Talking Telomeres

[Lbrown]

Awesome bit of good news! Merry Christmas!

Deb

[cathybee1]

Greg,

Awesome news! What a wonderful holiday gift. And yes, I would expect different doctors to disagree a bit. After all...they're doctors. But "stable" and "perhaps improving" is still great feedback.

Happy holidays, and hugs,

[Darice]

Wow! That's wonderful news.

[Greg H]

Hey guys!

Thanks for all the good wishes.

A Happy Chanuka and Merry Christmas to all of you, who without doubt comprise the most-supportive, best-informed, and (I am absolutely confident) best-looking bunch of bone marrow warriors on the planet.

May the New Year bring us all good news, as well as renewed strength and determination to learn more, love more, and fight harder.

Take care!

Greg

[Al's Wife]

You go, Greg. Your analysis sounds good to me. Merry Christmas!

[cathybee1]

Merry Christmas, Greg. And about good looking...well, Bruce's doctors say he looks deceptively healthy. Does that count?

[Marlene]

Folate Study
http://www.ncbi.nlm.nih.gov/pubmed/19458030
http://jn.nutrition.org/content/139/7/1273.full.pdf

Overall nutrition's role in healthy telomeres
http://www.wellnessresources.com/hea...our_telomeres/

[celebrations]

Hi Greg,
congrats for your results. The labs at my hospital do not have the facilities to check my telomeres...
I was attending the ASH 2011 in San Diego and looking for "telomere-talking".
The only thing I got was this:

Human Telomerase Reverse Transcriptase (hTERT) Deficiency in Myelodysplastic Syndrome (MDS) Demonstrates Mechanistic Linkage to Aplastic Anemia Pathophysiology
Lili Yang, PhD*,1, Adam W Mailloux, PhD*,2, Dana E Rollison, PhD3, Jong Park, PhD*,4, Jeffrey S. Painter, B.S.*,5, Rami S. Komrokji, MD6, Jaroslaw P Maciejewski, MD, PhD*,7, Ronald Paquette, MD, PhD*,8, Thomas P. Loughran, Jr., MD9, Sheng Wei, MD10, Alan F. List, MD6 and Pearlie K Epling-Burnette, Pharm D, PhD*,11

1 Immunology Program, Immunology program, Moffitt Cancer Center and Research Institute; Tianjin Cancer Institute and Hospital, Tampa, FL, USA,
2 Immunology, H. Lee Moffitt Cancer Ctr. & Rsch. Inst, Tampa, FL, USA,
3 Division of Cancer Prevention and controls, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA,
4 Cancer Prevention and Control, H. Lee Moffitt Cancer Center, Tampa, FL, USA,
5 Immunology, H. Lee Moffitt Cancer Ctr. & Rsch. Inst., Tampa, FL, USA,
6 Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA,
7 Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA,
8 UCLA Medical Hematology & Oncology, Los Angeles, CA, USA,
9 Penn State Hershey Cancer Institute - CH72, Hershey, PA, USA,
10 Immunology Program, Moffitt Cancer Center, Tampa, FL, USA,
11 Immunology Program, H. Lee Moffitt Cancer Ctr. & Rsch. Inst, Tampa, FL, USA

Abstract 791

Background: Myelodysplastic syndromes (MDS) are characterized by dysregulated myelopoiesis and peripheral cytopenias with enormous disease heterogeneity owing to diverse molecular pathobiology. The early manifestations of MDS, however, are relatively well conserved and include increased apoptosis coupled to excessive proliferation of myeloid progenitors. In addition to myeloid abnormalities, repertoire contraction and memory expansion is demonstrable in T cells. The notion that apoptosis of hematopoetic cells may be triggered through an immune–mediated mechanism arose from similarities with aplastic anemia (AA). Our recent data showed that MDS responsive to immunosuppressive therapy has accelerated naïve T cell turnover (ie, high proliferative index plus excessive cell death) which led us to hypothesize the presence of an inherent T cell abnormality impairing homeostatic regulation. AA can be caused by somatic mutations within telomere repair components. T-cells are one of a few somatic cells that retain telomerase function to control naïve T-cell survival, replication potential, and antigenic diversity. To this end, we examined telomere function and replicative burst capacity of MDS T cells as a possible mechanism for immune dysregulation.

