Accepted into Campath Trial at NIH

[Lbrown]

I guess the copper question depends on if the low copper is the cause of or the result of some of what's going on with the RBCs.

As for altitude, one year we went from Ottawa (400 ft above sea level) to Las Vegas and Zion National Park (4000 ft) and were so fatigued from the altitude that people in wheelchairs were passing us on walking trails.

Exjade. I don't have MDS, but it's a good question. I take it because my doctor told me my ferritin was too high, but I haven't a clue what that is based on, or what is an unsafe level.

When I had my EPO tested I was 40x normal, but still had low RBCs, the EPO wasn't working even though my kidneys were cranking it out.

Deb

[Neil Cuadra]

Originally Posted by Greg H

I didn't know that the high-altitude thing was a natural way to increase EPO. Mine tested high previously, so it might not help, but I do plan to see about having it tested again.

If I'm going for the high-altitude thing, though, I might prefer a nice six-month vacation in Aspen. I'll have to speak with my boss and insurance company to see if I can work that out!

The insurance company will probably offer something less, like paying for an old wooden chair that you can stand on.

The primary high altitudes difference for most patients is getting less oxygen in the air they breathe, making it that much harder to catch their breath and do anything strenuous, even what they're used to doing. We had taken a trip to the mountains shortly before my wife was first diagnosed, before we knew she had such low counts, and we realized in hindsight that it could easily have been a disaster if we'd gone for a long hike rather than just a stroll.

[Greg H]

Originally Posted by Neil Cuadra

The insurance company will probably offer something less, like paying for an old wooden chair that you can stand on.

Neil,

We must have the same insurance company.

Greg

[Greg H]

One thing you can confidently predict about MDS: it's unpredictable.

I'm writing this from the Same Day Surgery center at my local hospital, where I'm getting my usual monthly transfusion. Except, instead of the usual two units of packed red cells, I'm having three.

And it's not because they were having a buy-two-get-one-free sale!

My Hemoglobin, checked on Tuesday, was 6.9 -- the lowest it's been in a while, and well below the "usual" level for week four of my monthly cycle. Week 4 HgB numbers in recent months have been 8.0, 8.4, 8.3.

This low number on Tuesday wasn't a big surprise; I've been feeling pretty ragged for a week or so now. And my Week 2 number this cycle was 8.9, when it's usually over 9. I had hoped that result was an outlier.

This much quicker than usual Hgb depletion highlights one of the other predictable things about MDS: you're usually working with incomplete and faulty information when you try to figure out why unexpected stuff happens.

For example, my last two absolute reticulocyte counts were 47 and 35. That is way below the regular numbers I've been getting from my local lab, which have been well over 100. But the folks at NIH never believed -- and never confirmed with their own tests, those high retic numbers. So, I don't know whether the much lower retic numbers are real -- or the local lab finally had their machine calibrated.

My bone marrow biopsy at NIH showed that my Chromosome 1 abnormality had expanded to 85% of my cells, so maybe that's now approaching 100% and throwing heaps of sand in the gears of my RBC factory. But Dr. Olnes has never thought the dup1q was all that big a deal, nor was he all that concerned about the expanded clone, particularly given the small karyotype sample size.

Maybe I for some reason burned up some of my last batch of transfused RBCs through hemolysis. But the lab forgot to do the LDH study that might have shed some light on that possibility. And no new antibodies showed up this time in the type and cross match.

My copper is down to 60, but that's only 6 points lower than it was in February.

In other words, there's no telling.

So, we hope maybe the problem is just some anomaly -- like rough handling of last month's units breaking down the cells -- and we wait for the next two-week CBC, keeping fingers crossed for a result above 9.

MDS: predictably unpredictable.

Take care!

Greg

[mausmish]

Greg, so sorry about your lower Hgb! Michael (husband) often talk about the frustrations surrounding the unpredictability of the disease, not only between different patients but for the same patient on different days. Sending lots of positive, healing thoughts your way. Please keep us posted. Karen

[Greg H]

This extra-long post (which I will divide into a couple of parts) may well be the climax, if not the denouement, of the continuing saga of my experience with the NIH trial of Campath for MDS -- though it certainly won't be my last post here.

You may recall that, when I checked in early this month for my usual fourth-week CBC, I posted a hemoglobin count of 6.9, instead of the expected 8.0. That resulted in a three-unit transfusion to get me back into decent shape.

Eleven days later, my CBC turned up an 8.2, leading me back to Same Day Surgery for a two-unit RBC transfusion just two weeks after the last one.

