Sunday, January 25, 2009

My visit to the NCI, Part 3 - An enlightening meeting

Readers will recall that Marilyn and I took a road trip from Arizona to Maryland last July. Our destination was the National Cancer Institute/National Institutes of Health, where we were to discuss a clinical trial for a matched unrelated donor stem cell transplant. We had contacted the NCI/NIH in January, following completion of my R-C(V)P treatment for CLL and AIHA. I’d had a rough time in 2007; we didn’t know how well the chemo would work, and we were looking at the prospect of moving to transplant sooner rather than later if the chemo didn’t hold. The NCI trial, besides being well designed, had the advantage of being free of charge, and my health insurer specifically forbids stem cell (“bone marrow”) transplants. There was a possibility of a big win-win here, if the time was indeed right and a donor could be found.

As we made our
way from Hagerstown to Bethesda, the last 70 miles on our journey to the NCI/NIH, we had no idea that the question of my participation in the study had already been decided. Marilyn and I had concluded, after a day of reading and reflection while sequestered in our hotel room, that perhaps I might be jumping the gun, all things considered; we were about to find out that, for somewhat different reasons, there would be no trial for me, whether it was needed or not.

The NIH Clinical Center is shoehorned onto a cramped campus
not too far off the Capital Beltway. One is greeted at the entrance by a phalanx of bored security officers who check your ID and your car, rather lackadaisically on the lookout for terrorists. This continues as you enter the parking garage of the Mark O. Hatfield Clinical Research Center, which is part of a 40-acre complex that makes up the largest clinical research hospital in the world. A guard places an orange cone in your path as you head in, checking your visitor passes to again make sure that you are who you say you are.

The Hatfield Center is big and new; navigating through it involves a lot of sign-following and direction-taking. After being set up with an NCI patient number and file -- which was done incorrectly and led to delays -- we were sent to the 12th floor for our meeting with Dr. Steven Pavletic, the protocol chair.

It was pas
t 5 o’clock and Pavletic was running late; the place was practically empty, but had obviously gone through some heavy use earlier in the day. We couldn't help but notice how dirty and unkempt the seating area was. Lunch had happened. Not that this is the bottom line when choosing a transplant facility, but it added to our impression of a big, somewhat impersonal operation. Gone were the legion of senior citizen hospital volunteers we were used to seeing in Arizona, people who straightened the magazines, primped the cushions, and handed out complimentary fruit.

We were finally ushered into a tiny conference room by the transplant coordinator, a uniformed officer of the US Public Health Service. We chose the chairs witho
ut the potato chip remnants and awaited the good doctor.

Steven Zivko Pavletic originally hails from Croatia and is the head of the
Graft-versus-Host and Autoimmunity Unit in the Experimental Transplantation and Immunology Branch at the center. In other words, he knows his way around a transplant and has a specialty in graft vs. host issues. He’s a few years older than me; Pavletic graduated from medical school in Zagreb in 1979, the same year I earned my anthropology degree at UC Santa Cruz. His head of brown hair is starting to gray, he retains a gentle Slavic accent, and he has an easygoing if businesslike manner.

* * *

Our interview b
egan with some questions about how I was doing since my treatment had ended in December. This included a discussion of what lymph nodes can be palpated and a review of my latest CBC, which was about as picture-perfect as my CBCs get, and which elicited an “It’s wonderful!” from the doctor.

Pavletic asked if I had a history of other serious illnesses (no), allergies to m
edications (no), whether I smoked (briefly years ago), had any siblings (three half sibs, which means they may as well be strangers for transplant donor purposes), a history of cancer or leukemia in the family (not that I know of, but my mother was adopted), children (no), and what current medications I was on (2 mg of methylprednisolone plus Nasonex).

We discussed my treatment history, during the course of which I told Pavletic I was Coombs positive -- a sign that I might be prone to AIHA -- at diagnosis in 2003.

“So you never received fludarabine because they were concerned about the Coombs test?” he asked. Single-agent fludarabine has been shown to trigger AIHA in some cases, as many as 23% in one study.

