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 past 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 without 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 began 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 medications (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 mortality 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 should 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 ‘Why 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 would 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 role. 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 subsequent 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 of long-term, disease-free survival. That would be a conservative estimate. These other 30% going to --"

"Relapse or die," I interjected.

“Yes.

“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 immunosuppression 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 consideration. 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 conditioning 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 theory.

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.

IRONY DEPARTMENT

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?

Bernie Madoff screws leukemia patient

That would be me. I have been debating whether to write about this. I try to stick to chronic lymphocytic leukemia in my posts and up to now my financial situation has not been especially germane. But I have just lost my savings, and it is important to remember that not every aspect of the disease is medical.

Cancer changes lives in many ways. It refocuses energies -- mental, emotional, spiritual, financial. It transforms everything, from the mystical to the mundane. That mundane world includes money. Cancer can change your career, deplete your bank account, eat you out of house and home even as it eats away at your body.

Bernie Madoff, like a metastasizing financial tumor, has not helped matters of late.

Madoff is the former NASDAQ chairman whose Bernard L. Madoff Investment Securities LLC stole some $50 billion in history’s largest Ponzi scheme. I lost $65,000. That may not sound like much to Madoff, or perhaps even to you, but it meant a lot to me.

Ironically, when it comes to leukemia and lymphoma, I have something in common with the Madoff family. Madoff’s nephew Roger died of acute myelogenous leukemia in 2006 at the age of 32, shortly after he wrote a book called Leukemia for Chickens. His son Andrew was diagnosed with mantle cell lymphoma in 2003, which prompted Bernie to donate millions of dollars to the Lymphoma Research Foundation. My official diagnosis is CLL/SLL: chronic lymphocytic leukemia/small lymphatic lymphoma. In my more poetic moments I like to think that perhaps Bernie donated my money to efforts to beat our common beast.

Probably not.

* * *

Madoff and my family go way, way back. His wife, Ruth, went to high school with my stepmother, Cynthia, who is quoted in today's New York Times. (Cynthia is like a real mom, and is a good friend, and I love her dearly -- even when she beats me at Scrabble.) Cynthia's parents owned a small, rustic summer resort in New York's Catskill Mountains called Sunny Oaks; during the winter they lived in the same Brooklyn neighborhood as Ruth’s parents, Sol and Sarah Alpern, with whom they became friends.

The Alperns were regular guests at our hotel for two decades, arriving after Memorial Day each year and staying until Labor Day. When I was in college I waited on their table. Later, my Dad and Cynthia inherited the hotel, including the Alperns, and eventually Marilyn and I helped manage the family business and we became hosts to the Alperns. (Sunny Oaks finally closed in 1999, a relic of a Borscht Belt era that had long since passed. The Alperns had passed away by then, too.)

Sol and Sarah were easy guests. They never complained, and although they took one of the best rooms in the house, they weren’t fancy people. This wasn’t a four-star place. It was basically a collection of rickety old wooden bungalows that we dubbed “cottages,” and it was, as they say in Yiddish, haimish: homelike, friendly, folksy. The guests were treated like an extended family. And we took good care of the Alperns, even when Sarah got old and started to pee on cushions in the lounge. We’d mutter something like “Sarah Alpern is going senile” and just turn the cushions over. (This sort of thing explains why Fawlty Towers is my all-time favorite TV program, but I digress.)

It was Bernie Madoff who eventually gave us all the golden shower. But for the longest time, he was a distant acquaintance who professed nothing but gratitude for the way we took care of his in-laws. Sol, by the way, was an accountant. He knew people on Wall Street, certainly through Madoff and his circle, and he was instrumental in spreading the word at the hotel when good business opportunities came along.

Which, to make a long story short, is how we all ended up with accounts in Madoff. My history with it goes back almost 20 years. Nobody ever questioned its legitimacy. (It probably was legitimate in the beginning; Madoff was a pioneer in electronic trading back when MS-DOS was the world's most popular operating system.) Statements from Madoff came promptly and looked proper, providing endless lists of transactions. When Marilyn added it all up at tax time, it seemed entirely believable. We often got an annual return of about 10 percent or so, which actually declined in recent years.

Our theory about that decline was that ours was something of a nuisance account. We kept removing principal and were small financial potatoes, not worth any special effort on the part of the traders (or what we thought were the traders). Indeed, we were allowed to start our account with $50,000. This was in the early days -- a favor -- before Bernie decided you needed two million bucks to get in.

Way back when, our little hotel turned out to be fertile ground for investors for Bernie. Almost everyone in the family had a Madoff account. Accounts radiated out through the guest population, through our distant relatives and the distant relatives of guests. All told, I can think of a dozen people I know who are, collectively, out at least $5 million, and I am sure those people know another dozen people.

I was financially irresponsible, unlike a number of folks who let their money sit in Madoff and grow and grow. It turns out that irresponsibility has its rewards because at least I got to spend most of my money. I know people -- not rich to begin with -- who are essentially broke.

We’re not talking about the Palm Beach set that has grabbed much of the media’s attention. This is the Brooklyn-Far Rockaway-where-Madoff-grew-up set, the middle-class-people-who-worked-hard-and-saved set. I know people who lost in the hundreds of thousands, whose money represented their life’s work as well as inheritances from their parents. Some have careers or good equity in their homes or are old enough to be receiving social security or a pension. Others have less.

One cousin wrote that when her checking account is depleted in February, “I have nothing.”

* * *

I almost closed my Madoff account earlier this year. (Talk about a “D’oh” Homer Simpson kick- yourself moment.) The return was so small -- around 4 percent -- that I was tempted to find another place to put it. But the idea that the money wasn’t safe never crossed my mind. Nobody expects to be a victim of the world’s largest Ponzi scheme, especially after so many years, and especially by a man who was both a family friend and a respected Wall Streeter who had actually been hired as a consultant by the Securities and Exchange Commission at one point.