Methods: Primary specimens from MDS (n=37), AA (n=8), and controls (n=42) were investigated. Peripheral blood mononuclear cells were isolated from patient blood or buffy coats by Ficoll-Hypaque gradient centrifugation. Purified CD3+ T cells were isolated using negative selection and then stimulated with anti-CD3/anti-CD28 T cell activator beads (Dynabead®) for 3 days. Telomere length was assessed by quantitative PCR (q-PCR) and telomerase enzymatic function measured by Telomere Repeat Amplification Protocol (TRAP) assays.

Results: Mean telomere length in purified T cells was significantly shorter among MDS patients compared to controls after adjusting for age and sex (p<0.0001). To assess telomerase repair function in MDS T-cells, we performed TRAP assays with purified T cells after stimulation and found that inducible telomerase activity is severely suppressed in MDS compare to controls. In comparison to controls, the inducible telomerase activity fell below the 95% confidence internal in all cases (MDS median 18.70, 95% CI, 15.93–20.54 vs control median 45.0, 95% CI, 45.79 – 64.5, p<0.0001) and the amount of telomerase activity was unrelated to risk stratification by the International Prognostic Scoring System (IPSS), World Health Organization (WHO) classification, and age indicating that it is a frequent abnormality in the disease. Analysis of telomerase function and telomere length in T cells from patients with AA showed a similar deficiency in telomerase repair function. The mechanism responsible for telomerase insufficiency in MDS was mediated by defective induction of telomerase reverse transcriptase (hTERT) transcription; the key enzyme involved in telomere maintenance.

Next, to determine the functional consequences of the disturbance in telomere repair in MDS, the ability of T cells to enter S-phase and to undergo an antigen-induced proliferative burst were examined. TCR signaling was shown to be preserved, evidenced by induction of an early activation antigen CD69. Although some cells were capable of entering S-phase, the replicative burst potential was severely impaired in T cells form all patients. Telomere repair is exclusively present in naïve T cells and progressively declines after memory transition. TCR triggered telomerase activity was measured in sorted naïve (CD45RA+, CD45RO-) and memory (CD45RO+, CD45RA-) T cells. The telomere length in naïve cells was shorter in MDS patients compared to controls (p=0.018) and the telomerase activity was suppressed in naïve MDS T cells (p=0.0207) indicating that telomere dysfunction underlies the altered homeostasis of naïve T cells in MDS, a feature mechanistically akin to AA and other telomere repair disorders.

Conclusion: Results of this study indicate that there is loss of telomere maintenance in naïve T cells due to a defect in hTERT transcription is associated with impaired replicative potential. This abnormality in naïve T cell homeostasis represents an inherent defect that contributes to a memory cell growth advantage and repertoire contraction associated with autoimmunity in AA and MDS.

[Greg H]

I just realized it's been three months since I put up a blog post or updated this thread. I think instead of measuring out my life with coffee spoons, I've begun measuring it out with milk pails. At the moment, my MDS is more chronic than acute, and I've lived with it a while now. So the day-to-day ups-and-downs seem a bit less significant than they did early on.

Since starting Danazol at the end of November, my platelets have jumped from the 70s & 80s to reliably top 100. The last three CBCs have pegged them at 113 each time. This is kind of interesting, because I've had platelets in the 90s for 15 years.

My neutrophils are reliably over 2,000. My lymphocytes, which were stuck at 300 for months and months, seem to be climbing, with an average of 500 in my last three CBCs.

I don't know whether the Danazol is responsible for these improvements, or if it's the continuing impact of the Campath I had earlier.

That leaves the Hemoglobin, which seems to be showing some (painfully slow) improvement. I'm on an every-other-week transfusion schedule, which means my Hgb is checked two days prior to transfusion, close to its low point. Since starting Danazol, those low points have gradually increased: 7.1, 7.7, 7.9, 8.3, 8.4, 8.5.

That 8.5 persuaded my hematologist that we should wait an extra week for transfusion, which took me back down to 7.6, but meant I went three weeks between transfusions. It also meant I was really suffering that third week. Once you get used to having Hgb regularly above 8.0, it is hard to take the 7s. I fully expect that I won't make three weeks this time, but it will be interesting to see where the Hgb stands in two weeks.

