Foggy San Diego, Part 3

A little more than halfway through my appointment, after the background questions and the poking and prodding and saying of ahh, Dr. Januario Castro sat down on his swiveling stool and told me what he thought I should do about my CLL:

Fludarabine.

There is an old Gary Larson cartoon entitled “What we say to cats,” in which the first frame shows a woman talking to her cat. The second frame is called “What cats hear” and the cartoon bubble coming out of the cat’s head is a complete blank.

For a few moments anyway, that scene was repeated at UC San Diego’s Moores Cancer Center, as Marilyn and I sat, dumbstruck, on hard plastic chairs with our backs to the wall.

In retrospect, it should not have been a surprise. As Dr. Castro was quick to point out, fludarabine-based therapy is still the standard treatment for CLL.

“Just looking at you, with some good-sized lymph nodes, I think the time has come where we would probably need to incorporate some reatments that use fludarabine,” Castro said

He sees little merit in Rituxan alone, which I have had three times, as readers of this blog know.

“Personally, I never treat anybody with single-agent rituximab," Castro went on. “I think it’s not enough. With somebody as young as you are, with no other comorbid medical problems, I think that we should aim a little higher than just kind of letting the disease advance and go without a really good control. You know, you can have a very good response to fludarabine. I rarely or never use fludarabine as a single agent. From the data we have recently published by John Byrd and his group at Ohio State University, we know that fludarabine and rituximab (RF) not only obtain a better, total response, maybe a complete response, but also prolongs survival in patients with CLL. I think at the minimum, you should have fludarabine in combination with rituximab.”

It could give me a remission of two to four years, he added. We could consider following it with Campath consolidation, meaning that the monoclonal antibody could be used to (hopefully) eliminate most of the residual minimum residual disease.

Castro thumbed through my medical records. He noted that my absolute lymphocyte count had doubled in less than six months, which, in addition to extensive lymphadenopathy, is another NCI Working Group guideline for treatment. As any good doctor should, Castro follows those guidelines.

“For treatment of CLL we have some guidelines,” he explained. “We treat when the white cell count is rapidly growing and the doubling time is less than six months. We treat when there is anemia or low platelet count or when there are overwhelming symptoms, and you don’t have those. Or we treat when patients have a liver or a spleen that is enlarged. You have a spleen that is about 4 cm below the costal margin and that’s probably creating a little bit of that heaviness, that kind of sensation. But it’s not a huge spleen that I’d say we have to treat you right away for that reason.”

While it is true that my ALC has doubled, it is coming back from my Rituxan treatment in December, which knocked it to within a point of normal. Based on what has happened in the past after other Rituxan treatments, it will probably progress, plateau somewhere between 70,000 and 100,000, and dither around, climbing slowly, probably not doubling again within six months. That’s just a guess, though. As we all know, in CLL things can change. And at any rate, I cannot argue with the fact that I’ve got too many swollen nodes, and therefore that I will need treatment pretty soon.

Filling in the bubble

It was time, finally, for the cat to speak. I expressed my reservations about fludarabine, the same ones I have written about in the blog: Fludarabine, when it comes to potential immune problems, is like Russian Roulette. I am Coombs positive and wish to avoid autoimmune hemolytic anemia (AIHA). I have a history of squamous cell cancers and immunosuppression from fludarabine has been shown to lead to serious, even fatal, cases of those cancers. Fludarabine also selects for 17p-deleted CLL clones, which are the most aggressive and least treatable, and therefore the the last thing a CLL patient needs.

A followup to the Byrd study that Dr. Castro cited examined median progression-free survival (PFS) of unmutated patients treated with RF. It was 31 months, shorter for those with the 11q deletion, which I have recently acquired.

I wondered about the wisdom of obtaining what might be a fairly short remission from a “big gun,” so to speak -- one that is, perhaps, better saved for a pre-transplant situation, should it come to that. I know that this is not the conventional thinking, but I sometimes find that the conventional thinking does not take the long view. Dr. Byrd also once wrote about treatments for those on whom fludarabine no longer works -- those who become fludarabine-refractory, which means everyone who uses the drug. Frankly, it’s basically all downhill after that point is reached.

“I keep thinking I would rather not do fludarabine unless my back is to the wall,” I told the doctor, inching forward in my chair, “and I’m not sure that I’m at that point.”

Castro chuckled. “I have that impression,” he said. As the conversation went on, he assured me I wasn’t crazy.

“I cannot disagree with you, because those are valid concerns,” he said. “The only thing I need to make clear is that the conventional structure of the treatment of a patient with CLL is based on fludarabine.”

