Not-so-cold season

My niece Allyson is three years old, an adorable force of nature. She also arrived at our recent family gathering in Florida with a cough. It is hard to get a three-year-old to cover her mouth when she hacks.

Indeed, the family affair was beset by sick people. My cousin had a cough (“Don’t worry, it’s the end of the cold!”). My other niece had the sniffles. My sister-in-law had pink eye, which my stepmother caught, along with the cold that was going around, which was also caught by my brother after the gathering ended.

Here I was, the CLL patient, finding it hard to ignore Allyson when she looked at me with her plaintive eyes and said “Watch TV with me.” A half-hour of SpongeBob later, I wondered how many germs I had contracted. Prudently, when Ally later coughed into the salad bowl at dinner and stuck her hand in to grab some lettuce, I decided to pass on greens for the evening.

It was hard to avoid breathing the same air as the family, so I took other measures in addition to avoiding food that had been sneezed at: Purell, which Marilyn carries with her at all times, became our frequent friend.

And so I have evidently survived the family sickfest as well as two plane flights that involved any number of crying, coughing children, one of whom urinated on the seat in the opposite row. The boy’s father dabbed at it with some paper towels and it no doubt dried, ready to be filled by some hapless passenger the next time Continental used the plane. I remember the good old days of flying, when they actually cleaned the planes between uses, right down to replacing the paper things that were hung over the top of the headrests for sanitary reasons. You could fit into the seats, and they gave you three meal choices in coach. Things have now deteriorated to the point that I would not be surprised to see people boarding with babushkas and chickens. But I digress.

I am happy to be home and healthy, more or less. And the nodes have been cooperative of late; apparently my last treatment stalled them a bit better than I initially thought.

So Marilyn and I are expecting a happy new year, at least for now. It’s snowing in Sedona and we just put 225 auctions on eBay. I am listening to Ignaz Moscheles, who wrote some mean piano concertos. Life is good.

UPDATE: It's January 6 and Marilyn finally came down with the cold and has had it for several days. My father also has the cold and my nephew developed pink eye. This means leukemia boy was the only one not to come down with something. Go figure!

Raff and the struggle of man against lymphocyte

I am listening to the second violin concerto of Joseph Joachim Raff, a Swiss/German composer of the 19th century. One thing that can happen after decades of listening to classical music is that one gets off the beaten path and explores the byways of musical history. Beethoven, heard it. Mozart, done that. Now I have pretty much run myself through the standard repertory and am onto Raff, a fine composer with a gift for orchestration and melody. There is an excellent website dedicated to restoring his reputation, which once loomed as large as that of Brahms and Wagner.

I am a sucker for Romantic-era music, the time that roughly spans 1830 to 1900, and which takes us from Mendelssohn through Schumann, Berlioz, Wagner, Raff, Tchaikovsky, Brahms, and Dvorak. This is when “program music” emerged, in which the orchestra was liberated from the old forms and was used to describe something physical, literary, or emotional: a sojourn in the Alps, the witches’ Sabbath, the love of Romeo and Juliet, a hero’s journey. Proponents of this approach, notably Wagner and Liszt, called it the “music of the future.” Others, notably Brahms, thought it was balderdash.

But it stuck. We would not have film music today were it not for the leitmotivs of Wagner, the Symphonie Fantastique of Berlioz, or the Lenore Symphony of Raff. Lenore is Raff’s best-known work, championed in our time by the late film composer Bernard Hermann. It is based upon a poem about a woman who is reunited with her soldier-love, who turns out to be a little bit dead and ultimately a tad skeletal. In 1872 this was serious art; today it is still fun, right down to the orchestral rendering of the hoofbeats in the “Rapid Gallop of the Dead.”

As was fashionable at the time, Raff often wrote descriptions of his music that were intended to let the listener know what it was supposed to be about. (The downfall of program music is that one usually cannot understand what is being described without the benefit of some CliffsNotes from the composer.)

Concerning his second violin concerto, composed in 1877, Raff wrote, in the flowery language of his era: 1st movement: “You feel your life’s frail bark foundering, the tempest rages, and in vain do you pit your pious courage against the fury.” 2nd movement: “Coming from distant heights, the soft breath of consolation and hope nears; you feel a reviving warmth, and peace enters your heart.” 3rd movement: “The tempest seems about to resume, but you heed it not, for the pain that oppressed your heart has given way to joy and pleasure.”

Someone once commented on my blog and said he was amazed that I managed to somehow turn everything into a discussion of chronic lymphocytic leukemia. Can I do this with Raff’s violin concerto?

Is the Pope Catholic?

Does a bear shit in the woods?

Onward, dear reader!

Infusionary Raff

I brought my CD of Raff’s violin concerto to the infusion room of my hem/onc’s office, where I recently completed my latest treatment, which involved Rituxan dosing on a more frequent schedule, accompanied by some Beta-Glucan on the side. (I described the treatment plan in The Way of the Tortoise, Parts 1 and 2.)

