The "new normal," Part 2

My “new normal" began when I was diagnosed with chronic lymphocytic leukemia in the fall of 2003. This new normal has since evolved, or devolved, depending upon how you look at it. Each time I have settled into a comfort zone, things have gotten worse. There’s a reason why my sig line at CLL Forum is a quote from Gilda Radner’s Saturday Night Live character Roseanne Rosannadanna: “It’s always something. If it’s not one thing, it’s another.”

Since my diagnosis, unwelcome new wrinkles have demanded new responses, as well as renewed patience. Required, also, have been constant efforts to find psychic and emotional shelter from a disease that blithely marches on. As I have written here, hope is an active process -- but it is not always an easy one. This is the most challenging year yet, and to understand it, it helps to look back. I have had the disease long enough now to have some perspective on where it has been, and where it may go.

2003

As bad as 2003 was -- I was diagnosed at Stage 2 with swollen lymph nodes and spleen, which threw me directly from the frying pan into the fire -- a few good things came out of it, or seemed to. I learned that I had the inner strength to deal with devastating news and the resourcefulness to learn something about a complicated medical issue. I showed a modicum of wisdom by avoiding the treatment pushed mercilessly by my first oncologist, the fludarabine-happy Dr. Lippencot. I began Googling to save my life, literally, and I discovered that there is a patient community out there full of experienced and knowledgeable people. Largely through their efforts, I found another treatment option, single-agent Rituxan, that would buy me time without burning any big bridges.

In 2003, I also had one good test result -- my CD 38 came back at 12%, or well within the negative range. This was the only prognostic test available to me at that time, and it boded well. And then there was a gray memory that came back into full color: Prior to my diagnosis, my last CBC had been in 1996. I recalled that my white count had been a little high, and that my doctor had told me that it was probably just an infection but that I might want to get my blood retested in a month. His infection comment had struck me as odd, since I didn’t feel as if I had one. But I dismissed his advice, feeling rather immortal. And, of course, I didn’t bother to get a copy of the test report. It no longer exists, since the law requires that these things be kept for only so long, and I stopped seeing this doctor long ago. But what this memory told me was that my disease had not appeared overnight, and that I had likely had it for a long time, during which it had behaved itself for the most part, perhaps slowly building up, as might a more indolent form.

2004

2004 was, in retrospect, a breeze. I began the year with my Rituxan treatment. The progress with which my CLL cells died was so rapid that it created a buzz among the nurses in my oncologist’s office. I left treatment with a normal lymphocyte count, a spleen worthy of an anorexic, and very few visible lymph nodes. I turned my attention to telling my extended family about the disease, and I became involved in reaching out to newbies in the online patient community. Marilyn, Pyewacket, and I even enjoyed a long vacation through the Canadian Maritime provinces.

Upon our return, I underwent a couple of fancy new prognostic tests just made available to my oncologist through Impath Labs in Los Angeles. The first, a FISH test, came out “normal.” This was the second-best FISH result, and it served to confirm my belief that perhaps I had a fairly cooperative case of CLL. After all, my CD 38 was negative, I had evidently had the disease since at least 1996, and while it had slowly built up to Stage 2, it had never sent my red counts or platelets below normal, and I had never had any “B” symptoms. All that, and a mild treatment had appeared to work quite nicely. My lymphocyte count was slowly making its way back up, of course, but that was to be expected with single-agent Rituxan. If my disease could be looked at as a ship -- the SS CLL -- I was standing on the bow and feeling, if not exactly like king of the world, at least that there were no icebergs in sight.

Then the second test result came in: I was ZAP-70 positive. This gave me pause, knowing it was often a surrogate for mutational status. I liked to think then that I had one foot in Chaya’s Bucket A -- the CD 38 and FISH -- and one foot in bucket B -- the ZAP-70 and the fact that the disease had managed to progress to Stage 2. Bucket C was over there somewhere, with flies buzzing around it. And so far, I was avoiding it. At the end of 2004, I joined the board of directors of CLL Topics; there was no reason not to toast the new year with some optimism over a holiday brunch with friends amid the red rocks of Sedona.