In combination with Rituxan, fludarabine, warts and all, is “the best conventional treatment that we have available, that we know can give you two, three, four years of disease-free survival,” he said.

The unconventional route: R+HDMP

I asked about Rituxan plus High Dose Methylprednisolone, which was studied at UCSD in chemo-naïve patients in 2004. I have corresponded with some patients who have undergone this treatment, without serious incident and with good results.

Prior to the 2004 trial, R+HDMP had been reserved as a salvage therapy, something for those who are considered “relapsed and refractory” -- that is, those who have failed fludarabine and who are running low on options. The chemo-naïve protocol used a reduced amount of HDMP compared to that given salvage patients, and UCSD is about to start a new R+HDMP trial for the chemo-naïve that uses more Rituxan than before. UCSD will also be doing a new study of the protocol in salvage patients.

“We are expanding the core of patients because we have had such good success with it here,” Castro said.

An abstract was published for the American Society of Hematology meeting last December, summarizing the results of the 2004 trial. In it, Castro and the other authors reported: “Eighty-six percent of the [16] patients had high-risk disease prior to therapy, as per the modified Rai classification. Fifty-six percent of the patients had CLL cells that expressed ZAP-70 and/or unmutated immunoglobulin variable region genes. . . . Objective responses were observed in 14 out of 16 patients (Overall response rate 93%), with 1 patient achieving a complete response (CR) without disease detectable in the marrow, 1 patient achieving a nodular PR, 12 patients obtaining an excellent PR only with minimal residual disease in the bone marrow, and 1 patient having stable disease, as per the NCI-working group criteria. We observed significant reductions in the white blood cell counts, increases in hemoglobin, elevations in platelet counts, and dramatic reduction and resolution in lymphadenopathy and splenomegaly.”

It should be emphasized that this is a small study of barely more than a dozen patients at a single insititution. While I believe the treatment has merit -- after all, what’s not to like about watching the nodes melt away and substantially clearing the marrow without risking the dreaded 17p deletion -- it has not been so successful everywhere, as Castro pointed out.

“The main thing is during treatment to have a very strong surveillance in terms of potential infectious problems,” he said. “We had a patient with sinusitis, with pneumonia. Outside our institution we had a patient with a bowel perforation and actually we had some patients that died at a different institution. We have treated about maybe 60 patients total and we have not had any single death or any patient with major complications. It is an immunosuppressive kind of treatment so it is something that is supposed to be monitored.”

While I do not know any further details about the patients who died outside UCSD, it is possible they were in the salvage category, and those folks are always at higher risk of complications and death no matter what treatment they receive.

But the moral of the story is to be careful if you decide to try R+HDMP at home, so to speak. The exclusion criteria for the 2004 study were published at CLL Topics and are worth a review here if you are considering this treatment. Castro noted that UCSD is concerned about diabetes and bone densities, and does testing for that. I have also recently read two different anecdotal reports on patient forums about vision problems.

Nothing is without risk in CLL therapy, of course, and taking intelligent precautions is the key to minimizing complications

A little bit pregnant

It turns out, in Castro’s estimation, that I am a good candidate for R+HDMP -- pretty healthy other than CLL, nothing that would meet the exclusion criteria I mentioned above. The treatment could net me a remission of 1 ½ to 2 years, he said. (Perhaps more if I were to follow it with Campath, as many of the 2004 patients did.)

But I can’t do the treatment in a trial at UCSD because I have had Rituxan in the past. This means that I am neither fish nor fowl -- neither chemo-naïve (though I am very close to being so) nor fludarabine- refractory. Every trial at UCSD, including those involving Humax CD 20 and R+AT-101 (Gossypol), is geared toward one or the other. I gather UCSD is not alone in the way these things are set up.

“You are going to have problems getting into a clinical study because you are in limbo,” Castro said. “You are not fully pretreated, you have been treated with something but not the best option available, so that is going to create a problem for enrollment in clinical studies.”

Another possibility is to do the protocol outside the trial setting. While it can be done anywhere by downloading the information off the internet, Castro strongly advised that it be done at UCSD, where they are experienced with it.

Were I to do it -- and it is one of the top contenders as far as I am concerned -- I would prefer to do it at UCSD. Convincing my insurance to pay for an out-of-state treatment is another matter.

Conclusions

What I took away from my visit, aside from some photos of the beach at La Jolla that accompany this post, was the following:

In the USA there are certain hurdles on the track of treatment. The FDA has approved three drugs for CLL: chlorambucil, fludarabine, and Campath.