And inertia is a powerful force. “Madoff” was synonymous with “bank” in our circle. It was like “Kleenex” for "tissue" or “Xerox” for "photocopy." “I’ll put the money in Madoff.” “I’ll take it out of Madoff.” Gifts, trips, cars, down payments on houses, all came from “Madoff.”

Especially in recent years, when leukemia took a toll on my ability to work and required expensive visits to doctors, “taking another $10,000 out of Madoff” became a yearly event. In the end, I had $65,000 invested -- most of it in my father's account, which was earning a higher return. That money was there as a cushion, to be used in case I needed a transplant or other invasive therapy, in case Marilyn couldn’t work because she needed to spend several months taking care of me. (I was also secure in the knowledge that my folks -- who ultimately lost all their liquid assets to Madoff -- could lend us a financial hand if we really had our backs to the wall.)

And Madoff maintained his distant but cordial relationship with our family. As described in the Times article, Cynthia saw Bernie and Ruth at her 50th high school reunion in November 2007. Madoff gave her a big hug. This fall, when the market was showing signs of serious decline, Madoff assured a friend of ours that there was no cause to worry, that in September he had put everything into treasury bills.

Then, on December 11, I got a call unusually late in the evening. Cynthia was on the line and I asked her how she was.

“Not too good,” she said morosely. From her tone, I took it that someone had died, or been injured, or was diagnosed with a serious illness. I know all too well how such things can come out of left field.

What she told me was even more unexpected, that Madoff had been arrested and that we all had apparently “lost everything.”

In the ensuing weeks, we have been busy keeping up on the legal issues involved. It appears that eventually -- largely thanks to SIPC, the Securities Investor Protection Corporation -- some of us will see some of the money back. But it could take years, and most of us will never come close to recovering completely from the loss.

* * *

The Madoff mess has taken a toll on its victims in different ways. There is the obvious shock, the feeling of betrayal, the loss of security, the anger and the depression. I have been through all that, but I also have a potentially fatal leukemia and that means I have a somewhat different perspective.

Over the past few years I have lost many friends to disease. Seven months ago I lost an especially dear one, my buddy in the battle. I feel my own body struggling as the CLL progresses. I know that I may well be living my life in dog years, four years for every one. I have had to deal with the prospect of the loss of everything, and so I have become an expert on loss. I have a big picture way of looking at it.

Madoff hurts, it is a horrible inconvenience, but it will not transform my life the way it will for many others. This is because leukemia has already taught me what E. M. Forster once wrote, namely that "We must be willing to let go of the life we have planned so as to have the life that is waiting for us."

I have already had my life changed, redefined, redirected by events out of my control. For many Madoff stakeholders, this is a new and frightening experience. For me, it’s “been there, done that.”

I did not choose to be fighting a deadly, chronic disease in my late 40s and early 50s. It upset my assumptions, put an end to dreams. But it is the life I have, and the struggle has taught me some interesting lessons. There are lessons that money and status and ambition can never teach you, things that come in quiet moments when you face the reality of life and death.

The lessons are these:

It’s not what you do for a living, it’s who you are as a human being.

It’s not what you have, it’s who you have.

I have my soul-mate, a woman who will happily live with me in an old trailer on the edge of the desert so long as we can still be together. We discussed this long before Madoff collapsed, knowing that chronic disease + medical bills + self employment = a recipe for poverty.

From Marilyn (and family and friends) I have endless love in my life, and I would not trade that life -- cancer included -- for all of Madoff’s billions. And so, even in the starkest moments of financial despair, I still regard myself as the richest man in the world.

That is the perspective I keep coming back to, though sometimes it takes awhile after I hear new stories of the pain Madoff has inflicted on others, or I see his smirking face on TV as he walks back from the courthouse to his penthouse.

The media likes to say that Bernie Madoff, financial psychopath, “destroyed lives.” He certainly disrupted lives, created misery in lives, brought great heartache. I take none of that away from anyone.

But my message to the world is that he destroyed money, not lives.

Believe me, there is a difference.

Five years after our hotel closed, this was Sol and Sarah Alpern's room, right before demolition. There's something symbolic about the wreckage, in restrospect. It sums op our family's Alpern/Madoff experience.

UPDATE

Yours truly was interviewed for this Jan. 29 Bloomberg news report, which is mostly accurate, though Madoff was never a guest at our hotel. He and Ruth visited the Alperns a few times just for the day.

There but for the grace of God

I am reminded, whenever I am in the chemo room -- as I was Monday -- that there are worse things to have than chronic lymphocytic leukemia.

A man, three years older than me, in a wheelchair . . . Had a massive heart attack in 2001, died and was revived, six months of memory loss that led him to wonder why he had scars on his chest. Two more heart attacks.

He has myelodysplastic syndrome -- unable to create sufficient cells in the marrow. He lives on transfusions, goes in when the platelets get to 13. After getting red cells, he enjoys a hemoglobin of 10 for a few days until it starts dropping like a rock again.

He also has rectal cancer, spent six months with a colostomy bag, and is now refractory to the original treatment. Trying something new, hoping it works.

His wife runs their business, has learned the caretaker's art, deserves an honorary RN at this point. Jokes that they call him "la cucaracha" because he, like cockroaches that would manage to navigate the end of the world, is a survivor.

He makes jokes about "asshole doctors," manages some smiles. He's rooting for the Cardinals (this is Arizona). Life goes on.

Dave's doing drugs

Among the skills I have picked up in the strange alternate universe of CLL -- I think many of us have earned a Junior Hematologist badge, for example -- is Armchair Urologist, or Parser of Piss.