2005

2005 sucked, pretty much. If 2004 was punctuated by moments of ease, the year that followed seemed to ratchet up the stress at every opportunity. The new normal shifted from bizarre but comfortable to disquieting. Life with CLL became an unending process of adapting to bad stuff.

The year began with the surgical removal of a squamous cell skin cancer from the top of my head. (“It’s just a pimple,” I had been telling Marilyn. “No, it’s not!” she had insisted. Guys, women know pimples. It’s genetic. Just give in and don’t bother arguing.) I had been reading up on the heightened risk of skin cancer in CLL patients and knew that I was at even higher risk; my skin tone is akin to that of the Pillsbury Doughboy and I have always burned in the sun. In 1999, I had had my first squamous cell growth, a pinkish thing that reminded me of a toadstool, frozen off the side of my face. Now I had a second one, which had implications beyond those of vanity: My CLL-compromised immunity was not stopping the damned things. And treatments that severely impair T cell function -- that’s the thing that keeps those squamous cancers in check -- might be a problem for me. Those treatments include fludarabine and Campath, two of the biggest guns we have.

On top of this, Typhoid Charlene came to visit and gave us colds. I got mine last, and I got over it first -- all of which told me that my immune system was still pretty functional in some respects -- but my lymph nodes ballooned in response. They went back down after a week or two, but provided a visible reminder that my immunity was laboring under a new burden. My immune system was no longer an aerodynamic Prius or a sleek Mustang convertible -- it was, perhaps, starting to look like a clunky and dented 1972 Oldsmobile Cutlass, still making it from point A to point B, but not without some grinding of gears and black smoke coming out the tailpipe.

I received Rituxan again in April and May of 2005; the response, while adequate, wasn’t quite as good as before, and it did not last as long. This implied, of course, that the soft-glove approach might not be effective forever. This wasn't, of course, what I wanted to hear.

And for the first time, prior to starting treatment, I had felt a little pressure in my lower left pelvic region, where lymph nodes had begun to grow. The treatment did not ameliorate it. I was left with an occasional reminder, if I lay flat on my back, that I was sick with something. Slowly, this pressure got worse, until I noticed it when laying on my right side. It is there now, noticeable also when laying on my left side, or when sitting.

Adapting all these things into the new “new normal” took some doing but paled in comparison to the news I would soon get from Quest Diagnostics: my CLL is IgVH unmutated. I still remember the call from my oncologist’s nurse, and I can still see the scrap of paper on which I wrote the single word: “unmutated.” I can also recall the sick feeling I had in the pit of my stomach. “Unmutated” brings with it some “un” implications: “Un-controllable” “Un-stoppable” “Un-likely to have an easy time of it.”

Slowly, as test results had continued to emerge and treatment had became less effective -- renewed Rituxan ending in December fared no better than had April’s doses -- everything I had initially assumed about my CLL started to turn on its head. A newer and meaner new normal was in the offing.

I toasted the arrival of 2006 with trepidation. I told my friends that maybe it would be nice if we could just have a little time without stress, without anything eventful, without something else bad happening. I suppose it was the champagne talking.

This is getting a little long, and so there will be a “The new normal, Part 3," which will bring you up to date on my treatment quest and what the new normal is for me today.

The "new normal," Part 1

The “new normal” is a phrase I run across sometimes in the CLL community. It’s shorthand for what things are like when you are living with the disease. For all of us, the new normal means accepting that we have leukemia, and that this may shorten our lives.

Beyond that, the new normal can vary. Indeed, it is always changing or threatening to change.

For newbies, the new normal may mean coping with shock, traversing the unfamiliar terrain of prognostic testing and blood drawing and busy oncology offices where women with bald heads sit in chairs, their arms linked to bags of fluid on IV poles. The new normal can mean sorting out who your friends really are, who your mate really is, what kind of a work environment you really have -- and that perennial CLL rite of passage, figuring out if your doctor knows his ass from a hole in the ground. It can be stressful and bumpy and yet perhaps strangely exhilarating. After all, when looking mortality in the face, even with a sideways glance, one can sometimes put things in perspective and find ways to live more meaningfully. So, for some, the new normal can be transformative in a good way at the same time that it is fearsome as hell. The new normal is contradictory, and often surreal.