Chlorambucil is dismissed by most of the experts here -- though not in the UK and some other places -- and therefore fludarabine is at the center of standard, formal treatment. Clinical trials are geared largely to those who have had no treatment, or who have failed the standard treatment. Those of us who spend a lot of time on the internet, and who read about the interesting approaches discussed in such places as CLL Topics and Dr. Terry Hamblin's blog, tend to forget that in the real world, it’s still fludarabine, fludarabine, fludarabine.

But there is also a growing sense that the drug is problematic (except, perhaps, at MD Anderson, which seems almost religious in its devotion at times). This wondering aloud can be found in the writings of Byrd, and in the remarks of Castro.

Castro said my concerns about fludarabine “are part of investigational issues at this point.”

“I don’t think we have a clear, final answer about how fludarabine impacts your immune system,” he said “In the long run, it’s going to be a medication that maybe in 20 years we’re going to say: ‘You know, 20 years ago we used to treat patients with fludarabine and that was crazy because that was creating all these problems that we later on discovered, a lot of immunosuppression, all these patients that were turning p53 (17p) deficient and were selecting only a population of cells that were resistant and then it was very hard to get those patients treated. The current data doesn’t show that is the case, but --“

I assured the doctor that I understood that when it comes to CLL, as my friend Steve Madden says, the answer is always “We don’t know.”

“I understand how up in the air all of this is,” I said, “and I understand that there are no guarantees no matter what, conventionally or experimentally, in a result or in long-term effect.”

As much as it was important to hear Dr. Castro’s take on my case -- I am glad I made the trip to San Diego -- it was also important for him to hear from a patient who doesn’t believe the standard approach is always the best one. I am not the only one with these concerns, or with this view. The more we in the grassroots push for better options, the faster we are likely to have them.

These better options are likely to come from research at places like UCSD, or Ohio State, which is the next stop on my Summer of Advice Tour.

Goodnight, sweet prince

Pyewacket, 1987-2006

The first cat I ever knew who preferred love to food. He has been one of the greatest blessings in our lives. He was our companion, our friend, and our fellow explorer. May your journey be a good one, my sweet Pye, and may we meet again.

These little lights

“This little light of mine, I’m gonna let it shine.” – from an old African-American spiritual

On Saturday night, Greg Martin’s extended CLL family lit candles in his memory. The idea came from a member of CLL Forum after news of Greg's death had been posted there; it was a grassroots gesture of the heart.

I met Greg at the forum, which has only been around since February. Greg was one of the first and most frequent posters, and he felt at home there. He was able to speak honestly and openly about his anger and frustration as refractory CLL and severe ITP eroded his life. He needed constant platelet infusions and, even then, had platelets in the single digits. He also had severe fatigue. He once railed loudly against CLL being called an “old man’s disease” because, at 47, he already felt like an old man. It was the little things that were often the hardest: One day he wrote, angry that his koi pond had to be torn out because he could no longer take care of it.

Greg also wrote with great strength and wisdom, telling us not to be afraid of the prospect of death, or of his decision to go into hospice. As much as we were all surprised at his passing -- which was, thankfully, gentle -- he had done much to prepare us for it.

Greg had devoted his last energies to preparing his family for that prospect, also. He had been a Marine -- he posted a photo of himself in uniform back in the 1970s -- and in his final months he soldiered on with one purpose in mind: to continue working so that his wife could get a nursing degree, so that she could support herself and their sons. Greg told us he would fall asleep at his desk, was so fatigued that he was afraid to drive to work. But he kept putting one foot in front of the other for his family.

Greg also had his hopes, one of which was to take his family to Disney World. A few weeks ago he managed to do it, no doubt creating some wonderful memories that his sons and wife will always cherish.

Sometimes Greg would discuss the details of his disease and the limited options for treating it. He once told me that not everyone with CLL is rich, not everyone can just take off from work and go see all the best specialists. His story is a reminder that there are more important things to some CLL patients than their own conditions, and that for many of us, circumstances can limit our choices.

Greg’s spelling wasn’t great, but he could speak with great eloquence. He was angry sometimes, but he was seldom fearful. Bravely, he prepared us for what lay ahead:

”There is another life after this one this I know with all my heart,” he wrote. “I'll be back after this and may be then will meet again. I've been here before. I found my soul mate this time with Polly. I hope in my next life I'll find her again. When you believe like I do, death is a natural thing and not to be feared. To me there is no heaven or hell, but there is a new beginning, a new journey to go on. In away it's kind of exciting, I only wish I could bring some of my knowledge with me from this life, may-be we do. Genetic knowledge, some animals have it, they call it instinct. Our children are getting smarter so may-be we do bring some back with us. I wish I knew.”

Yet, even as he prepared for the next journey, Greg, like all of us, did not want to be done with this one.