For those who don’t know it -- and, given Raff's obscurity, I assume that is almost everyone on the planet -- the first movement of Raff’s concerto contains what one writer has called a “a quietly beautiful and autumnal melody” that is developed into a chorale-like theme said to represent “pious courage.” (Listen to the first mp3 here, in which you can hear a full statement of it at the end, starting at 1:30.) To me, anyway, the music is affecting, with a heartfelt, longing quality that lifts it from mere beauty to the level of a spiritual cry.

In some ways, Raff’s concerto reminds me of my struggle with CLL: I can feel my life’s frail bark foundering, and I must throw my courage, however pious or not, into the fight. Coming from distant heights, consolation and hope enter. On a mundane level, hope comes from workaday advances in medicine. But on a more profound level, I take consolation in knowing that my struggle for my life is part of the eternal ebb and flow of creation, and that some form of grace may exist at the end of this process. If this is fatalism, it is a liberating kind of it. When the tempest resumes -- the disease again rears its head -- the pain of the struggle is kept in context, my joy and pleasure in life and faith in its course assert themselves. The issue becomes not quantity of time but of qualities that transcends time.

And, so, each of us participates in our own epic struggle, which is what this disease is: a long journey, a vision quest as much as a physical fight, an enforced opportunity to face our fears and find something more powerful, the struggle of the mortal in search of the enduring.

Needless to say, I am a romantic at heart, and I could have been at home in the Romantic era -- had it been accompanied by air conditioning and toilet paper.

My latest treatment

Against this backdrop, and with Raff’s music filling my headphones as I sat in the infusion chair, I proceeded with treatment: The plan was to do Rituxan three days a week for two weeks, 375 mg/m2 each time. To this I added 2000 mg of Beta-Glucan daily, the same product being used in a clinical trial of CLL patients at the University of Louisville, Kentucky.

My CBC was done before each infusion, so I had the opportunity to see what was happening more frequently than in the past.

The treatment, which began exactly one year from the day I had last started treatment, opened with a bang. My absolute lymphocyte count of 153,600 dropped to 48,200 within 48 hours. My chipmunky neck began to slim down. Another 48 hours put my count at 26,600. And that’s about where it stopped. By the middle of the second week I was reaching my Rituxan plateau, both in terms of nodes and counts. This is a place I have reached every time, though in this case it was reached at a higher count -- 22,600 after the fifth infusion versus 5,100 a year ago -- and with somewhat less reduction of nodes. My doctor suggested, and I concurred, that there was little point in doing the sixth infusion. And if Rituxan’s effectiveness was exhausted at this point, adding a steroid to it for a couple more infusions wouldn’t do much good, either.

And so this remission is more imperfect than all the others I have had. I was not expecting great things -- in fact, in a previous post I said I would be happy enough with an old clunker as long as it got me down the road. That is what I got, even if it sometimes seems to resemble the car driven by the Flintstones. Some of the nodes began to return within a month, far sooner than in the past (though the bothersome pelvic nodes I have written about were made a bit more tolerable).

What have I learned?

Keep in mind that I am providing you with an anecdotal report, not a clinical study.

It is possible that I am simply more resistant to Rituxan than I was before. This is consistent with some other case histories I have heard about, in which the drug becomes less effective when used over time. Prior to starting my latest treatment, I had had 20 infusions of Rituxan during the preceding 33 months.

Whether my past response was better because I was less resistant to the drug, or because the usual dosing schedule of once a week for eight weeks simply works better, is a big unknown. Dr. John Byrd, whom I saw in June, expressed a fair amount of faith in his frequent-dosing protocol. Indeed, it is possible that the more intensive dosing brought me a better remission than I would have had otherwise; it is also possible that just the opposite is true.

I do surmise from the huge response at the start, which soon petered out, that my complement may have become quickly exhausted. And/or that Rituxan shaving occurred, in which, overwhelmed by CD 20-Rituxan complexes, my CLL cells were transported to the liver, shorn of the offending pair, and returned to the bloodstream.

I am guessing, but it is only a guess, that had I received an infusion of complement via fresh frozen plasma -- this was tried on one patient in Israel with great success -- my response would have been better and deeper than it was. (Alas, this was not a practical move for me and carries the risk of infection from the donated plasma.) But this idea is not without merit. As Ron Taylor (of complement-depletion-Rituxan-shaving fame) and some colleagues noted in a 2004 study: “Therefore, we suggest that if complement is required to promote killing of RTX-opsonized cells, then use of C2, or compatible fresh frozen plasma as a complement source, may enhance the action of RTX in patients with reduced or depleted complement levels.”

As to Beta-Glucan, there is no way of measuring its effect. Like EGCG, it may work better in some people than in others. All I can say is that it is not, in my case, a miracle "drug," nor is it something I would necessarily use again.