For patients like myself who are past the newbie stage and whose disease is progressing, the new normal can mean arranging your time and finances around visits with experts, who often contradict one another. It can mean serious study about treatment options, none of which is without risk. This new normal means living with a higher level of risk -- risk that the disease could take off even faster if something is not done, or if something particular is done. It means a little more anxiety within the family, an end to the lingering sense of security new patients often enjoy. “Watch and wait” becomes a serious affair and can be akin to sitting in a foxhole not knowing when the first shell will land. In this new normal, time can begin to take on the element of a luxury. For many it is accompanied by symptoms -- fatigue, infections, night sweats, lymph nodes that have grown big enough to hurt, spleens that twinge in the night.

For patients who are at later stages than I, I imagine the new normal can be all-consuming. Heavy-duty treatment, and recovery from that treatment, or complications from that treatment, or the failure of that treatment, all may bring an element of emergency to having CLL that was missing before. Wondering what in God's name is next, searching for something that might work, spending tens of thousands of dollars to find a perfect bone marrow donor, fighting insurance companies, all can be rolled into a ball in which the new normal is little more than a constant state of anxiety -- anxiety carried with you on the proverbial emotional roller coaster with its exhausting ups and downs. For those who have undergone transplants, graft versus host disease is a constant reminder of where the journey has led. And for some, perhaps, the success of a transplant may mean, at long last, the easing of fear, the release of the dragon, a profound relaxation. At any point in the journey, we all enjoy remissions. So successful chemotherapy, too, can restore life almost to its original gait -- until the sword of Damocles returns again from the mist.

And for those less fortunate, for whom the last options have failed, the new normal can mean acceptance that the battle has ended, entry into hospice, precious time spent with loved ones, and then a journey none of us know, but which is likely to be far from anything that seems normal here on Earth.

What is clear from all these stages of the new normal is that once you have entered this world you can never truly go back to the old normal, what life was before diagnosis.

Learning to navigate the new normal can be quite a challenge. Some are alarmed at the first appearance of a pea-sized lymph node, and then they get used to it, and then the lymph node becomes almond-sized. This leads to a bit more anxiety, perhaps a doctor visit, heightened watch-and-wait. Eventually, one can learn that two dozen swollen lymph nodes are the new normal, some as big as a golf ball, some causing pressure or pain. A once-slim neck becomes chunky, the limits of one’s vanity get tested when one is seen in public. The new normal means showing signs that others can see that something is wrong. And yet life goes on, the dog needs walking, the rose bush needs pruning, the bills need paying, the kids or grandkids have birthdays that need celebrating.

In the new normal, time moves both faster and slower. Faster in the sense that there may be less of it than planned, slower in that for many people the adage “be here now” begins to happen, often for the first time. Yet, as much as the new normal can be a place of spiritual growth, or growth by tapping inner resources you didn’t know you had, it can also be a depressing place. For some, this means taking antidepressants, or just dealing with perceived doom through layers of gloom. There are moments, common to us all, when we just sit back and sigh and realize, once again, what a bitch it is to have CLL.

Learning what the new normal is for me has been a challenge, and will no doubt continue to be. As readers may know, I have been searching for the next step in my treatment, and for some broader sense of my long-term treatment plan. I have consulted now with four CLL experts, most recently John Byrd at the James Cancer Center at Ohio State University. In The "new normal," Part 2, I will tell you what I have learned along the way, and what I have concluded -- at least for now, until the new normal changes again.

Hope defined: Groopman's "Anatomy of Hope"

One thing cancer patients do, reflexively, is look for hope. Some turn inward. Some turn to doctors. Some turn to unorthodox treatments. Some turn to God. Some bury their heads in the sand and call it hope.

But what is hope, exactly? And how does it affect the course of disease?

Some answers can be found in a well-written and thoughtful book called The Anatomy of Hope: How People Prevail in the Face of Illness, by Dr. Jerome Groopman. Groopman is a hematologist/oncologist and the chief of experimental medicine at the Beth Israel Deaconess Medical Center in Boston. He has practiced medicine for several decades and for nearly 20 years was a patient himself, suffering from a chronic back condition. Level-headed and science-minded, Groopman provides some insights into what hope is, and what it is not. His search is for the middle ground, “where both truth and hope reside.”