Conferring with the Campath trial's Principal Investigator Dr. Matt Olnes, I sense that he has reached the conclusion that I am, in fact, a bona fide "non-responder" to the therapy.

If had responded "robustly" to the drug, then we'd probably try cyclosporine. Dr. Olnes explained that about half the folks who have a good response to Campath, and then relapse, respond to cyclosporine. But cyclosporine hasn't proven effective for non-responders. Given the side effects, it doesn't make much sense for me to try it.

So, what do we do now?

The answer falls into two parts: finding out what's up and, then, deciding what to do.


Diagnostics

Our first step, Dr. Olnes suggested, is to make sure this sudden drop in hemoglobin isn't the result of some anemia unrelated to my MDS. So I had both B12 and Folate checked, and both are well within normal ranges. Iron isn't a problem, given iron build-up from my frequent transfusions.

Before I was first diagnosed with MDS, we ruled out GI tract bleeding with an endoscopy-colonoscopy. Dr. Olnes felt that bleeding is not likely the cause of my sudden hemoglobin drop, because my reticulocyte count has fallen as well. Normally, a loss of blood would lower hemoglobin but increase reticulocytes, as the marrow tries to make up the losses.

Though I understand that reasoning, and have no signs of GI tract bleeding, I may nonetheless book an appointment with my family doc or GI doc, just to be sure. I'll consult with my local hematologist about this first.

Most important, Dr. Olnes said, was to repeat a bone marrow biopsy, even though I had one in May that showed no significant change. We need to make sure something hasn't come up that would explain my change in symptoms. We'll do cytogenetics, of course, as well as a FISH analysis of Chromosomes 5, 7, 8, 13, & 20, which Dr. Olnes indicated are the standard areas to check in MDS. If a FISH probe is available for my rare Chromosome 1 problem, we may check it as well.

We'll do FISH because it utilizes a larger sample size than the standard karyotype analysis, making it more likely to detect an abnormality present in only a small number of cells, as well as providing a more reliable indication of the proportion of my stem cells that are defective.

Assuming my local hematologist agrees with all of this, we will likely do the bone marrow locally rather than at NIH. My luck with NIH bone marrows hasn't been all that great; and pretty much everyone, including NIH, sends their cytogenetics and FISH out to one or another of a few big commercial labs.

[Greg H]

Treatment

What treatment we turn to next will depend on the results of the biopsy.

If I've suddenly developed some scary abnormality, like Monosomy 7, or a big blast count, that would bump me into a higher-risk category and we'd probably be looking toward something like Vidaza with an eye toward transplant.

But, if I remain in my current INT-1, lower risk category, Dr. Olnes said, we're in "a bit of a gray area."

ESAs. If My natural EPO level was low, we could try Procrit or Aranesp to try and stimulate more red blood cell production. I, in fact, had one dose of Aranesp early on in my MDS experience. But Aranesp works best for folks with EPO under 100, and is generally not prescribed for folks with EPO over 500. The two times mine has been tested, I clocked in a 1550 and 1080. Dr. Olnes said it's highly unlikely to have slid all the way down to 100, and is likely even higher now than it was before.

Vidaza. He's not a fan of Vidaza for low-risk folks, because much of the research has shown it's most effective in higher-risk patients. It's also used as a bridge to transplant by my transplant center, so we wouldn't want to be doing Vidaza unless we were, in fact, moving toward transplant, and that's not something I expect to do as long as I am lower-risk and have a manageable transfusion requirement. I haven't decided whether I think every two weeks is "manageable." I know that many folks would consider that interval a blessing, because they have even more frequent transfusions.

Revlimid. Though Revlimid, or lenalidomide, is generally used for folks with the deletion 5q chromosomal abnormality, Dr. Olnes said the drug seems to be effective in 30-40% of MDSers who do not have that particular abnormality. That's a bit higher than the percentages I've seen, which have been more like 25%. Revlimid typically lowers platelet counts, which can make it a problem for some folks. My platelets bounce back and forth across the bottom of the reference range, and Dr. Olnes said he doubted Revlimid would depress them enough to cause a problem. So Revlimid is an option. Getting insurance to pay for it may be difficult, but there are a variety of clinical trials of Revlimid in non-5q folks that I might be able to access.

HDAC Inhibitors. Valproic Acid and other drugs in its class have been trialed among low-risk MDSers. Used alone (as a "monotherapy"), Dr. Olnes said, they haven't provided results that were all that impressive. But I've seen studies in which HDAC Inhibitors have produced improvement in about 25% of patients. Unfortunately, most of the current trials seem to be aimed at higher-risk patients, with combinations of Vidaza or Dacogen with an HDAC inhibitor.

