronauts. They'd also be a bit far away from their treatment center!

[Greg H]

It's been more than a year since I last posted in this space. My August 2014 visit to NIH turned up nothing remarkable. In fact, my bone marrow was remarkably like it had been on previous visits: dysplasia in all three cells lines and a few messed up Chromosomes. This time, the trisomy 8 was not detected; only a translocation in chromosome 1.

Given my slowly descending Hgb, Dr. Dumitriu recommended resuming Danazol, but at a lower dose. On trial, I was taking 800mg per day; we resumed at only 200.

That appeared to do the trick. Though my hemoglobin had been sinking, it gradually began to rise, settling fairly consistently in the mid 9s.

In April of this year, I was visited with a nasty attack of acute necrotizing pancreatitis, which landed me in the hospital for sixteen days. About two-thirds of my pancreas was destroyed.

I don't believe that Danazol was implicated in the pancreatitis attack, though there are a few isolated case studies out there that suggest some link. My docs believe the problem was a gallstone that plugged up the common bile duct, which carries bile from the liver and gallbladder, as well as pancreatic juices from the pancreas, dumping it all into the small intestine.

Evidently, when things get plugged up that way, the pancreas does not have the good sense to hold off on making digestive juices. Instead, they back up and digest the pancreas itself.

The key risk in acute pancreatitis is that the various nasty fluids and dead bits of tissue involved will become infected. Fortunately, this did not happen in my case. My bone marrow, perhaps sensing the need for extra protection, started pumping out white blood cells like a madman. That left little time for making platelets or red blood cells. So, in the sixteen days I was in the hospital, I received four units of RBCs, and one of platelets, my first ever platelet transfusion.

Since then, I have had two RBC transfusions, despite the Danazol. I am taking Oxycodone daily to suppress ongoing pain, and that, or the ongoing pancreatitis process itself, could be suppressing the bone marrow a bit.

In some cases, the body will eventually wall off the dead portions of the pancreas in a "pseudocyst." And, sometimes, the pseudocyst's contents will be gradually reabsorbed by the body.

In my case, the pseudocyst formed, but it has stubbornly remained the same size since April. So, on Tuesday, I am scheduled for laparoscopic surgery to remove my gallbladder and drain the cyst. The expectation is that I will be in the hospital for four or five days.

I am hopeful that, after a couple of months, I will be good as new, able to dispense with the Oxycodone, and and my bone marrow will respond positively. If not, I may suggest that we increase the dosage of Danazol to 400mg per day.

I did visit NIH in August for my annual bone marrow biopsy. The results included dysplasia in all three cell lines, as usual. Interestingly, this time the chromosome analysis found nothing at all abnormal.

[bailie]

Welcome back Greg. I want to thank you for introducing me to telomeres. I think that a few years from now the people above my pay grade will decide that telomere length is the key to cures. I wish you the best, thank you for posting.

[tom30]

hi greg, I wish you the best of luck with your surgery!

[Cheryl C]

All the best with the surgery Greg.

Just as a side-note, Danazol was prescribed for me to combat severe endometriosis about 25 years ago. When I was on it (9 months) I felt the best I had in years. There were a couple of side effects which disappeared when I stopped taking it. It did help me a lot with the endometriosis too.

[Hopeful]

Best of luck in your surgery and recovery, Greg. Hopefully, resolving the pancreas issues will eventually help resolve the marrow production issues as well.

[DanL]

Greg,

It is great to see an update from you. I wish you a strong and speedy recovery from the surgery and continued success with the danazol treatment.

[Greg H]

Hi All!

My posts here have been infrequent over the past couple of years, because, frankly, I have been reasonably well . . . aside from that whole acute necrotic pancreatitis thing. Hematologically, things have been decent. The resumption of Danazol staved off most of my need for transfusion.


Since January, however, I've needed blood almost twice a week. That prompted a return trip to NIH four months early and some not good news from my bone marrow biopsy on Tuesday.


But first, about that pancreatitis . . . The planned laparoscopic surgery turned into a six inch incision in my abdomen when the cyst wouldn't cooperate. And rather than healing up like a well-behaved wound, mine turned into something called pyoderma gangrenosum.


I left the hospital after fourteen days with a wide abdominal belt and large wet-to-dry dressing holding together a wound that looked like two pieces of flank steak laid side by side, about one-half inch apart. Plus I had a bottle of 50mg prednisone tablets.


Daily changes of the dressing and a gradual taper of the predisone did the trick, and my wound is now a very large scar, covered with new skin and healing nicely.


My BMB at NIH earlier this week did not provide so happy a result. After cruising for five years with hardly any blasts to speak of, I now have fifteen percent blasts in my marrow. Blasts are immature white blood cells. They clog up the marrow and prevent it from doing its job of producing blood cells. Once that hits twenty percent, they start calling it Acute Myeloid Leukemia.