Groopman began his medical career in the 1970s, when doctors were trained to deal with the clinical aspects of disease, not the human ones. There was a tendency to view people as collections of symptoms and test results, passive participants in the medical process. Over time, Groopman realized the limits of his training. He encountered some remarkable patients who taught him a great deal about how human emotions and expectations could affect the clinical outcome of disease, both positively and negatively.

When it came to balancing truth and hope, Groopman as a young doctor went overboard one way, then the other. At first, he avoided telling patients much about their conditions, believing this would foster a sense of hope. When patients became angry and resentful that he had not been honest, Groopman took the opposite tack: telling them the cold, hard facts. This included the now-outdated “you have two years to live” sort of thing, which Groopman abandoned after one patient lived to just the expected two years, after which her family informed him that she had been miserable the whole time, waiting for the clock to run out.

(To be fair, patients do not always agree about what they want to know. In CLL, some patients roll their eyes when they are told they have “the good cancer,” but there are no doubt others who are thrilled to hear it. For some patients, knowledge is power; for others, ignorance is bliss. It is the doctor’s delicate role to finesse each patient’s level of interest and involvement while still insuring that the individual gets a basic overview of the medical facts. This is why the cues you send your doctor -- verbally, emotionally, even in terms of body language -- are so important.)

Eventually, Groopman was to conclude that “omniscience about life and death is not within a physician’s purview. A doctor should never write off a person a priori. At the moment of initial diagnosis, closing off options and denying choices is premature and clinically wrong.”

Exceptions to the rule

Groopman reached that conclusion because he discovered that there are some people’s diseases that “did not seem to read the textbook.” He talked of one patient who “didn’t surrender from the start, and not surrendering has sustained her life.” Another, a fellow physician named George, beat stomach cancer, where the odds were 99% in favor of fatality, through sheer will and excruciating chemotherapy and surgery.

“The mustering of the will to engage the foe and the strength to sustain the battle, in themselves, became a form of victory,” Groopman writes. Later, he adds: “To hope under the most extreme circumstances is an act of defiance that, as George explained, permits a person to live his life on his own terms. It is part of the human spirit to endure and give a miracle a chance to happen.”

These miracles, Groopman takes pain to emphasize, are medical ones, and they are rare. Sometimes hope cannot put off the inevitable, but it can make the road to the end easier. As such, hope can take many forms.

One patient, Barbara, fought her cancer with equanimity and good humor. Groopman detected none of the seesaw of emotions that we associate with such a battle.

“Barbara Wilson’s unique calm and acceptance were present from the outset -- not surrender, but steady realism; she set the parameters on her care with a clear-eyed vision of what was possible, what made sense to her, how she wanted to live, when it was time to die. . . . Barbara did not cling to a desperate belief that I would arrive at the bedside with a cure from the laboratory just in the nick of time, though I deeply wish such a moment had occurred . . .

“Barbara’s hope was real and undying . . . it reflected the fact that she had found purpose and created meaning in her life through relationships with her loved ones, and with her God. Barbara did not dwell on the ineffable questions “Why me?” and “Why now?” She saw death as a natural part of life. It is not necessary to be a person of profound faith to hold this view and to act on it. I sensed that my father had the same approach to life and death. Personal philosophy and experience, rather than faith, seemingly prepared him to acknowledge the reality of his mortality.”

Hope, then, can be seen both in will, and in acceptance. This may seem contradictory, but it isn’t. Hope is what gets us through the experience of our disease. Depending upon our personalities and our medical conditions, it may take different forms.

Searching for the mind-body connection

The mind-body connection comes under scrutiny in the book as Groopman searches for a “biology of hope,” science-based evidence to support the improvements and cures that he has seen defy the odds.

Through Groopman’s interviews with some leading researchers in this nascent field, we learn that some aspects of this biology are coming into focus, though we are far from understanding exactly how it works.