His last post, the day before he died, was under the topic “1001 Things To Do Before You Die”:

“See my grand kids,” he wrote, “watch my sons grow old, see how it feels to be 100, see next christmas.”

As Greg said many times, I will say now: I am so angry at this disease. It is the robber of dreams, and of good men and women.

Foggy San Diego, Part 2

Dr. Januario Castro is a soft-spoken man with a Spanish accent, the product of his Colombian roots. He appears to be in his early 30s, judging from his clear complexion and lack of worry lines. Castro’s white lab coat covered much of his medium frame, stethoscope slung about his shoulders, as he shook hands with us and got down to business.

“Our time today is going to be precious and I hope we can accomplish a lot of things,” he said. During the next hour we were to learn that the doctor is both personable and focused on the task at hand.

As you know from my last blog entry, Marilyn and I went to UCSD’s Moores Cancer Center in search of some answers and options about my CLL. Castro is an assistant clinical professor in the Blood and Marrow Transplantation Division there, which could be a plus down the road if I ever need to take the transplant step. He completed his hematology/oncology fellowship at UCSD, and is board certified in internal medicine and in hematology and oncology. The CLL Research Consortium lists his research interests as “immunotherapy, gene therapy and mechanism of apoptosis applied to CLL.” Basically, he’s devoting his career to the cause.

My main interest, of course, was finding out what Castro thought of my case, and of options for treatment. I brought along a tape recorder, which Castro welcomed, as he doesn’t like patients to focus on scribbling notes at the expense of the conversation. It is his practice to send patients a three-to-four-page dictated synopsis of the visit, so a tape recorder is not essential. But I know from my experience as a newspaper reporter that a recording will be more detailed than notes, and I would recommend recording any important visit with a doctor.

Castro is a second-opinion visit, paid for out of pocket. While at UCSD, I learned that return visits, lab work, and even chemotherapy come with a 30% discount for those in the dreaded self-paying category. I am self-paying here because my insurance is limited to Arizona. It won’t pay out of state without going through the appeals process, and I am likely to get approval only if the insurance company saves money over treatment I would otherwise have had in state. In short, that means they might pay for the ancillary expenses associated with a clinical trial, where the drugs are provided free, but they will not pay for routine treatment outside the sainted borders of the Grand Canyon State. Insurance issues are a headache I can do without, but my experience is not uncommon, and it is a factor in the "where," and maybe even "what," of my treatment.

Case history: nuclear, er nucleus, explosions

The first thing Dr. Castro asked me to do was explain the history of my disease in my own words. Sometimes doctor’s reports are not accurate or thorough, he said, and “you have lived the history of your disease.”

And so, I recounted very briefly what I have explained in detail in this blog, including my diagnosis and subsequent treatments with single-agent Rituxan.

Dr. Castro asked about anemia, low platelets, white blood cell count at diagnosis, symptoms such as night sweats and fevers, and whether I had had any CT scans. He also wanted a detailed recounting of my Rituxan dosages and numbers of infusions.

I had made his job a little easier by preparing a cover letter and some cheat sheets that I included with the medical records I obtained from my local oncologist. The letter explained what I hoped to accomplish with my visit, as well as my reservations about some treatments and interest in others. The cheat sheets came in two parts: The first was a single-page recounting of the results of my prognostic testing. The second was a detailed three-page chart of all my bloodwork since diagnosis, as well as treatment history.

“You have the best summary that I have ever seen,” he said, and I imagine it saved us some time. As he said, time is precious, and I could have used another half-hour on top of the hour I had.

In reviewing my case, Dr. Castro did ask an interesting question about my background: “In your life, have you had any exposure to chemicals, organic solvents, or radiation?”

There has been speculation about the various causes of CLL, and it is interesting to note that researchers are trying to put their fingers on some commonalities. Anyone who has been around the CLL Internetwork has run across stories of Vietnam vets suffering from Agent Orange or workers exposed to benzene or factory chemicals so thick that they formed a haze in the air.

The only thing that may be relevant in my case is the events of July 1962, when I was almost six years old and living along the Colorado River near Parker, Arizona. At that time there was a nuclear bomb test in Nevada, not too far away as the crow flies, and a large swath of the region has since been declared by the federal government to have been potentially affected by fallout. Some “downwinders” in these areas have come down with leukemias and other cancers. The county I was living in was not designated as being at risk for this, but it was adjacent to a county that was. The government has also specifically excluded CLL as being a potential outcome of exposure to fallout, but how many times has the government been wrong about how many things? And does the wind always follow the county line?