I explained my story: At first we didn’t know my disease was as bad as it is, so we didn’t think we needed to bash it with heavy-duty chemo. We were concerned about fludarabine's T cell suppression leading to squamous cell skin cancers, of which I have a history. Only later, as more prognostic tests became available, did we learn that my biological markers are pretty poor. The positive Coombs had not really been an issue in the beginning -- indeed, my first oncologist had pushed me to use single-agent fludarabine without explaining, or perhaps without knowing, that it might lead to AIHA -- and I had converted to Coombs negativity after using Rituxan.

Pavletic then began what I like to think of as the good news part of our good news/bad news interview (his comments are provided here courtesy of my trusty tape recorder; don’t visit a major medical facility without one):

“The purpose of this visit is to answer your questions. You don’t have siblings so the next choice would be an unrelated donor . . . The preliminary search shows you have a reasonably good chance of a good match. [There will be much more on the donor situation in a later post.]

“You want more than one donor . . . It’s good to have a few choices because it takes a little time to get it set up, and you never know, donors can back out due to medical reasons, private reasons. So we try to have a backup, find two or three so if one falls out we have a backup.

“So I think it’s a reasonable option in your situation. You are relatively young for a transplant, and age is an important prognostic factor for outcomes.”

Here I asked at what point is one too old, or do one’s chances of success become significantly lessened by age.

“It’s linear. Ten years old is better than 35 and 35 is better than 55 and 55 is better than 70. The risk goes up mainly because the risk of Graft vs. Host Disease (GVHD) goes up with age. That’s one of the main complications, although graft vs. host can be beneficial if it’s mild. It is immunologically active against leukemia. A little graft vs. host is good.

“That’s a risk, and then other comorbidities. Right now I don’t see much in your case that you would have other comorbidities -- lung, heart, kidney, liver issues, another autoimmune disease, diabetes, an ongoing infection that’s not under control.” Pavletic said that the echocardiogram and pulmonary function tests that I had been asked to undergo before coming east were both “good.”

* * *

“That doesn’t mean doing a transplant is risk-free,” he went on. “It’s a journey, it’s a process that’s not without certain mort
ality risks, but the whole objective is to eradicate your disease. It’s not recommended unless somebody has enough high-risk features to justify that approach.

“The main prognostic factor is how the disease behaves. Certainly your biological factors, you know, like ZAP-70, are consistent with this more aggressive type, and clinically it’s been demonstrated with the recurrences of disease . . . I think it’s reasonable to consider transplantation.

“We usually recommend, if someone fails one type of therapy and the disease comes back, you sho
uld consider a transplant. Maybe we can still give another cycle of something and see how things go, you know, depends what is the interval between the first and second, but once you fail two attempts for treatment you should consider a transplant.

“In your case, [the possibility of long] life expectancy is still significant, and the likelihood that CLL is going to continue to cause trouble for you in the next year or two is very high.

“You responded well to this cyclophosphamide-based regimen, you are enjoying a good quality of life this last eight months, so you may ask ‘W
hy transplant?’"

I told him about two friends of mine who underwent transplant. One had terrible refractory disease,
couldn’t get anything approaching a CR, but had a 10/10 match and was doing fine almost a year later. The other, PC Venkat, had a double cord blood transplant and did everything right going in but was felled by something unexpected even after he had engrafted.

"I realize there is
an element of chance," I said.

“There are two reasons why people may die after transplant. One is called non-relapse mortality (NRM). It means something bad happens from the complication of the transplant procedure -- stirs up your immune system, immune suppression, toxicities, you can get infections when GVHD, or just from drugs.

“Certainly transplants that are mismatched are a little bit more risky. I would say a cord is more risky than unrelated and unrelated is more risky than sibling, though if you have a 10 out of 10 match that we are looking for, it is fairly close risk to doing a sibling transplant. It certainly inches up in terms of risk, but it’s not dramatically different . . . I w
ould say maybe the risk of GVHD, the risk of infection is certainly somewhat higher.

“Non-relapse mortality goes up with organ dysfunction and comorbidities, the performance status -- all these things are pretty good in your case. How good is the donor match. Age as well plays some rol
e. With the regimens we use these days, I would say NRM is between 10% and 15%, depends on the situation.