Dr. Bruce Cohen, a professor at Harvard Medical School, talked about mind, body, and soul. Our emotions, thoughts, perceptions, and desires appear to be a product of “mind,” and therefore somehow disembodied, “hovering in an ether several inches above our heads.”

“Of course,” Groopman quotes Cohen as saying, “this is not the case. ‘Mind’ is a manifestation of brain. What we view as products of the mind -- thoughts, feelings, and emotions -- are a mighty mix of chemicals and electrical circuits that have evolved over the millennia, and still are changing. So, too, is consciousness -- our memory of the past, awareness of the present, and anticipation of the future. ‘Body’ includes brain, and thus mind, so that the construct ‘body-mind connection’ only emphasizes the artificiality of how we have traditionally divided them.”

(“Soul,” Cohen added, is something else again, “a fundamentally metaphysical and religious concept where the divine spark resides.” The soul is not the product of “cerebral chemicals and neuronal circuits.” There is no way for scientists to “experimentally locate or characterize such a metaphysical entity. It was beyond science; it was a matter of faith.”)

Cohen recommended that Groopman study the placebo effect, and Groopman details accounts where it has been found to be real. The placebo effect can change the autonomic nervous system, help control asthma, speed recovery from a heart attack, reduce joint pain, and help release dopamine from “untapped” areas of the brain, which is an aid to those with Parkinson’s Disease. Hope can, in actual practice, release chemicals in the brain that make one feel better.

“Within our brains are chemicals akin to opiates,” Groopman writes. “These chemicals are called ‘endorphins’ and ‘enkephalins.’ Belief and expectation, cardinal components of hope, can block pain by releasing the brain’s endorphins and enkephalins, thereby mimicking the effect of morphine.”

There is a flip side. Groopman points out that physical pain and deterioration can feed our anxieties and confirm our worst fears. This has the effect of reducing the outflow of the brain’s “good” chemicals, and perhaps heightening those, such as cholecystokinin, or CCK, which can amplify the pain circuitry.

“This is a vicious cycle,” Groopman writes. “When we feel pain from our physical debility, that pain emphasizes our sense of hopelessness; the less hopeful we feel, the fewer endorphins and enkephalins and the more CCK we release. The more pain we experience due to these neurochemicals, the less able we are to feel hope.”

Sometimes treatment of physical symptoms can help restore a patient’s sense of hope and well-being, presumably with a resulting chemical cascade in the brain.

Take fatigue, for example. This is a common complaint among CLLers, and Groopman uses as an example the case of a depressed CLL patient. Her anemia was gradually worsening, and so was her sense of despair, Upping her dose of erythropoietin, to boost red blood cell production, changed her attitude.

The patient told Groopman she felt better. “I’m still tired,” she said. “But not like I was, so fatigued that I didn’t want to move out of bed in the morning.” Groopman writes: “It was as if the relentless signals from her tissues, demanding hemoglobin and the gift of oxygen, had crowded every corner of her mind and allowed no room for hope.”

Hope deconstructed

It is in his interview with Wisconsin Professor Richard Davidson, an experimental psychologist and expert on positive emotions, that Groopman “deconstructs” hope, getting at its essence.

Hope, Davidson posits, is “an emotion made up of two parts: a cognitive part and an affective part. When we hope for something, we employ to some degree our cognition, marshaling information and data relevant to a future desired event.” A cancer patient, for example, has to generate a different vision of his or her condition. “That picture is painted,” Davidson explains, “in part by assimilating information about the disease and its potential treatments.”

But hope also involves a second component, what Davidson calls “affective forecasting – that is, the comforting, energizing, elevating feeling that you experience when you project in your mind a positive future.”

Together, these components “interweave and modify each other.”

Dr. Antonio Damasio, a professor of neurology at the University of Iowa, argues that emotions are “cognitive guides, fostering the process of logic rather than retarding it.”

Hope and other emotions, Groopman writes, can “powerfully influence cognition and other deliberative feeling. They impact the machinery of perception, the circuits that are used to take in and process data and make decisions.”

In other words, as one of my CLL heroes -- the late David Covell -- once put it, hope is an active process. And an essential one for any cancer patient to get a handle on.