Ezatiostat. I haven't spoken with Dr. Olnes about this drug, which has been the subject of trials in both intravenous and oral formulations. Kind of like the other options, it seems to produce improvement in 20-25% of folks with MDS. There aren't any trials currently recruiting, but I'm interested in learning more about this one.

Other options? We won't be making any decisions about treatment until the results of the bone marrow biopsy are in. But it's never too early to get started on the research. If you have suggestions, ideas, or links to good research, either about the options listed above or others I've missed, I'm all ears.

One of the things I have noticed is that most of the drugs being investigated seem to help 20-25% of patients. If you believe, as I do, that MDS is not one thing, but really a collection of related diseases, then this makes perfect sense. Some of the new drugs help one kind of MDS; some help another, but the trials include all types, because they are just getting started. Unfortunately, there's not much data to go on so far to figure out which patients are helped by which drugs. My reading so far suggests that Revlimid and the HDAC inhibitors seem more active amongst folks with mostly red cell problems, while ezatiostat seems more active on platelets and neutrophils.


And Campath?

The obvious question: "Do you regret participating in the Campath trial?"

Not for a minute. If you looked at the odds -- age under 60, trisomy 8, HLA-DR15 positive -- I had a high probability of response to immunosuppressive therapy. If it was going to work, it needed to be tried sooner rather than later, to prevent additional chromosomal damage. My platelets and my neutrophils were both trending down prior to enrolling in the trial.

Give the same scenario, I'd do it again in a heartbeat.

It may not have worked out for me, but there's no question that, for some folks, MDS is an immune system problem. The research is there. And maybe my participation in the trial will help the folks at NIH ultimately figure out exactly which patients are the right patients for IST and Campath.

I would do that trial again -- and will do other trials when appropriate to my disease profile. We aren't going to whip this disease by being timid.

[Birgitta-A]

Hi Greg,
Very interesting report about treatment! Since my dx 2006 i have been looking for info about what patients that will respond to a special treatment. The info about the TET2 mutation - one study showed that 83% of patients with this mutation responded to Vidaza - is one of many reports about how to choose the best treatment for a patient.

Otherwise the rather old small study about Vidaza in combination with Zolinza (a HDAC inhibitor) has given the best results I have seen - 86%: http://ash.confex.com/ash/2008/webpr...aper15277.html

Hope your doctor and you will find a good treatment for you!
Kind regards
Birgitta-A

[Greg H]

Hi Birgitta!

Thanks for that reference. I'll try to post a couple of the studies I've run across on HDACs and the others so they are on marrowforums for folks to find. LynnI's recent update on her success with valproic acid got me digging through the net for information on HDAC inhibitors, and I found a few Phase I studies with small, but not unreasonable results. So I was surprised to find few on-going trials in low-risk patients. But I am still looking.

I would think that finding response in 20-25% of all types of MDS patients, given the heterogeneity of the disease, would be a result worthy of follow-up to try to determine which patients are more likely to respond. (I noticed the trial Cheri is hoping to enter was looking for at least a 20% response rate.)

But research moves slowly, and is likely dependent on rounding up funding.

Thanks, and take care!

Greg

[Lisa Z]

I'm sorry to hear that you have been determined to not have responded to the Campath. I am sure, however, with all the research you do, you will move on to something that will, perhaps, work well for you

I am anxixous not, to talk w/Dr. Olnes since he appears to have some data that he discussed with you in regard to Campath patients who have relapsed. I'l like to know the percentage and how long it was before relapse.

I see my counts (after 2 yrs. and 5 months) very slightly going down. Nothing to worry about unless it continues!!! But, I am getting a little nervous!

Try to enjoy the rest of the summer. Keep us posted on what you decide - after your BMB results come back. AND, you make an excellet point about the BMB. My last 2 at NIH have been horrible, and they do sent their cytogenics out, just like our local labs, so why have a "fellow" do the procedure when you can get a doc or nurse who does them all the time, without all that pain!!

good luck!

[Hopeful]

Hi Greg,

I don't think you should take cyclosporine off the table. I've read many studies that associate the trisomy 8 mutation with a cyclosporine dependent response (and a good long term prognosis). If you still have the trisomy 8 mutation after Campath, perhaps cyclosporine is a legitimate strategy for you to try.

[mausmish]

Greg,

Sorry about the Campath non-response! Like you, I'm a big proponent of clinical trials and am glad you have no regrets about yours. You're such a positive, intelligent guy, as well as being a great researcher, that I can't help but think you'll come up with something that works for you and will help others along the way. Thanks for keeping us posted. Your posts are always both interesting and enlightening.