“Nobody has a crystal ball. What works for one person, if you survive and do well, then 1% is good. Ballpark, looking at your whole features, I would say from doing the procedure there should be a risk of somewhere between 15 and 20% of mortality within two years after procedure from some complication. That would be on the higher end, but I would say the risk is real.

* * *

“The other risk of mortality is from disease progression -- if somebody has refractory disease that’s not in remission, it’s certainly more likely to come back or not go away than if somebody has a chemo-sensitive disease and remission. As you do clearly have a chemo sensitive disease, that improves the odds of staying in remission.

“This is why we do transplants in CLL. We tend to say that it’s an uncurable disease by chemotherapy. It tends to come back.”

Pavletic used his hands to mimic a survival chart.

“This is like 5 years, 10 years, we have those survival curves maybe you have seen. If disease is more aggressive, if someone is diagnosed with disease of your features, I would say the data show the survival is somewhere like seven years. With each subse
quent treatment, the disease gets more aggressive, so -- I will make it up -- but your anticipated survival curve is maybe here, two years or something.”

I made a mental note to self: Two years seems awfully pessimistic given my situation -- Dr. Terry Hamblin has pegged survival for patients of my unmutated, 11q-ilk at between 8 and 15 years -- but the general point is well-taken.

“So a transplant kind of fits. You can get all these complications and you can potentially die during the initial phases and then it tends to kind of plateau like this [more hands] where I can’t project exactly, but I would say somebody like you has somewhere around a 70% chance o
f long-term, disease-free survival. That would be a conservative estimate. These other 30% going to --"

"Relapse or die," I interjected.


“And then you get this immunotherapy portion where we really are with CLL in transplants. You know, we get rid of the disease, but it comes back . . . It can come back, late relapses have been described occasionally, but most of this stuff happens the first years. It doesn’t mean somebody can’t relapse at seven years or fourteen years.

“The other risks of transplant besides the mortality include chronic graft vs. host disease. It could be some interrupted quality of life or disability. Some people can control this, get off all the immuno
suppression we give, but there could be some residual damage from GVHD to lungs or some other organs that can be a little bit impaired. But most of the time people can get back to normal function -- I would say in 80 to 90% of cases.

“Late effects
are cataracts, second cancers like squamous cancers, the risks go slightly up. They have to be watched for.”

Since we were on the subject, I went through a list of questions I had brought and got some interesting answers:

If someone has a history of squamous cell cancers and a tendency to rashes -- can you extrapolate from this that after transplant they may be more likely to have a graft vs. host skin condition?

“No, no. You still have to watch for skin cancers. That does increase slightly, even for people who have had no skin cancers.”

I had mononucleosis as a kid and still have the Epstein-Barr virus running around in my system. What does that imply?

“Certainly compared to situations where both you and the donor would be negative for that sort of thing, you have potential for reacting the EB virus somewhere during the transplant, but it rarely has major implications. Rarely people can develop what we call post-transplant lymphomas that can be life threatening but usually not in this kind of transplant that you would get; usually that happens in T cell-depleted transplants. Most people are positive for EBV, so it is hard to find a situation where someone is negative.”

Splenectomy is used for refractory AIHA. Would I be shooting myself in the foot, transplant-wise, by having one?

“Not really. Having no spleen theoretically makes patients in the general population a little bit more susceptible to certain bacterial infections. But in transplant the immune system is compromised already, we would do all the necessary prophylaxis, so I
would say there’s no major impact on transplant.”

If I have a successful transplant, might I be rid of the AIHA as well as the CLL?

“We don’t ever say 'never' here, but once you get a good engraftment, it would be highly unlikely to have a flare-up of AIHA.”

Pavletic began to sum up:

“So the options in your case: We can say 'Let’s see how long it goes,' maybe re-treat, some other things. Hemolytic anemia -- you never know when it’s going to hit; it could be life threatening -- rarely -- but it is certainly something that complicates this whole picture.