Given that it happened when I was young, one would think that I might have developed symptoms sooner had I been exposed, and attributing my CLL to this is highly speculative at best. That is not to say that it couldn't have had something to do with it, or that I couldn’t have picked up a bit of a problem somewhere along the line that my body held in check for years -- before, fatefully, turning its back on the cancer. Some three percent of adults are believed to have CLL cells, but only a few have CLL. The body produces cancer cells daily and the body usually destroys them. When it slips up, shit happens.

During my childhood I also had a severe case of infectious mononucleosis, in which the Epstein-Barr virus invades B cells, and which can be a risk factor for some lymphoproliferative diseases, though not, it appears, CLL. I caught it after having had Thanksgiving dinner at a neighbor’s house. The neighbor was the black sheep of a famous New York publishing family, exiled to teaching second grade in the middle of nowhere. Aside from handing out mono, she was also blissfully ignorant of the rattlesnakes that wandered around the school yard. “If you think it’s a pretty stick,” my mother would warn her, “don’t try to pick it up.”

My mono experience, as well as childhood chicken pox, means that I have some viruses tucked away in my system -- including the Epstein-Barr virus, obviously — and these are waiting to be reactivated by immunosuppressive treatment. Viruses are another theory behind CLL, the idea being that CLL can be an overreaction to the (over)presentation of an antigen. And if that’s the case, who knows what antigen, or when it started.

Dr. Castro jumped to the present day and asked how I felt. Any fevers, night sweats, weight loss? None of the first two and, alas, none of the latter.

How much am I bid for this ZAP-70 test?

The two things that most seemed to intrigue the doctor about me were my discordant ZAP-70 results and the fact that Marilyn and I make a living as eBay powersellers.

There must be something about doctors and eBay, because I once had a primary care physician whose intensity of interest in eBay was not unlike that of a cat following a shiny, moving object. Marilyn’s gynecologist recently spent three-quarters of an appointment discussing the ins-and-outs of eBay, openly wondering about chucking her practice and entering the glamorous world of sitting at home in front of the computer in her underwear. We explained to Dr. Castro a bit about what we sold, the fees we pay eBay, how we interact with customers, field their special requests, and so on.

“eBay is powerful,” he said at one point. The doctor also used it as a metaphor when discussing my ZAP-70 results. Readers will recall from Part 1 that I have had three ZAP-70 tests through Quest Diagnostics, the first two coming out positive and the most recent one negative. Quest is a reputable outfit, headed by Dr. Maher Albitar, formerly chief of testing at MD Anderson.

Castro addressed the issue as part of his general discussion of where things stand in the world of CLL, which he called “CLL 101”:

“It’s getting more recognized that this is a disease where we need to pay more attention,” he said. “Years ago it was seen as a ‘non-important’ disease because patients seemed to be living many, many years with it and the treatment did not make any difference.

“People still argue that patients don’t get a benefit from intense treatment and I don’t think that is the case. I think we are making patients live longer and especially with better quality of life. That’s something that has changed dramatically.

“Analysis of prognostic markers is a major issue and now we have tools that can help us identify patients who can go without treatment for longer periods of time and others who need to have treatment relatively soon after they are diagnosed. We have some information we have published that says that probably the best prognostic marker we have nowadays is ZAP-70.

“The problem with ZAP-70 is that it is a test that is a little tricky to do. There is not a good way to know if it is positive or negative. You need to have your internal controls, there is nothing that you can use that is produced by a machine, to calibrate your machine. It’s more of a human sample versus a human sample. It’s like if someone is telling you on eBay ‘I want a blue shirt,’ it’s like ‘What is blue?’ – it can be a dark blue, a light blue.. . .

“That has created a problem that has been recognized by many people. I know very well Dr. Albitar. He was at MD Anderson. He does a good job. But it is kind of interesting to see that kind of variation that has been reported in your ZAP 70. We have not seen that.”

To help get to the bottom of this, Castro made me an offer I couldn’t refuse: namely a free ZAP-70 test and a free mutational status test at the UCSD lab. This is part of a study by the CLL Research Consortium, in which a patient signs a release and the blood samples are taken (“five yellow-top tubes for Dr. Kipps’ lab”) and given a number to protect the patient’s privacy. The blood is then made available for research, the results of which are not necessarily disclosed to the patient.

“I highly recommend to every patient that I see to get into that study,” Castro said. “We’re going to do some testing, put it in the cell bank and maybe later use it for research type of experiments . . . When we see something that we believe will be beneficial to the patient, we will disclose that information to the patient. The ZAP-70 and mutational status is something that we can give you.”

Both Castro and I now await the results, to see what color blue my ZAP-70 shirt is. UCSD is considered by many experts to be the best place in the country for ZAP-70 testing, so I am willing to accept the result as definitive.