I'm not sure which title I like better. It all depends on how the medal will look on my CLL Cadet uniform. I am providing a graphic of the hematology badge here, but obviously more work needs to be done on the concept, including a helmet to protect us from small children with hacking coughs.

However, I digress.

Readers may recall that hemolysis, the process by which autoimmune hemolytic anemia destroys red blood cells, can turn urine orange. This is because the red cells are red and their dead hulks combine with urine's natural yellow to make, as we all learned in first grade, orange. Several times during 2007 -- my annus horribilus of hemolysis -- I was alerted to sudden ill-fortune by the color of my urine.

On Wednesday it happened again. What floated in the toilet that evening was just too dark, too burnt, too damned orange. By Thursday morning there was no doubt about the consistency of the color. This wasn't a one-time thing; it couldn't be blamed on the contrast I had to drink for my CT scan Wednesday morning. Things had definitely changed for the worse. Marilyn verified my suspicions (oh, the wonderful stuff CLL couples get to share). I am sparing you photographic examples, dear readers, despite the age of the cheap and easy digital camera.

Since I had enough hemoglobin in reserve -- it was measured at 12.1 on Monday -- I did not hear the pounding in my ears that often comes when I am hemolyzing and the red cells are quickly declining. Which just goes to show that you need to multitask when looking for symptoms of hemolysis. Besides listening for pounding and examining urine, I would recommend being aware of subtle changes to your physical stamina -- for example, did you get more winded walking up the steps today than you did yesterday?

(Since we're discussing the art of hemolysis divination, this may be a useful aside: Although my hemoglobin was higher on Christmas Eve eve when I did hear the pounding, I had also had a lot of brandy and egg nog that night -- ho, ho, ho! -- and my theory is that the alcohol in my blood may have facilitated a thinning or enhanced an echoing that I might not have otherwise heard. This is yet another reason why getting drunk periodically is very important for those in my situation.)

* * *

Meanwhile, back at Orange Elimination Ranch . . . A phone chat with Dr. Belle on Thursday led to doubling my dose of Decadron (dexamethasone) to 8 mg daily, as well as to a stat CBC Friday morning. Sure enough, my HGB had dropped to 10.9 in just a few days; my overall red count went from 3.48 to 3.05.

The good news is that the higher dose of Decadron turned my urine a lovely pale yellow again, something that would probably be named "whispering sunrise" in the Ralph Lauren paint section (what have we come to?) at Home Depot.

But I know all too well that it won't hold me for long. So I will be arriving bright and early Monday at Dr. Belle's office for some chemotherapy, which I prefer to think of as my Day of Hematological Beauty.

We're doing a round of RCD -- Rituxan plus cyclophosphamide plus dexamethasone -- the protocol advanced by Kanti Rai and his group to combat CLL and AIHA (as well as ITP). This is quite similar to what I had three rounds of starting in October 2007, just without the one baby dose of vincristine and with dex instead of methylprednisolone. Hopefully that will nail the AIHA like it did in the past (all the relapsed patients in Rai's study responded when treated with RCD again).

We'll be doing a second act, of course, and maybe a third. We may do more rounds of RCD, we will explore some other ideas, and I'm sure we'll go over the CT scan to determine how hard we feel we need to hit the disease.

The fact is that I can't rely forever on RCD or a variant to get me through the CLL-AIHA double whammy. I need to consider sterner measures that don't also have the effect of shooting myself in the foot, or at least not blowing the whole foot off. (I'm thinking that cadet uniform needs some lead boots.) Whether this means going with a traditional approach or something more experimental, only time, education, and discussion with my doctor will tell.

* * *

Meanwhile, I'll try to fit in a little rest on chemo Monday. I plan to bring a good book, The Pirate Hunter: The True Story of Captain Kidd, an entertaining read about privateers and pirates at the turn of the 18th century. This is what probably started me thinking in terms of costumes for CLLers.

That, and my natural tendency toward eccentricity, which is only enhanced by the Decadron's powerful side effects. It should be said here that having had both dex and methylprednisolone (Medrol), I can see a definite difference in the mental as well as physical effects of the 'roids. Medrol made me just a tad worried about things. I remember staring into the mirror one night and wondering if my gums were receding. Dex puts me more into overdrive, in a positive and focused way. I'm getting less sleep, but, hey, have you noticed that there are a lot more posts to this blog of late?

Speaking of which, I am promising you an interesting post next week about something else that has happened in my life, torn from today's headlines. It tuns out that yours truly sort of knows someone famous, or that would probably be "infamous." A modern-day pirate, matey.

Aaaarrrghh! And I do mean aaaarrrghh (as opposed to aaaarrr), with all the frustration the word entails. Stay tuned.

I’m a lymph node baby daddy

OK, I’ll sheepishly admit that if it’s late at night and I can’t sleep, I’ll watch the Maury Povich show. It’s more mindless than medication and a lot less expensive.

Maury, for those of you who have your TVs tuned to PBS, is a long-running talk show host whose specialty is DNA paternity testing. If there’s a woman in America who slept with 20 men two years ago and can’t figure out who the father of adorable little Brandy is, Maury will keep testing until he finds out.

Like a Kabuki dance or the Oberammagau Passion Play, each Maury set piece opens with a predictable series of events, usually involving a couple and a lot of bleeped cursing and protestations of the "I'm not your baby daddy!" variety. There are two possible outcomes after Maury rips open the envelope with the test results: One is to shout “You ARE the father!,” which usually leads to a crestfallen look on the part of a young gentleman. Alternately, Maury will shout “You are NOT the father!,” which will cause the man to do a little victory jig while the woman runs screaming from the stage.