Karen

[Greg H]

Originally Posted by Hopeful

Hi Greg,
I don't think you should take cyclosporine off the table. I've read many studies that associate the trisomy 8 mutation with a cyclosporine dependent response (and a good long term prognosis). If you still have the trisomy 8 mutation after Campath, perhaps cyclosporine is a legitimate strategy for you to try.

Hi Hopeful!

Thanks for that. If you've got any references to those studies you can share, I'd love to read them. Meanwhile, I'll be looking around for them myself. And I'll chat with Dr. Olnes about it.

I'm glad that we're going to be doing FISH on Chromosome 8, because it's been kind of variable in my cytogenetics over the course of the disease. It cropped up after the Chromosome 1 abnormality, then seemed to be equal in size, and then much smaller again. The FISH should give us a line on how much Trisomy 8 I actually have.

Thanks!

Greg

[Greg H]

Originally Posted by Lisa Z

I am anxixous not, to talk w/Dr. Olnes since he appears to have some data that he discussed with you in regard to Campath patients who have relapsed. I'l like to know the percentage and how long it was before relapse.

I see my counts (after 2 yrs. and 5 months) very slightly going down. Nothing to worry about unless it continues!!! But, I am getting a little nervous!

Hey Lisa!

Thanks much. I can't remember whether the studies I have from the Campath trial have any data on relapse. It may not have been long enough by the time the studies were put out. But I'll check and let you know what I find out.

I'm sure Dr. Olnes could give you some info on that score. All he told me was that, among the robust responders who relapse, about half respond to cyclosporine. He didn't indicate what percentage relapse.

I hope your numbers start to rebound.

Take care!

Greg

[Greg H]

Originally Posted by mausmish

Sorry about the Campath non-response! Like you, I'm a big proponent of clinical trials and am glad you have no regrets about yours.

Karen,

I figure we have got to do everything we can to get all those "It helps 20-25% of folks" turned into "It helps 75% of folks with a duplication on the long arm of Chromosome 1."

Clinical trials are the only way to get that done.

Thanks for the kind words, and take care!

Greg

[cathybee1]

Awwww, Greg, this latest series of events must be very disappointing, yet you, with your good grace and wit, turned it into another learning opportunity for the rest of us. I'm so glad Dr. Olnes was available to help piece the information together for you (and for us).

Here's hoping that your BMB will give you better information on how to proceed next -- and that the next BMB is less eventful and owie than the last two.

Hugs, Catherine.

[Greg H]

Hey Catherine!

As always, you are too kind. I just hope my lack of success with IST -- given that I've spilled all this ink on it, doesn't discourage other folks from trying it. The research is really solid, and I've noticed IST creeping into the various published standards of care for MDS.

But even if you have all the right markers, that doesn't mean it works for everyone

I'm still getting the BMB lined up. Not sure if it will happen next week, or in three weeks.

It sounds like you guys are having a great summer. It is blazing hot here! And dripping humid. But, at least I don't have to buy a sauna to detox.

Take care!

Greg

[Hopeful]

Originally Posted by Greg H

Thanks for that. If you've got any references to those studies you can share, I'd love to read them. Meanwhile, I'll be looking around for them myself. And I'll chat with Dr. Olnes about it.

Hi Greg,

My memory must have mixed things up, as I read both AA and MDS articles. The studies on cyclosporine dependency are with reference to SAA with trisomy 8, not MDS with trisomy 8. It seems like trisomy 8 may be an overlap area between the two diseases??? Maybe it indicates the immune component to your disease.

I hope your BMB results shed some insight on the best path to take.

[Greg H]

Hi Hopeful!

Thanks much. I am beginning to wonder, like you, whether Trisomy 8 is, in fact, often related to some immune system issues in the marrow. One person's experience doesn't really count as research, but the history of my disease so far may suggest that.

My first BMB showed only a Chromosome 1 problem, in about half of the cells. When I had a repeat BMB a couple of months later at a different lab, I had still had the Chromosome 1 problem, but FISH analysis (which is more sensitive) picked up about 5% Trisomy 8.

Three months later, I again had about half of my cells with dup1q, but now most of those also had Trisomy 8.

My most recent BMB -- six months after Campath knocked my T-cells flat -- showed 85% dup1q but only 15% Trisomy 8.

In other words, it seems like the Trisomy 8 cropped up after the dupq1, expanded rapidly, and then declined under immunosuppressive therapy. A big caveat here: all of this except the original 5% +8 is based on 20-cell cytogenetic counts, which aren't very statistically significant.