“I have tested samples that are 15, 20 years old, the same patient 15 years apart, and we have not seen variation in the ZAP-70 expression," said Castro. "So I am kind of curious to know. Maybe we can do it sequentially, see if there is anything particular, because of your cells, or if it is something that is more in relation to a variation of the technique that they are doing outside [at Quest].”

Then it was time for a physical exam, followed by the doctor’s recommendations about treatment, and I learned that, metaphorically speaking, I am a little pregnant. (Certainly, with any number of lymph nodes swelling up in my abdomen, I am starting to look that way.) The story of my visit will conclude in Foggy San Diego, Part III.

Speaking of blue, the photo above is lifted from an eBay auction of a few years ago, in which the seller was hawking a "blue fur robe." In it, a couple of eBay captains of industry are seen accompanying their merchandise, plying their trade in informal attire. By the way, there was a "lucky winner," as eBay sellers are prone to say, of this auction. . . . So doctors, is this the life you dream of outside medicine?

Foggy San Diego, Part 1

Ah, the fog. Coming from Arizona, where the sun seems to shine 366 days a year, it was a pleasure to visit San Diego, which was covered in gray, moist fog for much of the four days that we were there.

This is a broad atmospheric fog brought on by the Pacific Ocean, not the thick stuff that lays on top of roads in the middle of the country. The ocean fog is higher up, replacing the blue of the sky, occasionally misting car windows and people’s faces. At night it gives the moon a fuzzy glow. When Marilyn and I arrived at our hotel, bleary after the nine-hour drive, I looked up and noticed a couple of fuzzy full moons. Tired as I was, I knew the Earth was unlikely to have acquired any additional satellites while we were passing through Yuma. Turns out these were white balls on the power lines high above us; in the fog they looked like moons, which contributed to the other-worldy atmosphere.

Coming from a land that is so dry that one can create static electricity while petting the cat, there was something comforting about humid, cool air near the sea. We used to live in the San Francisco Bay Area and on the Oregon coast, so the weather sent us back to the past. They say that smell, more than anything else, can trigger memories. The odor of the ocean, and its fog, brought us back to easier, simpler days.

Those were the days before CLL, which, alas, was the reason for our visit to San Diego. If you have followed this blog, you know that I am searching for the next step in treatment beyond single-agent Rituxan. The Moores Cancer Center at UC San Diego is part of the CLL Research Consortium, and Drs. Thomas Kipps and Januario Castro have done some interesting research and clinical trials that seek a softer-glove approach to our chronic disease. These include Rituxan and High Dose Methylprednisolone (HDMP) in both new and relapsed patients, as well as research into ways to attack the ZAP-70 protein that many of us CLLers unfortunately express.

I have had the pleasure of corresponding by e-mail with several bright and helpful people who have had good experiences at UCSD. While Dr. Kipps is better known, I decided to visit his junior partner, Dr. Castro, for a variety of reasons. The main one is that I felt I would get more time and attention from Castro, who isn’t quite as busy as Kipps. Another is that Castro has done much of the hands-on work with patients in the various clinical trials, and therefore might have detailed and direct knowledge of the results and side effects of the treatments.

The Moores Cancer Center is a large, modern facility, but no more complicated to navigate than your average hospital. The staff was organized and helpful, and except for one obviously burned-out technician in the blood-drawing department, universally friendly. Marilyn and I also received a personal welcome from a fellow patient and UCSD veteran, Lise Rasmussen-Wright. Lise dropped by the waiting room and just as we entered maybe the fifth minute of our conversation, I was called in for my appointment. Apparently one can usually expect to be called in late, and I became perhaps the first patient ever to be called in early, so our visit with Lise was far too short.

After the weighing in, for which I was asked to remove my shoes but not my 40-pound lead belt, and a blood pressure check, from which White Coat Syndrome could be deduced, we were led to the examination room. White Coat Syndrome? Well, here I was, in an institution of the vaunted CLL Research Consortium, about to be seen by a doctor whose name I have actually seen on abstracts.

It is a setting that helped the seriousness of my situation sink in. As we walked across the parking lot toward the imposing cancer center, finished in colors of sea green and sand, I told Marilyn: “I guess this means I really do have a problem.” I am past the point of local doctors in out-of-the-way places telling me that I have the good cancer, and not to worry. What I have merits a big building and busy researchers.

Perplexing prognostics

It would be useful here, before I tell you about my visit with Dr. Castro, to back up for a moment.