Well, no special testing required, I am here to report that I am a lymph node baby daddy. When I began 4 mg of Decadron (dexamethasone) to control my autoimmune hemolytic anemia on Christmas Eve, I weighed 212 pounds. A week later I was down to 202. My neck was noticeably thinner, as was my abdomen. I had lost my pregnant look.

I discussed this with my doctor, Dr. Belle, during an office visit on New Year’s Eve. (In case you hadn't noticed by now, I like to mark every holiday with a special medical event.) It is common for people to gain weight on steroids but not to lose it, she said. Not unless there is a whole lot of CLL and attendant nonsense sloshing around in the body’s 600 or so lymph nodes.

This happened to me before, in March 2007, when I first took steroids to combat the initial attack of hemolysis that led to my diagnosis with AIHA. I was on 72 mg of methylprednisolone daily then (4 mg of Decadron is worth about 21 mg of MP) and lost 20 pounds in nine days. I was bulkier to start with and was doing Rituxan at the same time, which had a synergistic effect when it comes to cell kill. In both cases I spent the first couple of nights peeing like a horse.

* * *

My weight loss has slowed for now, and despite the joy of effortlessly losing ten pounds, the whole episode raises some serious questions that have bearing on my next steps in terms of therapy.

One, for example, is just how pregnant with lymph nodes am I? Do I have twins in there? Triplets? (The average baby weighs six to nine pounds at birth, so I appear to be working on a second one.)

All the usual blood-based monitoring tools -- lymphocyte count, hemoglobin, platelets, annual FISH -- give us a glimpse into the state of our disease. But especially in “bulky”or “SLL-ey” or 11q CLL patients like me -- 11q clones love to collect in the nodes -- these tests can show us just the tip of the iceberg.

It wasn’t the visible part of the berg that sunk the Titanic, after all, and more than one CLLer has awakened from testing complacency to find something going haywire fast. Count me as one of them. I was Coombs negative in November, resting on my RBC laurels. By Christmas Eve I was hemolyzing again. The Coombs was positive, reticulocytes were high, and haptoglobin was low. It was the pattern of 2007 repeating itself again.

During the year’s remission that I enjoyed following the completion of R-C(V)P therapy in December 2007, the disease began to return, creating the conditions of immune dysfunction that led to hemolysis again. I could see the lymph nodes in my neck slowly coming back. This was no surprise -- It’s a chronic disease, after all. That I was lulled into thinking all was well by looking at the numbers -- well, that was shortsighted.

* * *

A word is in order here about lulling. I had a very rough year in 2007. So when 2008 dawned with a pencil-thin neck, low lymphocyte count, and red cells on the rebound, I was prepared to embrace the good news. Despite my trip to the NCI to discuss a stem cell transplant trial, I made an effort to spend as much time as possible not thinking and worrying about CLL. Managing this disease can lead to burnout, a depletion almost as profound in its own way as the effects of leukemia upon the immune system. It did not help that I lost more friends to the disease, including a particularly good one.

And so I took a break, which gave my ever-loving and giving caregiver a break, too. I didn't look for clues. I figured no news was good news, and when I got good news on a test -- and I kept getting such news into November -- I embraced it. I knew the nodes were growing and I knew I would have to be back in this fight again, so I cherished and jealously guarded the time that I was, as they say in the military, on leave.

In the end, worrying all year probably would have made little difference to the outcome. I don't blame myself for taking some down time, especially as I was ready by dint of past experience and knowledge to jump into action immediately when needed, and especially as I have a doctor who is really and truly there when I need her. Those factors made me a little more comfortable turning my back on CLL for awhile, which means that I didn't flirt -- too much -- with danger.

* * *

In CLL, many things go on where the sun don’t shine, and this especially includes the peritoneal (abdomonal) cavity. God knows how many more lymph node babies I have in there, gumming up the works and growing into masses that not even Decadron can flush away. It can be notoriously hard to feel these nodes, or any large abdominal mass. Marilyn once had an ovarian cyst the size of a cantaloupe that she couldn’t feel until it twisted on its axis and started to abscess.

Doctors will tell you that, especially as time goes on, CLL can change in the way it behaves and the locations it chooses to hide out in. When docs refer to "the natural history of CLL," they mean the course it takes, which can in many ways be affected by the treatment we throw at it as well as the clonal evolution of the disease itself. (Clonal evolution is what happens as more bad copies of CLL cells are made, giving rise to new groups of clones with particular properties. For example, I began my CLL career without 11q and later developed it.)

One's CLL may go from being more leukemic -- present in the blood -- to congregating where it is safest from therapy, namely the deep abdominal nodes. There is a reason this is the location where Richter’s Transformation to lymphoma occurs. Not that I’m worried about that at the moment, but a constellation of such nodes provides the breeding ground for that sort of thing if sufficient T cell suppression occurs. At the very least, hidden interior bulk may be keeping my immune system so dysfunctional that the AIHA can never be put somewhat confidently to rest.

* * *

So, what to do? Well, aside from Philippine psychic surgery, there’s the CT scan, and that is what Dr. Belle and Marilyn and I have agreed to do to help us develop a treatment plan. The last time I had a thorough one was at diagnosis in 2003. I'm going in tomorrow for another.

I know there are those with reservations about radiation, but the prudent use of X-Ray technology can answer some important questions. Here I am, with 11q CLL, prone to bulkiness, having lost enormous lymph node weight, having relapsed rather suddenly. "Don't worry about what you can't see" is a rather hollow option, even though this is often repeated to us patients, sometimes by doctors. Power, such as we have it over this disease, comes from knowledge. The Titanic had a watchman who saw the iceberg in advance, just not soon enough to avoid the damage. (For a reasoned opinion on the use of CT scans and other imaging in CLL, read Dr. Terry Hamblin's blog post entitled CT Scans.)