“My point is, you are a good transplant candidate. I think it’s a good c
onsideration. There are reasonably good choices of donors. It’s not without risk. It’s not that you need to rush for a transplant tomorrow; you can see how long it goes. I think some other drug combinations or something can again put you into remission. But it’s your personal decision. You shouldn’t feel being pressed into this. If it’s something you are considering, you’re never going to be at a better point for transplant than you are now, because later the disease may be more refractory, you may get some other medical problems. But it’s not a situation when you have to jump tomorrow, but it is a consideration that is very fair.”

* * *

And then the other shoe began to drop.

“Now, speaking of what we can do here, I have one concern that’s quite serious, because we have only one program and that protocol includes fludarabine, not only for conditioning but for preparing -- the way our protocol is written -- to get you to that conditi
oning for transplant. If your immune system is not suppressed enough, measuring by lymphocyte count, we give between one and three cycles of chemotherapy called EPOCH-FR [etoposide, prednisone, vincristine, cyclophosphamide, and adriamyacin plus fludarabine and rituximab]. We have found that it improves, accelerates the engraftment. And you get another dose of FC for conditioning, which means chemotherapy that is supposed to finally prepare your immune system. That’s how we do it here, and we don’t have wiggle room changing that protocol."

I made my pitch. I explained that I’m OK with fludarabine if I’m not actively hemolyzing and if the risks are worth the reward. I described data from MD Anderson showing that when used in combination with cyclophosphamide and Rituxan, both of which act against AIHA, the effects of fludarabine appear to be mitigated and AIHA is triggered no more than usual.

Pavletic didn't appear to be impressed by the MD Anderson study.

“I don’t think anybody would give fludarabine as part of FCR to somebody with active hemolytic anemia --"

You’d be surprised, I told him, and there was a fair amount of laughter in the room.

“It may be a consideration if that’s the only option for somebody. Yes, as you say, some people give it or some people don’t even give it with a positive Coombs test and some people, they think it’s nonsense not to give it -- so there’s a little spectrum of opinions there.

“I would personally say, if you have to give it, then give it, but if you don’t have to give it, do something else . . .

“Sometimes hemolysis can be very violent, and nobody can say if it’s going to be mild, moderate, or severe.

“I think your disease is, so far as I understand here, at a good point. I don’t feel like you need anything right now. Maybe I’m wrong on that, but it sounds like you had a good response to your treatment. Maybe they can give you a few more of this CP-Rs. It would probably have a beneficial effect again. I’m not seeing anywhere now written on the wall that
you must get fludarabine for any purpose. There’s still wiggle room around that.

“Speaking of our protocol, there are conditioning regimens and there are protocols that don’t use fludarabine. Not too many choices -- fludarabine is very popular as part of conditioning regimens -- but there are options like using total body irradiation in middle-of-the-road doses.

“So if you do a transplant here you are taking a risk, biting the bullet. There are cases we’ve done in transplant situations where nothing bad happens, and there are cases where something bad did happen. But we have this extra layer, we’re asking for more fludarabine before the transplant.

“My bottom line, what I’m saying, is it would not be a good choice to go for this study if you can find one that has no fludarabine in the conditioning. It’s just taking unnecessary risks for us and for you.

“This is a very specific protocol that may not be acceptable either to you or the study to expose you to those risks where we don’t know how it’s going to pan out. If you ask my gut feeling, there’s probably at least a 50% chance you would go through this and have no problem relating to hemolytic anemia, but why take another 50% chance or risk or 30% or 20% that something may go wrong and you say, 'Oh, my god, why did we do that?’

“Why take a 10% risk if you can not take a 10% risk? You have other headaches with a transplant.”

* * *

Pavletic suggested visiting other transplant centers where the induction and conditioning regimens would be more flexible. Much as I was disappointed in being rejected for the NCI study -- it would have been nice to have the option, if I decided I wanted it -- both Marilyn and I agreed that in an ideal world, Pavletic was right. Our plans to get better health insurance, which include moving to a state that has an insurance pool for high-risk patients that will cover a transplant, began to look more like a necessity and less like a

The doctor spoke a little more about where my case stood and what I need to consider:

“It’s your decision entirely. Do you want to move on [to transplant] or not? I think everybody would agree that it would be reasonable to move on. Nobody has a crystal ball saying how your CLL is going to behave, and you have to understand that if you say ‘I’m going to sit and wait,’ you may have some disease progression that is going to make it hard to get in remission for transplant.