Even before reading Groopman’s book, I had the intuitive sense that hope was more than just an emotion. After reading the book, I think it can be seen as the synthesis of emotion and rational thought into a realistic plan for a better future. Creating this vision allows the patient to be proactive and intelligently involved in medical care. Hope is, perhaps, the difference between wanting to do something, and having to.

As time goes on, new information and circumstances can cause us to adjust the vision that arises from our hope, but as a rule hope stands the test of tough times. Once firmly established, it is hard to uproot.

True and false hope

In his final chapters, Groopman looks at hope as a tool for coping with disease.

“While it is a convenient construct to divide hope into a cognitive and an affective component, the two are tightly coupled. Feelings and emotions mold logical feelings and deliberate decision making . . . True hope, then, is not initiated and sustained by completely erasing the emotions, like fear and anxiety, that are often its greatest obstacles. An equilibrium needs to be established, integrating the genuine threats and dangers that exist into the proposed strategies to subsume them. So when a person tells me that he doesn’t want to know about the problems and risks, that he believes ignorance is necessary for bliss, I acknowledge that yes, unbridled fear can shatter a fragile sense of hope. But I assert that he still needs to know a minimum amount of information about his diagnosis and the course of his problem; otherwise, his hope is false, and false hope is an insubstantial foundation upon which to stand and weather the vicissitudes of difficult circumstances. It is only true hope that carries its companions, courage and resilience, through. False hope causes them to ultimately fall by the wayside as reality intervenes and overpowers illusion.”

I would argue that, in CLL, the bar of “knowing a minimum amount of information” about our diagnosis and its course is far higher than in most cancers. This is simply because, as has been well-established, the disease is idiosyncratic, treatments are all over the map if one treats at all, and even the experts disagree on what to do. Therefore, the cognitive element of hope -- the process of marshaling information and data -- is more complex, but no less essential.

What is clear from The Anatomy of Hope is that we patients cannot sit back and expect hope to happen to us. It is an active process, something we must create, and recreate when necessary. Part of this is learning, part of it is intuiting, all of it is essential if we want to live longer.

Hope is a mechanism that optimizes our ability to function. Groopman calls hope “as vital to our lives as the very oxygen we breathe.” As a doctor he searches for it whenever he sees a new patient.

We patients, too, must search within ourselves for it.

As Groopman concludes:

“Patients are awash in a sea of statements about their emotions and their maladies. For years I diverted or dismissed their inquiries because I did not know how to answer. Now my response is formed by the lessons taught to me by my patients and the stirrings of serious science. I recount some of the narratives here, and say we are just beginning to appreciate hope’s reach and have not defined its limits. I see hope as the very heart of healing. For those who have hope, it may help some to live longer, and it will help all to live better.”

Report from the road

Occasionally, as Marilyn and I traveled the 1806 miles from our home to Columbus, Ohio to see Dr. John Byrd, I wondered if it was worth it. The United States is a big country, and the time away from our business and the expense of travel, as well as that of the appointment, was racking up dollars to match the miles.

Making it brief -- we are still mid-trip, visiting family and friends -- the answer to "was it worth it" is an unequivocal "yes." Dr. Byrd, for those who don't know, works at the James Cancer Center at Ohio State University and is one of the leading CLL researchers/doctors in the world. He is very busy, but he had taken the time to familiarize himself with my medical history, as well as the questions and concerns I had posed in my two-page cover letter. He had obviously given some thought to my case.

Dr. Byrd lives and breathes CLL, knows the facts and nuances like the back of his hand, and has a command of where things stand and where they might go, both for me personally and CLL research in general. During our hour, he spoke directly and succinctly to me as an adult, and I felt comfortable with his sense of judgment. There was no pressure to join any clinical trials, no "cover your ass" suggestions, just an honest give and take.

Like me, Dr. Byrd is a conservative when it comes to treatment. He gave me a few things to think about, which I will continue to mull over in the miles returning home through Tulsa and Tucumcari. My visit may lead to a changed perspective, in some ways. Certainly there are a couple of surprising new entrants and changes in the treatment beauty pageant (see my earlier post "Here they come . . .")