To develop a strategy without knowing as much as I can about the enemy is wasted effort. To do treatment and say that it’s a success because all the peripheral blood numbers look fine is also folly.

We need to see as complete a picture as possible going in. Once we have that picture, we’ll have a better idea of know how to proceed. In the meantime, the steroids are holding me, just barely. My hemoglobin has been stable, at 12.1, for the last week. I feel pretty good, despite the Decadron, which gives me a wired effect that tends to make me want to dance like one of those relieved guests on Maury.

The new adventures of old vincristine

And no, I won’t be having any more of that drug again.

Readers may recall that my doctor and I settled on R-CVP therapy (Rituxan + cyclophosphamide, vincristine, and prednisone) to treat CLL and AIHA during my hemolytic crisis of October 2007. In the research of those frantic days, I ran across all the usual warnings about chemotherapy side effects.

I also ran across what, it turns out, are disagreements among top doctors about which drugs are more disagreeable.

Dr. Clive Zent, CLL autoimmune expert at the Mayo Clinic, told me:

"Vincristine has very good activity against AIHA and ITP in many patients -- acts against macrophages causing RBC and platelet destruction -- and is thus a useful component of treatment. Vincristine also has activity against CLL. The drug has very little other toxicity and in particular minimal bone marrow toxicity. In contrast both cyclophosphamide and corticosteroids have a wide spectrum of serious toxicities. Obviously patients need to be monitored carefully for vincristine neurotoxicity and the drug stopped early if this occurs. In most cases full recovery is likely.”

Dr. Terry Hamblin, the well-known UK researcher and clinician, had another view of vincristine:

“ . . . It also has the added side effect of peripheral neuropathy. Experience can be dangerous here, too. Perhaps I am unfairly prejudiced against the drug after seeing an old lady confined to a wheelchair for the rest of her life after just one dose.”

Well, me, I’m not an old lady right? As my grandma from the Old Country might have said, “You are young and strong like bull.” What could go wrong?

* * *

Vincristine received FDA approval in 1963 under the trade name Oncovin, which is the “O” in R-CHOP, another chemo regimen that node-heavy CLL and lymphoma patients sometimes find themselves experiencing. The drug is a derivative of the Madagascar periwinkle, formerly known as “Vinca rosea,” and had been used as a folk remedy before its refinement for cancer purposes.

I have provided pictures of this very pretty plant and I can almost see the lemurs of Madagascar swinging about by their tails and chomping on the inviting foliage -- until peripheral neuropathy sets in and they all come crashing down from the branches with a thud.

My doctor, Dr. Belle, made a good call on the first day of R-CVP therapy back in October ‘07. Because my heart was under extra stress (my hemoglobin was down to 6.8), she ordered what she called a “baby dose” of vincristine. I would normally have received 1.4/mg per meter squared -- around 3 mg given my body weight. Instead I was given 1.4 mg total.

That's all the vincristine I have ever had because it turned out that I am highly sensitive to it. Within days, peripheral neuropathy (numbness of the fingers) set in, which lasted a couple of months. My vision became blurred, which at first I blamed on all the steroids I had been taking to control the AIHA. But this was a marked blurring, which set in over a few days, hung around for several weeks, and then resolved. Given these symptoms, Dr. Belle deleted vincristine from my other two rounds of treatment, with my blessing.

* * *

Months later, in the Spring of ‘08, I began to notice what I called a “creakiness” in my legs. If I sat for awhile, my thighs would tend to fall halfway asleep and I would be very stiff when getting up. I’d walk like an old man -- weakly, unsteadily -- for a minute or so until I got “warmed up.” Even then, when my steps were more or less normal, I experienced a subtle achiness and discomfort that I had never noticed before.

I was also having trouble being limber: Let’s say you’re laying on your back with your left knee bent. You want to raise your right leg up in the air and cross it over the left, resting it against that bent knee. I was having a lot of trouble doing that sort of thing. I would need to be using my arm to pull my right leg up and over. My leg wasn't dead weight, exactly, but it didn't want to move on its own very easily.

Getting down on my knees to look for something on the floor became an almost superhuman challenge. That's because getting back up was nearly impossible, with most of the effort having to come from my arms, grabbing hold of armchairs and tables and such to give me enough leverage to stand.

At night, I would toss and turn in bed. My hips would ache, especially where the thigh muscles seemed to attach. This achiness would generally stay with me throughout the day to one degree or another. I spent a lot of time grumbling at the mattress, which is made of pure latex rubber and had never given me such trouble before.

My primary care physician had no idea what might be causing these symptoms, and Google searches only led me to a host of scary-sounding websites that discussed in detail everything that can and will go wrong with the hips.

I eventually laid it at the feet of the steroids I had been on -- loss of muscle mass does indeed accompany steroid use. The thing is, that mass comes back as you use the muscles again. And no matter what I did -- which included several sessions of physical therapy last summer -- I did not get better. Things just stayed the same.

Until a few weeks ago when, like a storm lifting, my hips and legs went back to the way they used to be -- suddenly and unexpectedly -- over the course of no more than two days.

Which is when the light bulb went off and I realized that I had been experiencing delayed symptoms from that baby dose of vincristine. That the Madagascar periwinkle might have been the source of my trouble had occurred to me before; but compared to the finger numbness and blurred vision, the onset of the creakiness was delayed enough, and the effects lasted so long, that it didn't fit the pattern of what I expected, especially since I'd had such a small dose. So I blamed the steroids.