“There are no great options, but maybe the same thing [R-CP] would work, maybe high-dose chlorambucil, maybe Campath, maybe investigational drugs. These sort of things could buy another inch of time, maybe a year without symptoms, maybe six months, it’s hard to say. But the more subsequent relapses you get, certainly the likelihood of transplant being effective, it’s going down. And nobody with age gets younger and healthier.

“So I think you have some wiggle room. Go around, think it out, work on
your life issues, go some other places and get a consult, stuff like that. It’s not a state of panic, but I would encourage not getting complacent.”

* * *

And so, here I am, in January 2009 having relapsed at last, not getting complacent.

There is another little NCI piece of the puzzle that merits its own post, in which I finally learned in detail what my chances really are of finding a 10/10 donor match. That will be coming soon to a blog near you.

It will, along with recent CT and FISH results and my responsiveness to just-completed R-CD therapy, shed some light on my long-term strategy. I am reviewing that now, given all that I have learned since our visit to the NCI in July. A post summarizing that, and the options as I see them, will eventually follow.

In the meantime, those keeping score will be happy to hear that my one round of R-CD has turned the corner on my hemolysis. Red counts are heading back up, my dexamethasone dose has been reduced to 2 mg a day, I've lost more weight -- another lymph node baby -- and the lymphocyte count is heading down.

It will hold me -- for now.


I received a call in August from the transplant coordinator with Dr. Pavletic's official recommendation: Enjoy my remission and then use FCR if the disease progresses, which is an interesting turn in his thinking given his objections to giving me fludarabine. FCR would then make me a candidate for a transplant. Relapse after fludarabine therapy is a common step on the way to transplant; must I prove my bona fides at some point by having fludarabine and relapsing? Or is there another path?


Anonymous said...


You write so well that I wouldn't begin to write specifically about my visit last week to discuss the issue of possible HSCT... but I will point out that save for the characters involved, the disussion was essentially the same...almost as if I had taped my visit and you, in turn, wrote about it.

These are very difficult choices indeed!


Anonymous said...

Don't worry about health care! Obama will make all health care free. I'm sure whatever health care you want, will be available, no matter how expensive.

Anonymous said...

Thanks for the latest posting. The information you provide is very informative. My partner is only 39, nearly stage 2 CLL.

We have all this to come.

Keep up the postings and thank you.

Kindest Regards from Australia

Anonymous said...

I don't know if the second comment was a joke, but would point out that any program that places healthcare spending under government aegis necessitates cost controls (controls that have never successfully been implemented with Medicare) which in turn brings up the issue of healthcare rationing. No one can say for certain how this will be implemented, but governmental agencies akin to the UK's NICE are a distinct possibility...and costly procedures of uncertain outcome in older people are less likely to gain approval than more mainstream medical care.

It is ironic that legislation was passed years ago to "contain" Medicare costs and never followed. Each year congress has passed "emergency" legislation to turn back the proposed cuts in reimbursements. My belieef is that physicians would grouse about it, but very few would cease to care for Medicare patients.

We'll see what happens


soapy said...

David, I am sure that now you feel you don't know which way to jump? I was originally thinking of a stem cell transplant, but at that time they couldn't get any cells from me. I was upset, it wasn't that I wanted a transplant, what I wanted was the choice. As someone who has done FC for 6 months, then FC ending after 2 cycles in sepsis, Campath and in relapse again with AIHA, I have been advised to try FC again (!) or Campath again.
The question is - what to do? What a difficult decision for you. Thankyou for your excellent, informative blog. Soapy

David Arenson said...


As I recall, you are in the UK, so things may work a little differently over there. A SCT with cells from a matched unrelated donor is much more likely to be long-lasting and possibly curative than a SCT using your own cells (autologous). Have they run a preliminary donor search?