For one paragraph, let us return to September 2003, when I was diagnosed. At that time, the only prognostic test generally available was CD 38. Mine came out at 12%, or “negative.” Based on that result, and the fact that I suspected having had CLL since an elevated white cell count in 1996, we assumed my case might be fairly cooperative. It had progressed to the point where my spleen was moderately enlarged, as were many lymph nodes, and my absolute lymphocyte count (ALC) was 130,000. But from what little we could make out in the fog of knowledge, my case did not seem especially aggressive. That view was compounded when I responded quite well to single-agent Rituxan in January 2004. This treatment knocked my ALC down to 2.2 and reduced the spleen to normal. Many nodes, but not the largest ones, also disappeared.

In May 2005, I had Quest Diagnostics run a complete profile on me. Thanks to the negotiating efforts of CLL Topics, Quest prognostic packages had just become readily accessible. Quest is headed by Dr. Maher Albitar, formerly the chief testing dude at MD Anderson, and no slouch in finessing and developing all manner of tests.

The results were a mixed bag: The worst news was that I failed the IgVH mutational status test, coming out as unmutated. ZAP-70 was at 18%, then retested a month later -- long story, don’t ask -- at 27%. Both exceeded the 15% cutoff and made me, sadly, ZAP-70 positive. If there was any consolation, it was that my FISH was “normal” with none of the problematic deletions such as 11q or 17p.

It was becoming apparent that my CLL was a little worse that I had originally figured. But I must insert a big word of caution here: The prognostic tests we have today, as much as they are an improvement over what we had just a few years ago, do not provide a complete picture of an individual patient’s CLL. There are other pieces of the puzzle waiting to be discovered. Today’s tests can also yield contradictory, discordant results -- of which, it turns out, I am a prime example.

The main purpose of prognostics is to indicate which cases are likely to progress. In my case, it is a moot point because my disease had already been progressing prior to diagnosis.

But we are learning now that prognostics can have value in determining treatment, and in duration of response to treatment. Those with 17p deletions have the CLL clones that are hardest to kill, and they don’t respond well to fludarabine. Campath is perhaps the drug of choice for those folks. People with 11q have clones that don’t like to die, and that tend to settle in the lymph nodes. Those with 13q seem to do the best. While most classes of patients can achieve a deep remission with such treatments as fludarabine and Rituxan, the duration of those remissions is shorter in unmutated patients, and in those with 17p and 11q deletions. For an interesting report on this, read Chaya Venkat's review at CLL Topics, which looks at Dr. John Byrd’s study of RF therapy by mutational status and FISH results.

Fast-forward to March 2006. I saw my local oncologist, Dr. Chopin, the one who is leaving her practice at the end of this month. At my request, she ordered the Quest Diagnostics Monitoring Package, which consists of everything but the kitchen sink, which in CLL is the IgVH mutational status test. Since that status cannot change, there is little point in testing it periodically.

The monitoring package retests for FISH, CD 38, ZAP-70, and B2M. When I asked my doctor to order it, I had assumed that things would probably be as they had been last year: “normal” FISH and ZAP-70 positive. I hadn’t had my CD 38 tested in some time, and since it can change with disease progression, I feared that it might be on the rise. (After all, single-agent Rituxan was working on me less well, and for shorter durations.) My doc had checked B2M a few times, and at its worst, just before needing treatment, it had been a fairly respectable 3.0.

Black Monday

The first surprise came tumbling through my fax machine on a Monday, which I nicknamed Black Monday, in honor of the stock market crash of 1929. That, as we all know, led to the Great Depression. I could have fallen into my own Great Depression, but I picked myself up, dusted myself off, and began to figure out how to remake lemonade now that I had another big lemon on my hands: My FISH test was positive for the ATM deletion -- the “high risk” 11q -- on 24% of cells.

In terms of prognostics, my two saving graces had been the “normal” FISH and negative CD 38. Now I had been dealt a serious blow; some 20% of CLLers have 11q. In unmutated patients, where the disease reproduces faster, 11q can be a big problem. (Some of us remember the difficult case of the late Joe Tullman, the original CLL blogger.) But it can also be manageable -- I have two friends with 11q who have kept it under control without resorting to nuclear chemo combos. The other problem with 11q is enlarging lymph nodes: My respectable nodes, which seemed to top out at 3 to 4 cm, might soon get much bigger if the disease were left unchecked.

From Monday until Wednesday, when I got the second half of the results, I assumed the rest of the sky would fall. Progression to 11q is a sign that things are getting worse, not better. And except for a handful of cases, CLL never gets better on its own.

I took a walk in my favorite spot here in the red rocks of Sedona, which ends in a panoramic view of Boynton Canyon. I can sit there, in a quiet and shaded spot, and think.