If you look at the dose-limiting side effects chart of this PDF on vincristine, you’ll see that symptoms are defined as immediate (onset hours to days), early (days to weeks), delayed (weeks to months), and late (months to years). Peripheral neuropathy gets an “early,” but in my case the leg part of the problem was definitely “delayed.”

And for the record, let me quote:

Neurotoxicity involves peripheral, autonomic and central neuropathy. It is the primary and dose-limiting toxicity of vincristine. Most side effects are dose related and reversible, but neurotoxicity can persist for months after discontinuation of therapy in some patients, and in rare cases may be disabling.

Peripheral neuropathy is the most common type of neuropathy and develops in almost all patients. Loss of deep tendon reflexes, peripheral paresthesias, pain and tingling can occur. If therapy is prolonged or high doses are administered, wrist and foot drop, ataxia, a slapping gait and difficulty in walking can occur.

I'll close with a cautionary note. Your mileage may vary, of course, but as it turned out my experience with the drug was a little closer to Dr. Hamblin’s than to Dr. Zent’s. Which goes to show you again that when it comes to chemotherapy (and CLL in general), we are all individuals. Statistics are general; results are personal.

The good news is that I am hypersensitive to vincristine, which presumably means it works effectively in my case. The bad news is that I am so sensitive to it that I can never use it again. At least my experience with it did not involve regular or large doses and massive system shock and permanent damage. So in a backhanded way, I guess I was lucky.

Interesting what sometimes passes for luck when it comes to cancer.

My Christmas lump of coal

On the eve of Christmas Eve I had a little too much egg nog with brandy. One thing I have learned over time is that alcohol really does thin the blood, so to speak. Indeed, studies show that low hemoglobin can accompany chronic alcoholism. My excuse for low hemoglobin is autoimmmune hemolytic anemia resulting from my CLL (though if life keeps getting more stressful I may decide to add chronic alcoholism to the list).

Hemolysis, in which the body destroys its own red blood cells, is the thing to watch for in AIHA. It can come on suddenly, and over time I have become adept at looking for the signs and signals. Catching hemolysis early on is essential to keeping it in check. The more it begins to snowball, to use a seasonal metaphor, the more it can get out of control, requiring tougher steps to control it. Oh, and there’s that little thing about putting your life in danger as your body runs out of red blood cells. You never want that particular Elvis to leave the building.

If there is a decline in my hemoglobin, the first thing I usually notice is a pounding in my ears. What I’m hearing is my heart pumping away, and when HGB is really low, it’s like a marching band. When HGB is just a bit low, it’s like an occasional lone drummer offstage. When HGB is normal, I don't hear it at all.

Well, the Little Drummer Boy was busy as I tossed and turned in bed a few hours after placing my nog-drenched frame in the prone position. The easiest way for me to tell how my HGB is doing is to drink a lot, then go to bed. That’s just one of the tricks of the AIHA trade that your doctor probably won’t tell you about.

Sure enough, blood tests the next day -- I have that holiday miracle, a doctor who answers her cell phone on Christmas Eve -- confirm that I’m hemolyzing again. On Dec. 2 all my red counts were normal. Twenty-two days later the HGB was down to 11.6 (from 13.5), the MCH and RDW were high, and overall RBC was 3.66, down from 4.47. My LDH, which measures turnover of cellular activity -- as in red cells being chomped by macrophages -- had gone from mid-normal to high-normal, and total bilirubin was now at the very top of normal, meaning debris was moving through the liver.

Results of the Direct Coombs, haptoglobin and reticulocyte tests will have to wait until Friday or Monday. But based on past experience, what we have here is active hemolysis, not quite out of control but definitely past the Miss Manners stage of fine macrophage dining.

So, hello Decadron. Hello, doctor next week. Hello, chemo very soon.

And hello, CLL curveball. As they used to say on Monty Python, “Nobody expects the Spanish Inquisition!” We CLLers with active disease had better learn to expect it at any time, and that includes holidays.

Ataraxia

I ran across the word “ataraxia” a while back and I liked it. Not only for the way it rolls across the tongue (at-uh-RAK-see-uh), sounding like so many things: an exotic city on a distant continent, a make-believe world conjured by a child, a potent drink that promises to liberate the soul.

No, I also liked it because of its meaning, from the Greek ataraktos, or “not disturbed”: A state of freedom from disturbance of mind. Calmness untroubled by mental or emotional disquiet

Faced with the ever-shifting challenges of the “new normal” that is life with chronic lymphocytic leukemia, ataraxia is something that we patients and caregivers often find lacking in our lives. We crave calmness of mind. Every bad test result or new symptom is a reminder of just how far we can find ourselves from peace and serenity.

It is therefore no surprise that ataraxia is hard to come by in CLL, as the Mayo Clinic has officially found -- I do believe this disease would present something of a challenge to the coping skills of the Dalai Lama. But nothing is impossible, and I sometimes find vignettes, little triumphs of the spirit that show ataraxia is possible in the face of adversity:

A caregiver, whose husband is in ill health and responding poorly to chemotherapy, wakes up to find that her cow broke through a fence and ate her carefully-tended garden. After she cries her eyes out, she and her daughter go out and buy new plants and, together, start all over again. In replanting, she finds strength.

A patient, who has bad prognostics and is undergoing tough chemotherapy, feels like crap. But he loves to cook, and he cooks a dinner for his wife and their two closest friends. At the end of the night they shoot off fireworks.

A man in his 50s, having fought aggressive CLL with aggressive therapy, including a failed stem cell transplant, rides out into the desert on his motorcycle and plays his guitar, composing songs amid the windswept rocks.

A young mother, whose disease has transformed to something worse after chemotherapy, is in hospice care at home. She is in pain, lymph nodes are pressing on her, but her husband buys her a new coat and the two of them and their three-year-old daughter go to the beach and play in the sand and the waves.