Still, if I were a betting man, I'd say what happened is this. I developed a dupq1 abnormality. My T-Cells started attacking those malignant stem cells. That immune system war created a +8 abnormality that expanded rapidly. The Campath shut down the war, and the +8 subsided. Unfortunately, with no T-cells attacking, the dup1q was free to expand.

That's completely guess work on my part and could be completely wrong. But we humans like a story with a plot and that's the best one I can make up right now.

The plotline might change once I have the results of another BMB with FISH. I just wish NIH had done FISH last October and this May, so we'd have a better read on whether my storyline is correct.

Take Care!

Greg

[Neil Cuadra]

Greg,

Originally Posted by Greg H

...if I were a betting man...

Greg,

If you think about it, we're all betting men and betting women. As long as there are factors that we and the doctors can't predict and/or don't understand, everyone here is playing the odds.

But it's not just luck. The key to our self-empowerment is placing the smartest bets we can, and that's what we do. Why take drug X instead of drug Y? The odds of improvement. Why bet on Campath? The chances of success. Why study the evolution of your chromosomes? For inside information that helps us put our money on the horse that's most likely to win, place, or show.

We're gamblers, but we're smart gamblers!

[Hopeful]

Originally Posted by Greg H

My first BMB showed only a Chromosome 1 problem, in about half of the cells. When I had a repeat BMB a couple of months later at a different lab, I had still had the Chromosome 1 problem, but FISH analysis (which is more sensitive) picked up about 5% Trisomy 8.

Three months later, I again had about half of my cells with dup1q, but now most of those also had Trisomy 8.

My most recent BMB -- six months after Campath knocked my T-cells flat -- showed 85% dup1q but only 15% Trisomy 8.

In other words, it seems like the Trisomy 8 cropped up after the dupq1, expanded rapidly, and then declined under immunosuppressive therapy. A big caveat here: all of this except the original 5% +8 is based on 20-cell cytogenetic counts, which aren't very statistically significant.

Still, if I were a betting man, I'd say what happened is this. I developed a dupq1 abnormality. My T-Cells started attacking those malignant stem cells. That immune system war created a +8 abnormality that expanded rapidly. The Campath shut down the war, and the +8 subsided. Unfortunately, with no T-cells attacking, the dup1q was free to expand.

That seems like a very logical argument to me. Since the trisomy 8 mutation is in the same cells with the dup1 mutatation, further immune suppression seems risky. In retrospect, it seems like the dup1 mutation must be controlled first.

[Greg H]

"Hey, you never know!"

That's my all-time favorite advertising slogan. It was used by the New York State Lottery in the '90s and evidently is still in use -- at least on their website.

Sometimes, it's a pretty good slogan for the intrepid MDS warrior:

Hey, you never know -- 'til you see the CBC.

Hey, you never know -- 'til you get back the BMB.

Hey, you never know, period.

I figured in did know what I'd be looking at when I went to my local hematologist's office on Tuesday for my regular two-week CBC: a 7.7.

A 7.7 hemoglobin count was what I was expecting, given my recent trend of HgB falling off the cliff, resulting in a two-week transfusion interval. I figured a 7.7, followed by a transfusion on Friday, with a bone marrow biopsy thrown in for good measure. That was the plan, after which we'd figure out whether it was time to move to Revlimid or some other new drug.

But, hey! You never know!

I got an 8.6. That's no great shakes, but it's above my transfusion level. And my reticulocytes, which had slid way down into the 40s, were back in the 80s. (Platelets, ANC, & lymphocytes all pretty much in my normal ranges, thank you for asking.)

So, despite having the pleasure of wearing my little green blood bank bracelet with the peel off stickers to the supermarket, no transfusion.

And, since my local heme and I have no idea what to make of this at the moment, no BMB either. We're going to wait and see what happens before poking yet another hole in my behind.

I'm back to his office on Tuesday for another CBC, which I fully expect will put me in the 7s and in line for a transfusion on Friday.

But, hey, you never know.

[lindy]

Hey Greg! That's great to know you got a 8.6!

Come Tuesday, it could be another it's great to know---!

Here's wishing that all your counts (wow platelet up to your normal) stay up.

Hmm...could it be something might finally kick in from your trial?

[Greg H]

Thanks, Lindy!

I'm baffled, but I'm not getting my hopes up that my Campath is back on track.

I'll take just having a three-week transfusion interval instead of two.

I've decided that, with MDS, you just kind of have to roll with the punches.

Take care!

Greg

[mausmish]

Congrats on your hgb and retics doing a bit of a comeback . Keep up the good work! Karen