As much as my visit was enlightening, it was also humbling. No matter how much we patients may try to learn, to finesses the choices, to balance the options, there is no substitute for having a doctor to work with who has the expertise and quality of judgment to help guide us through the maze.

If I may paraphrase the MasterCard commercial:

The cost of a tank of gas for a Toyota Prius: $27.

One night at the Best Western Suites in Columbus, Ohio: $70.

A CLL expert who knows what he's talking about with the wisdom to apply it properly: Priceless.

Walking in beauty

As leukemia patients, we face the emotional as well as the medical challenges of our disease. If CLL does anything, it reminds us that we are mortal. For some, this can bring positive changes, and for others it can lead to depression. Sometimes it does both.

There is an ongoing discussion of this at CLL Forum, which is one of my favorite places because people can speak openly and honestly there. This discussion got me to thinking, and a post that I wrote for the Forum says something that I think merits being said here, in a slightly expanded version:

Life is terminal, even for the healthiest of people. Personally, I do not know if I will die of CLL. I may get hit by a truck. I may come down with something else. I may die with CLL. For all I know, there may be a cure in ten years, or I may have to do a stem cell transplant in ten years and it might cure me. None of us knows what tomorrow will bring.

Which brings me to the larger point: Focus on today. Find things to enjoy and appreciate, even the little things that once might have seemed inconsequential. Savor life, not because you have CLL, not because your life will end one day -- and who knows what our journey is after that -- savor it because you are blessed to be here.

The Navajos live not far from where I do. They have a ceremony called the Beautyway (also called the Nightway), which a sick person goes through in order to re-establish balance and beauty in his or her life. This sums up what I think is the best attitude to have toward life, even in illness.

First, here is a little background from a Navajo website:

"The Diné [or "the people," as the Navajos call themselves] journeyed through three lower worlds in various forms of being, faced by many trials and tribulations before they emerged into this world that we call Disoos, the Glittering or Sparkling World. We inhabit the land between the four sacred mountains bounded by the great rivers. The Holy People created this world for us from which we are never to stray and which we must always protect. The Holy People also live in this world, in sacred places, on the mountaintops, in the canyons, and the valleys. They have power over our daily lives by requiring us to walk and stay on the path of Hozhóó (harmony). Each day our morning prayers are said toward the east before the sun rises. We express gratitude for our good life, for our livestock, for our land, and the wonders we live among."

The prayer:

May it be beautiful before me.
May it be beautiful behind me.
May it be beautiful above me.
May it be beautiful below me.
May I walk in beauty.

Here is a discussion of the Beautyway ceremony from another site:

"The reasons why one may lose their sense of beauty, of balance and of harmony are many. But the cure, for the Navajos, is one and the same. One must find the way to Beauty, and if one wanders away from this way, from the Beautyway, then one must re-establish one's link to the natural world in order to regain it.

"To Walk in Beauty means not only walking physically. It also, and primarily, means being in harmony with all things and all people, with all objects, all the animals, all the feelings, the plants, the weather and all the events in your life. It means being at peace, serene in the knowledge that all around you is well and that you are well with everything in your life. You accept and are accepted, there is nothing that pulls you in one direction or the other, the polarities are neutralized, you are one with everything. You are ready to walk in Beauty."

The Navajo beautyway ceremony
(anonymous Navajo author)

In beauty may I walk
All day long may I walk
Through the returning seasons may I walk
Beautifully I will possess again
Beautifully birds
Beautifully joyful birds
On the trail marked with pollen may I walk
With grasshoppers about my feet may I walk
With dew about my feet may I walk
With beauty may I walk

With beauty before me may I walk
With beauty behind me may I walk
With beauty above me may I walk
With beauty all around me may I walk

In old age, wandering on a trail of beauty, lively, may I walk
In old age, wandering on a trail of beauty, living again, may I walk
It is finished in beauty
It is finished in beauty

BLOGGER'S NOTE: Later this week Marilyn and I will drive in beauty to Ohio, where I will consult Dr. John Byrd for a second opinion on my CLL. Given the disruptions of travel, posts to the blog may be a bit irregular during the next few weeks.

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.