On a another front, I am sad to report that my wheatgrass tablets have not been able to keep up with my transfusion schedule. When checked a week ago, my ferritin was at 5,178. So, despite considerable skepticism from my hematologist, I'll be starting Exjade later this week.

My doc is right to be skeptical, because there simply is no really good data that shows iron chelation increases overall survival in MDS patients. But there is data that shows real harm caused by iron overload among thalassemia and sickle cell patients, who often start transfusions when they are children or teenagers, and have the chance to build up a lot of iron. I'm considerably older than that, but, at 55, I'm considerably younger than the typical MDS patient. I may have a lot of transfusions in my future. That suggests chelation would be a good idea. In addition, there is some decent data that indicates too much ferritin can create problems during stem cell transplant. Though I'm not an immediate candidate for transplant, the possibility is always out there.

I struggled with whether to use Exjade or Desferal. Dr. Dumitriu at NIH said he felt the gradual administration of the Desferal made it a superior chelator. But I couldn't find data to back up that preference. And I was concerned that I'd be less compliant with the Desferal needle and pump than with Exjade. I am very concerned about GI side effects with Exjade, since I really, really hate GI disturbances. But the data suggest only about twenty percent of folks have significant GI problems with Exjade. If it turns out I'm in that twenty percent, and the problems persist, I'll likely switch to Desferal.

I've seen folks ask from time to time on this and other forums about the cost of Exjade. My group health insurance has me buy it from a specialty mail order pharmacy, and the representatives there told me the monthly tab for my 1500 mg per day would be $7,300. I'm not sure whether that includes a discount negotiated by my health insurance carrier. Given my transfusion schedule, I've already hit my maximum out-of pocket for this plan year, so I won't be paying for the first two months.

If you follow politics or popular culture in the US, you've undoubtedly seen references to "the one percent," those folks at the very top of the income ladder. It turns out there's another "one percent," namely, the one percent of patients who account for twenty-five percent of health care spending in the US, and average $100,000 or more in health care costs each year.

With the addition of Exjade to my $6,000 per month packed red blood cell habit, I, sadly, will be joining that one percent. Thankfully, I have excellent health insurance.

Take care!

Greg

[Neil Cuadra]

Thanks for the update, Greg.

I think you are wise to assume, even without ironclad proof, that chelation makes sense. Iron buildup and relief from iron buildup are long-term issues, and perhaps it's unsurprising that chelation makes less difference for the older patients with more acute MDS since they don't have as much time to benefit from it.

Let's hope you are in the top 1% when it comes to lack of Exjade side effects.

[Greg H]

Thanks Neil!

Despite the reservations of my local doc, the folks at NIH, even while acknowledging the lack of data, were strongly in favor of chelation.

There's data on the Exjade package insert that compares the side effects of Desferal and Exjade, and Desferal definitely wins that competition. But the greater convenience of the former is hard to beat -- if you're in the 80% that doesn't have a problem.

I'm keeping my fingers crossed.

Take care!

Greg

[mausmish]

Hi Greg,

Thanks for the update! I think of you often and wonder how you're doing. That's excellent news about your improving blood counts. I agree that the high ferritin is a concern. Hopefully, the chelation will go well with no adverse effects! Keep us updated, please.

Karen

[Marlene]

Good luck with the chelation. Hopefully, your red cells will start holding at a higher level and you can stop the transfusions.

[cathybee1]

Hi Greg,

Oh boy, yes, use of iron chelators is very controversial. Out of Bruce's 3 hematologists he's consulted, 2 were agin Exjade, and 1 was for it (the local doc). The local hematologist finally wore Bruce down. Bruce so far has had minimal side effects. He is currently at 1000 mg/day. And he is able to go 5 weeks without transfusion, which is an improvement by a week of where he was earlier. We don't know if that has been affected by the gluten free diet (local family doc thinks that will improve the liver function), or the Exjade.

Going on chelators is a very personal decision. I know this has not been an easy one for you. And I certainly hope your cost for the medication is not that high. That number sounds closer to what we were told the pre-insurance costs would be for Bruce. Unfortunately, every insurance company and plan handles things differently.