So, Monday I start Vidaza to bring down the blasts while we wait to find a donor and pick out transplant center. The logical choice is Duke, because they do a lot of transplants and they're in NC, a couple of hours from home.


My telomeres are still short, and I still have a TERT mutation. But Danazol therapy is no longer the top plot line in the story of my MDS. So, I'll likely start a new thread when I next post.

[bailie]

Greg, we wish you the best. Your accounts are always interesting and especially helpful. I am always wondering about the telomere length and its effect on the marrow. Has anyone mentioned to you that the shortened telomeres can be the culprit for MDS/AML? If so, can anything be done to lengthen the telomeres? Do the telomeres get shorter as a result marrow failure, or can they cause marrow failure? Just curious if you have run across any helpful answers?

[Greg H]

Hi Bailie!

Yes indeed, the folks who have been treating me at NIH have found a link between shortened telomeres and marrow failure, though having shortened telomeres apparently does not guarantee marrow failure. They have also linked "telomere disease" to pulmonary fibrosis and cirrhosis of the liver.

One of my primary docs there once told me, "If you have short telomeres and you smoke, you will get pulmonary fibrosis; if you drink, you will get cirrhosis." But some folks with short telomeres apparently have no related health problems.

The thought is that the short telomeres contribute to bone marrow failure, and not the other way round. My short telomeres are the result of a mutation in my TERT gene, which helps rebuild telomeres, after cell division.

[DanL]

Hey Greg,

thank you for the update. It has been a while indeed. While I am sorry to hear about the mutation, I am glad to hear from you at all. Good luck with your treatment with Vidaza. A lot of us have received vidaza with pretty good success. I hope that you continue the trend and then cruise into and out of transplant.

Dan

[triumphe64]

Greg,

I always find your posts very informative.
Good luck with your new treatment.

[cathybee1]

Gosh, Greg, while it is great to hear from you again and that you were transfusion free for so long and you finally got the upper hand with the pancreatitis, but what a bummer about the blasts. Life with this disease is a whirlwind, isn't it? I hope you find a donor quickly. Duke is a wonderful hospital.

[Greg H]

Thanks for the welcome back, guys. I'm going to be mining the forum for info going forward, since I shelved my research into Vidaza and transplant a few years ago.

It's definitely the sort of disease that decides to throw you a curve ball when you least expect it.

Thanks!

Greg

[marmab]

Hi Greg. If you don't already, you might want to follow Chris at A Marrow Chronicle. He, like you, writes a great blog. He had his transplant (for MDS) at Duke.

[Greg H]

Originally Posted by marmab

Hi Greg. If you don't already, you might want to follow Chris at A Marrow Chronicle. He, like you, writes a great blog. He had his transplant (for MDS) at Duke.

Thanks much, Marmab! I have checked that out, and it looks like it will be very, very useful in educating me about what I might be in for. I appreciate the tip!

Greg

[DanL]

Greg,

I know that you have done more than your share and my share and many other peoples' share of research on MDS and have all the knowledge you need and then some.

I wanted to share some informal research that I have done through conversations with doctors and some scanning of articles on the internet regarding pre-treatment of MDS with Vidaza prior to transplant. It seems that lot of doctors have begun using Vidaza at least a couple of months prior to transplant not only as a bridge, but as a bit of a mini-conditioning agent to reduce the tumor burden and potentially chemo-sensitize your MDS to the harder stuff given at the time of transplant. It is not considered a standard of treatment, but it seems that several institutions are treating it as such, especially if you are at risk of converting to AML.

I began taking Vidaza 2 months prior to transplant, experienced a bit of a blast crisis with my previously under control blasts - nothing in the blood and 4% in the marrow, ,but just before transplant, I jumped to almost 16% in the blood - we didn't have a newer marrow. When we got to transplant day, I had no blasts in the peripheral blood - I did the fully ablative marrow destruction -

The bad news was that I relapsed 6 months from transplant, but it was very minor. We hit it with 6 cycles of Vidaza, followed with some Rituxan to push away the GVHD that I developed, and I have been off of Vidaza for 1 year and 2 months now, no blasts, no immature granulocytes, the best blood counts of my post-MDS diagnosis across the board - 223k platelets, 13.7 HGB, 6.4 wbc, with all components normal finally.

I guess that I am saying that it seems like Vidaza may have a place in pre and/or post-transplant conditioning and that it is a good option to discuss with your doctor while you are waiting for transplant. Based on what I have seen recently in the forums, several members have had pre and/or post treatment with good success, even in the face of relapse post-transplant. Whether it is durable or not, I don't know - I sure hope so for my sake and the sake of others. Also, I have not seen any real evidence that any significant population has been harmed by pre-transplant treatment with vidaza.

I am sure that you know that this is all opinion with a little bit of experience and not any real validated science coming off of my fingertips here - it is a forum, just sharing.