There are more stories like these. I like to keep them in mind. Those of us touched by CLL quickly learn that life is fragile, but these stories also tell me that the will to live is strong and that we are resilient. That at times, even in the worst of times, we can reach ataraxia.

My visit to the NCI, Part 2 - The expert consensus on transplants

Readers will recall that in Part 1, I had approached the National Cancer Institute about a transplant clinical trial, a possible donor had been identified, and I was asked to meet with a transplant doctor to determine what to do next. Marilyn and I set out from Arizona on a road trip to Bethesda, MD, where the NCI -- and possible salvation from CLL -- awaited.

Tucked under the passenger seat of our Prius was a black folder stuffed with articles and studies that weighed the risks and rewards of a transplant. Taken together, Marilyn and I hoped they would help provide an answer to the question: When is a transplant a good idea, and am I at that point? At the very least, we hoped to learn enough to be able to walk into the NCI and have an adult conversation.

The day before our meeting in Bethesda, we sequestered ourselves in our hotel room and read. And read. Avoiding temptations like The Simpsons Movie on HBO, we spent the day awash in Post-Its and highlighters, scribbling notes and occasionally announcing epiphanies.

Some of the articles were especially helpful in getting the lay of the land. Among these were a CLL Topics piece called What Say You Dr. Expert?; an overview by Dr. Andrew Pettitt written for the UK CLL Support Association; and a paper entitled Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus, which reflects the views of European experts (there is no US equivalent). The latter is hard to get hold of but I can send you a PDF if you write to me.

The bottom lines, as near as we could tell, are these (and I would encourage you to find your own hotel and do your own reading and reach your own conclusions):

• Allogeneic transplants are still too risky to undertake without serious thought and thorough investigation. There is a two-thirds or better chance that you’ll get a long term remission or a cure. But it doesn’t take a math genius to realize that there is a fair chance of death or relapse, not to mention the possibility of significantly reduced quality of life due to graft vs. host disease (GVHD).

• Prognostic tests (aka “biological risk factors” or “biomarkers”) alone (FISH, IgVH, ZAP-70, CD38) are insufficient grounds to undertake a transplant, except perhaps in the case of 17p-deleted patients, whose disease is by its very nature resistant to most chemo and likely to be aggressive and result in early death. As the European paper states, “. . . an adverse prognosis suggested by biological risk factors must be substantiated by an unfavorable clinical course.”

• The favorability of your clinical course is generally determined by how well you respond to purine-analogue based therapy (i.e., fludarabine or pentostatin). If you don’t respond well, or if you relapse within two years after combination therapy such as FCR or PCR, you are a good candidate for a transplant. (If you respond to FCR for at least two years, you’ll likely be given FCR again.) A short period (less than 12 months) between diagnosis and the need for treatment is another sign of aggressive disease, though I think it can be argued that since we are all diagnosed at different points in our disease progression, this is something of a moving target.
  
  Dr. Pettitt makes a useful point: “It is very important to remember that the clinical and therapeutic context has a major impact on the prognostic value of some biomarkers. For example the real strength of IgVH gene mutation, CD38 and ZAP70 is in predicting time to progression in newly diagnosed patients with early-stage disease. In patients who have already progressed to the point of requiring treatment, these biomarkers have a relative weak effect on outcome whereas 17p deletion retains its profound adverse prognostic effect. As for patients who are resistant to fludarabine-based regimens, this probably trumps all biomarkers, which therefore become redundant in this setting.”

• The 17p deletion indicates non-functionality of the p53 pathway, in which the 11q deletion is also implicated. The less the p53 pathway functions, the more the body is incapable of killing mangled, mutant cells even with chemotherapy, and therefore the more aggressive the disease. Dr. Terry Hamblin makes the point that “TP53 functional assays might be better than FISH.” Such an assay may be very helpful in further determining whether your CLL is reaching the point of getting out of control. Apparently such an assay is not easy to come by -- welcome to CLL.

• Doctors tend to agree that 17p-deleted patients are better off having a transplant when they achieve their first remission. For the rest of us, they tend to think it should be after the second remission and some might even advise waiting a bit longer, depending upon the patient’s age, general health, prognostics, ability to respond to chemo, duration of remission, and ways in which the disease may be impinging on quality of life.
  
  To see just how unclear the thinking is on this one, the Europeans note: “Although conclusive evidence for CLL is still lacking, experience from other entities suggests that the success rate of the allo-SCT can decrease as the number of pretreatment cytotoxic lines [English translation: chemo regimens] grows. This implies that it might be advisable to consider allo-SCT in eligible patients as soon as criteria for poor-risk CLL are fulfilled. However, the available body of evidence does not allow sound recommendations on this issue.”

• So, in the absence of conclusive evidence, what can we infer from the data we have? Does it make sense to transplant sooner rather than later?
  
  There are two big arguments for not waiting too long. One is that your general health is likely to be better the younger you are, and that means fewer comorbidities and a better chance of successfully undergoing the rigors of transplant. The second argument, and the conventional wisdom, is that CLLers going into transplant with a CR -- which is more likely to be achieved if you have not had too many "pretreatment cytotoxic lines" and become too resistant to drugs -- stand a better chance of success. From what I can tell, this is true. A 2007 study at the Hutch in Seattle showed that none of seven CLLers with a CR relapsed in the first 14 months, while out of 75 CLLers who didn’t have a CR, 31% relapsed.
  
  But that is not the end of the discussion because the risk of death is high enough -- and the success rate of non-CR patients is good enough -- to make waiting a little longer a reasonable course of action for some. It all depends on how you want to play the risk game: transplant sooner and risk not having time you would have had otherwise; transplant later and, having maximized your time already, assume a somewhat greater risk of not having any more of it. This is the crappy craps game you'll have to play.
  