What lay before me, besides the view, was finding my hope. I believe, as does Dr. Jerome Groopman, author of The Anatomy of Hope, that hope is a realistic path to a better future. I mulled over the treatment possibilities, the debates about burning bridges, the promising new drugs such as Humax CD 20 that are in the pipeline. I wondered, as Dr. Terry Hamblin asks, what is the aim of treatment?

Even before the news of the 11q, I knew that single-agent Rituxan was no longer the best option for me and that I would need treatment of some kind before the end of this year. The arrival of 11q did a couple of things for my thinking: It made me appreciate the idea of thoroughly clearing the nodes, where it tends to hide. It made me that much more wary of doing anything that might lead to a 17p deletion. And the concept of controlling the 11q, specifically, entered my mind. I have since learned, as Dr. Hamblin has written, about PARP inhibitors that may assist cell death in 11q. I also began to wonder about the merits of achieving a deep, deep remission, perhaps one that is negative for minimum residual disease (MRD). The thought was: if I can knock the 11q back while it is still a minority clone, so much the better.

With all these thoughts came a reminder about UC San Diego. In the summer of 2004, UCSD ran a clinical trial of Rituxan and HDMP in untreated patients. It was especially effective at reducing the nodes and spleen, but it also reduced CLL in the bone marrow significantly. Those patients with residual disease in the marrow were offered participation in a subsequent Campath trial, and some achieved MRD negativity. Since then, I have heard of no major complications with HDMP among trial participants, nothing to make me reject it out of hand. Rituxan + HDMP, perhaps with a Campath chaser, seemed like an option. Rituxan + chlorambucil, about which Dr. Hamblin has written, seemed like another.

And then there’s my old nemesis, fludarabine. Despite everything, fludarabine still seemed out of the question. If my back is moving toward the wall, it is not there yet. I am Coombs positive and risk autoimmune hemolytic anemia if I use fludarabine. I am also prone to squamous cell skin cancers and risk those as well (as I might with Campath, too). On top of this, fludarabine-based therapy brings with it a higher risk for Richter's Transformation and acquisition of the 17p deletion (read "Demographics and Clinical Features Associated with Fludarabine-Refractory CLL" here). If there is still some hope of muddling through with 11q, having 17p means a one-way ticket to a risky stem cell transplant. (And guess, of course, what my health insurance expressly refuses to pay for.) Dr. Hamblin has also pointed out that the immune system never totally recovers from fludarabine. It is important to remember that I feel fine, I am not coming down with B symptoms or lots of infections. CLL-filled as I am, I remain more functional than not.

As long as there are any other options, I see fludarabine as an “In case of emergency, break glass” choice. It is something, to my mind, to be reserved for clearing disease before a transplant, if it comes to that.

I know, of course, that this defies the conventional thinking. But the conventional thinking does not take the long view. The median time to disease progression of unmutated patients in Dr. Byrd’s RF study was 31 months. It is no doubt less for 11q patients. Why blow a big gun like that when I can achieve remissions that might last almost as long at much less cost to my body, and that still preserve options such as RF for the future?

With that in mind, as I took in the view of the red and purple canyon (the photo above shows it on a snowy day), I resolved to go to UCSD and ask about R + HDMP specifically and my case in general.

(I also resolved shortly thereafter to visit Dr. Byrd at Ohio State. They do interesting research there, too, and Byrd is about as respected a figure in the CLL world as one can find. I imagine he might challenge my views of fludarabine. I am seeing him next month.)

The wheels in the sky keep on turning

On Wednesday, I received the rest of my test results. I was happy to see that my B2M was normal, at 1.8, which was not too surprising since I had completed Rituxan therapy three months before the test was done. I was quite happy to find that my CD 38 was a paltry 1% -- about as negative as you can get, and lower than it had been at my diagnosis.

But the big surprise came in the ZAP-70 results -- I now tested at 8%, which was described in the report as “borderline negative.” (The cutoff was 10% for shipped blood samples, which mine was.)

The last thing I expected was for the ZAP to go down. I read through the Professors' Posts on the ACOR help page, and I gather that this is a very rare occurrence. It appears that, at first, this wasn’t even believed to be possible. Then it was reported in a small number of cases in Spain. Nobody seems to know much about the whys and wherefores of the change.

I wondered, of course, about testing errors, and recalled the words of one CLL expert as reported by a patient, that the ZAP-70 test is basically garbage at this point. Still, it’s not like I had the test done at Wal-Mart. Albitar and Quest are respected in their field.

And so, there I was, entering UCSD with conflicting prognostics: unmutated and new 11q, CD 38 in the cellar and ZAP-70 apparently heading that way. A disease ramping up and down at the same time.

The ZAP-70 results caught Dr. Castro’s eye, and I’ll tell you about my visit with him in the next installment.