Thanks for the update. I always look forward to your posts.

[Birgitta-A]

Hi Greg,
Very good results concerning platelets and WBCs!

Iron chelation is really a problem. I have always been afraid of a high ferritin level although my doctor has told me many times that we don't know the effect on MDS patients.

Still I like to have a ferritin level less than 1000 so I have tried Desferal, Ferriprox and Exjade. I had no adverse reactions after Desferal but after a few years the effects was no longer enough. We added Ferriprox, that decreased the WBCs. Then we tried to add Exjade and I could tolerate 500mg/day instead of 1250 that I should have had.

Desferal was stopped when I no longer needed txs and Exjade was stopped when the ferritin was less than 1000. I have autohemolysis (my red blood cells burst too early) and my ferritin will never be low.

Even if we don't get so much iron in our hearts (and other organs) as thalassemia patients a high ferritin level can make us more sensitive to infections.
Kind regards
Birgitta-A

[riccd2001]

The sheer number of possible side effects owing to Exjade use is a concern. For me, I've been keeping a close watch on my Creatinine build-up. As with many treatments, Exjade side effects vary considerably. My doc and I have agreed on keeping my Serum Ferritin under 1000. So I've been able to stop and restart Exjade from time-to-time and only have to deal with keeping close to a toilet 15-20 minutes after eating. It's an inconvenience to say the least but I simply couldn't tolerate the Desferal infusion process.

I like to think that the high costs to live with MDS are a payback for all the good work we have done with our lives in the past and in the days yet to come nomatter how many those will be. Good luck Greg.

[triumphe64]

Originally Posted by Greg H

Since starting Danazol at the end of November, my platelets have jumped from the 70s & 80s to reliably top 100. The last three CBCs have pegged them at 113 each time. This is kind of interesting, because I've had platelets in the 90s for 15 years.

That leaves the Hemoglobin, which seems to be showing some (painfully slow) improvement. I'm on an every-other-week transfusion schedule, which means my Hgb is checked two days prior to transfusion, close to its low point. Since starting Danazol, those low points have gradually increased: 7.1, 7.7, 7.9, 8.3, 8.4, 8.5.

Only my red cells are affected, but if it is of any encouragement, it took six or nine months for the Danazol to really kick in.

Good luck.

[Greg H]

Hi All!

Thanks for relating your experiences on Exjade. Keep your fingers crossed for me.

And thanks, Triumph, for the point on your very gradual response to Danazol. I have definitely planned to stick with it until my six-month follow-up in May, and it's good to know it could take even longer to make a difference.

Take care!

Greg

[Greg H]

Hi All!

I have some positive news to report. After months and months of every-other week red blood cell transfusions, I am seeing some signs that my transfusion interval is lengthening.

When I reported for my mid-February regular every-other-week CBC, expected hemoglobin in the 7s, I wound up with an 8.5. We put off transfusion for a week, I registered a 7.6, and we transfused two units. That was a three-week interval.

Two weeks later, I posted and 8.2, and we transfused. A two-week interval.

Another two weeks and my Hgb came back an astonishingly high 9.1. So we waited two weeks more, I posted an 8.0, and we transfused two units. That's a four week interval.

So, things are looking up! Here's hoping that improvement continues.

On another front, I've been on 1500 mg of Exjade for 40 days now. I'm grateful to have had no side effects. Ferritin bounces around so much that I can't say for sure I've made progress on that front, yet. But I'm happy not to be having side effects.

Take care!

Greg

[cathybee1]

Awesome news, Greg.

[Birgitta-A]

Hi Greg,
Congratulation to the increase of the transfusion intervals !

You probably know that Exjade - as all iron chelators - can increase transfusion intervals eventually due to less oxidative stress in the bone marrow. I had positive effects both from Desferal and Exjade.
Kind regards
Birgitta-A

[mausmish]

Woot! Great news, Greg!

[Marlene]

Great news!!!!!!

[Greg H]

Thanks for all the good wishes, y'all!

Take care!

Greg

[Lbrown]

That's great, hope it continues! What's 3 weeks away from the hospital like?!

Deb