  The European paper has a table that covers seven different studies of patients who underwent transplant. For each study, the percentage of fludarabine-refractory patients is given. I was surprised to see that there were not huge differences in overall survival between studies that had high percentages of fludarabine-refractory folks and those that didn’t. In one study of 73 patients, 82% of whom were fludarabine refractory -- which we can take as a rough guide for how many may have entered transplant without a CR -- the relapse rate was 28% after two years. Indeed, the relapse rate after two years seems to be about 30% in many studies.
  
  Despite the Hutch’s figures on that rather small group of seven patients, there is no guarantee that a CR patient will not relapse. or will not die for some other reason. Having a CR does not protect you from complications and early death (in the first 100 days), which is something around 7%. Nor is it a guarantee against transplant-related mortality, where you might well have a leg up on the non-CR people, but which runs about 15% to 20% in the first two years among all CLLers.
  
  My conclusion is that while a CR is preferable, the desire to attain it does not necessarily trump everything else in making the transplant decision. Statistics are significant from the angle that you look at them. The Hutch study indicates that 69% of non-CR patients had NOT relapsed. The European study shows that after two years 70% out of a heavily-fludarabine-refractory group had not relapsed. My guesstimate is that going into transplant with a CR might add another 10% or 15% to those numbers in your favor. That should not be dismissed, nor should it be seen as the certain difference between life and death. In the end, luck is going to play a crucial role in your outcome.

• For those of us playing softball with CLL by using single-agent Rituxan and the like, it may be hard to define “first” and “second” remission. Most of the experts assume you’ll be using purine-analogue-based combination therapy. How many relapses after Rituxan does it take to equal the “first” or “second” relapse that the experts talk about? All I can suggest is that you look at your ongoing responsiveness to Rituxan, and any additional chemo, as a guide. Eventually, because of AIHA, I needed to graduate to something stronger, the R-C(V)P I had at the end of 2007. I am making an educated guess that my relapse from that regimen will constitute the equivalent of “first” relapse.

• I am making that inference in large part because I seem to respond well to drugs. I always have, be it allergy medication or chemotherapy. The experts agree that disease resistance on the part of CLL will build; the question is at what rate. When there are signs that responsiveness is significantly diminishing, it’s time to think about transplant. Remember Dr. Pettitt’s point about resistance to fludarabine trumping all biomarkers; when the drugs stop working on you, nothing else is going to matter.

• The art of medicine is definitely in play here, as you can tell by reading “What say you, Dr. Expert?” There are the vagaries of the bell curve, the idiosyncratic individual CLL that may give you a break, or maybe not. Ultimately, as I see it, and as I think a lot of the doctors see it, your responsiveness to therapy, your quality of life, and your clinical course and status (e.g, is your marrow still functioning reasonably well?; can you fight off infections?) are the practical factors that outweigh all others. The path to a transplant does not go like clockwork; there is always the need to finesse.
  
  To illustrate that point, here are thoughts from two doctors about the dangers of starting too early and starting too late:
  
  “I had a young patient (50 years old) with unfavorable prognostic factors who was anxious to go to transplant,” Dr. William Wierda of MD Anderson wrote. “He was in CR after his initial treatment. He was transplanted by one of the other transplanters here at MDACC. I was somewhat relieved that he had a sister who was a full match and expected this would reduce his risk for complications. This patient died during transplant, before he had a chance to be discharged from the hospital. I have had many others that have been successfully transplanted, however, this one patient, and the painful conversations I had with his wife after his death, have clearly affected my view of transplant and when to transplant. This is something that I would not like to consider for a 45-year-old with five children.”
  
  Dr. Hamblin points out the dangers of waiting too long: “The thing that stands out for me is that transplanting too late is a disaster. I have seen patients who remain in hospital for over a year after their transplant before they die. They fluctuate between CMV reactivation and GVHD. The treatment for one makes the other one worse. What is common to these patients is that they were transplanted late in their disease.”

• So there is definitely a sweet spot, a best window of opportunity for transplant. Not too early (17p excepted, perhaps) and not too late. While you’re still responsive to therapy, but not while you still have a lot of bullets left. While you’re young and fit enough to cope with the rigors of transplant, but, um, not while you’re young and fit enough to enjoy good quality of life while controlling your CLL with chemotherapy.
  
  To quote Dr. Pettitt again: “At the end of the day, allografting amounts to a big gamble in which short-term risks are traded off against potential long-term gains. The dilemma is not only one of whether or not to have an allograft, but also when to have one. Thus, transplants consistently achieve the best results in patients who have not received too much in the way of previous treatment and are in remission at the time of transplantation. On the other hand, allografting has the potential to shorten as well as prolong life. This is very much an area where there are no clear answers, and under these circumstances patient choice is of paramount importance.”
  
  Which is why I always say: Go with your intuition.

After mulling over these points, Marilyn and I concluded that I was not yet ready to take the leap. While my 11q deletion is not the best of news -- though even 11q is not monolithic, so to speak, and there are better and worse variations that we are only beginning to understand, some of which Dr. John Byrd is testing for at his lab in Columbus -- my better-than-expected response to what was essentially mild chemotherapy was proof that my clinical course was not sufficiently unfavorable, at least not yet, to justify the risk.

Our feelings were validated when we returned home and a new CBC showed that my lymphocyte count was still stable, my red counts had climbed to mid-normal, and best of all I was finally Coombs negative, meaning the AIHA was now less likely to return.

In Part 3, I’ll report on my interview with Dr. Steven Pavletic, transplant protocol chair at the NCI, and his conclusions about my case and insights into the transplant process.