Meanwhile, can they possibly add Rituxan to your therapy? Not only is FCR more effective than FC, the R has been shown to act against AIHA. Here in the US it is often given as a single agent for that purpose.

I agree that these are difficult choices and that we patients always want a choice. There is something reassuring about having many options open. But I think at some point in progressing disease we need to develop a long-term strategy in which we make use of those choices in as effective an order and manner as possible.

Rethinking my long-term strategy is what I am doing now; my visit with the NCI helps fill in part of the picture in terms of one possible alternative.

I'll be posting a lot more of my considerations in the near future; in the meantime, all the best to you.


soapy said...

Thanks David, yes I have been offered FCR and it is probably what I will choose. You're right, I am in the UK. I have discussed an SCT with cells from a matched unrelated donor. My consultant has suggested it is not the right way for me to go as I have been so ill with previous treatments. He feels the time for SCT has passed for me. He says he doesn't want to kill me off!! I also have history of heart disease which is a factor.
I have also seen top CLL expert in London. Her advice for me was RFC or Campath. Cyberhugs, Soapy

Lynn M. said...

Just past the picture of the mouse in a maze, you wrote "And so, here I am, in January 2008." This only makes sense if you meant January 2009.

David Arenson said...

Thanks, Lynn. I plead "chemo brain" and have updated the post to reflect the correct year!

Anonymous said...

I think that transplants for CLL are the modern-day equivalent of Frankenstein's experiments. The statistics are lousy, and I think that the medical establishment is more interested in gathering more data for the future than in discouraging prospective patients with the nightmarish scenario that is more than likely to play out. I'll die the "natural" way before I let them kill me with "complications from leukemia."


bob larkin said...

I relate to so much of this, and to you, as usual. It seems like ages ago when I bit the bullet, leaving my business down south to escape lousy insurance that would not cover the recommended SCT. I relocated to CT; got a job at a big household name retailer (was that ever culture shock); waited for the insurance to vest (one year); then did my transplant at Dana Farber 4/05. My new insurer was spectacular. They assigned me a CLL savvy advocate; cut a turnkey deal with the transplant center; stayed with me through the whole ordeal; and lived up to all obligations. My fervent wish is that you can find as good an avenue to SCT if it becomes a step for you.

David Arenson said...

Interesting how Denny and Bob bring such different perspectives to this. I think we all have to decide what is right for us as individuals -- so much of CLL decision-making is a matter of personal preference, of how we choose to live our lives and the risks we are willing to take.

Bob, your story is a useful reminder to me that someone has walked the path I am walking and is here to tell the tale. As much as we read statistics and try to go by logic and reason, our sense of things is often formed by personal stories, anecdotes, vignettes. I would be lying if I didn't say that PC Venkat's death has made me think twice about jumping soon, but stories like yours -- and that of my friend in Ringwood who is doing quite well against terrible odds going in -- remind me that the outcome can just as easily take a good turn.

Ultimately, when it comes to transplant, our fate is out of our hands. To proceed with one, I think one has to be ready to give up (the illusion of) control. You bite the bullet and hope for the best.

bob larkin said...

PC's death shook me deeply and surprised me. I love PC and Kaya. I think of PC every time I use his fabulous "blood counts" spread sheet which has been, and still is, my most valuable tool. In spite of the wrenching loss of PC, I am an advocate for the transplant. As a member of that club, I see much anecdotal evidence of quality survival. Granted it is not for everyone, but at transplant savvy centers, I feel the sacles are tipped way in favor of survival over the alternative.

bob larkin said...

MY WORD!! I can't believe I spelled Chaya's name "Kaya" in my above comment. Sorry Chaya. I have three excuses .. 1)chemo brain, 2) old age, 3) my long time racquet ball friend's name is Kaya Weaver.

Anonymous said...

I don't know why anyone would resist free health care. I'll repeat. It's free! People live 20 or 30 years longer in free medical care countries. Only a knee jerk right-winger would oppose the inevitable.

Anonymous said...

The only thing which seems inevitable is the demise of the long it takes to unwind is the unknown.