Trial and error is the hallmark of CLL management, it seems. One patient responds well to Treatment A, another doesn’t. One develops resistance to a drug sooner, another does later. We can get some clues as to how we will respond from a FISH test, for example, but there are still no guarantees. Our heterogeneous disease, which runs the spectrum from the merely irksome to the immediately life-threatening, makes each patient a laboratory of one.

Looking ahead

It is clear in my lab that the next step has to involve something equal in power to Rituxan, not just a booster on the order of Beta-Glucan, EGCG, G-CSF, or GM-CSF. I meet with my doctor in January and expect, unless the unexpected happens, that we might aim for some kind of treatment in April or so, which would be six months after the conclusion of the last one. Rituxan will still be part of it simply because it seems to potentiate all other drugs in CLL therapy, I am still responding to it to some degree, and it remains the least toxic of the available treatment drugs.

What to add to it? The candidates are simple: a fairly high-dose steroid, mainly useful for reducing nodes. Or chlorambucil (CB), perhaps with a little dexamethasone added. The dex, aside from its node-reducing properties, may help protect the bone marrow from side effects of the CB.

(And before I go any further, let me state the obvious, which does need repeating from time to time: The opinions expressed in this blog are mine and may not be right for you. As with any treatment choice, I urge you to do your homework, consult with your doctor(s), and reach your own conclusions.)

Internet-savvy patients are familiar with the Rituxan + HDMP (High Dose Methylprednisolone) trials at UC San Diego, which are sometimes followed with Campath to solidify responses. Much has been written about R+HDMP, pro and con, and I have personally gotten earfuls from both sides of the argument. The bottom line, as I see it, is that chemo-naïve patients at UCSD seem to have had some good success with it. We CLL patients live in a world where there are few elegant choices. Everything carries some risk. R + HDMP, on the sliding scale of crap that can happen during and because of treatment, is preferable -- if properly managed -- to anything involving fludarabine, IMHO. If my real-world choice boils down to R + HDMP or RF/RFC, I know which one I'll take.

Dr. Michael Keating at MD Anderson is trying a “mini” version of R + HDMP, one that may have fewer problems in terms of steroidal immunosuppression (and which probably will be less effective as well). Nonetheless, it may be enough to keep me going, and to allow me to test the waters in steroid-land to see how well I can handle it given my skin cancer issues. The Keating protocol is Rituxan once a week for four weeks at 375 mg/m2 along with 500 mg of Solumedrol each week, Solumedrol being the trade name for methylprednisolone.

Alternately, I could forget the Solumedrol and add dexamethasone in node-busting dosages. But a synergy between Rituxan and methylprednisolone has been demonstrated, while its effectiveness with dexamethasone is, to my knowledge, less certain.

The other option, R + CB, may be especially useful if my marrow heads south. (So far it is holding on, but my hemoglobin has slid into low-normal -- the 13s -- from middle normal, where it had pretty much been since diagnosis.)

R + CB has been advocated by Dr. Terry Hamblin, my favorite CLL expert, and used successfully by any number of patients. My main concern here is whether it would be mutagenic, putting me at risk for developing a p53 (aka 17p) mutation. There is a study that shows that alkalyting agents, namely chlorambucil and cyclophosphamide, may be implicated in this; p53 deletions were found in 18 out of 62 patients treated with those alkalytors, compared to 4 out of 60 “alkalytor-naïve” patients. Using low-dose chlorambucil may minimize this risk, but provides no guarantees. And p53-deleted CLL is the most drug-resistant and the hardest to kill. To borrow another Romantic-era musical metaphor, think Gotterdammerung.

A final consideration is that "mini" R + Solumedrol or R + dexamethasone still leaves in reserve the possibility of 1) using full-fledged R + HDMP, and/or 2) using R + CB and getting the full benefit from the CB. So one might argue, logically, that when playing for time and looking at unburnt bridges, R + a non-high-dose steroid might be the better next step -- provided it appears to be up to the task at hand.

And what about the combination plate special (or WEP, for Whole Enchilada Protocol), if something pretty serious is needed: Keating’s “mini” R + Solumedrol with some chlorambucil thrown in?

I will, of course, seek to answer these questions to the best of my ability. And I will, when the going gets rough, turn my ears to Raff. He wrote more than 200 works, many of which have now been recorded. His sixth symphony is subtitled “Lived, strove, suffered, fought.” Sounds like music for CLL.

A HOLIDAY NOTE

This is probably my last post of the year. Marilyn and I have relatives to visit, places to go, and work to do. On December 26, we celebrate the High Holy Day of the eBay calendar: 10-cent listing day. For some reason, the week after Christmas is always our best (and busiest) week of the year when it comes to auctions. So I will see you in the new year, and I wish you all a joyful and happy holiday season. May Santa bring us all spontaneous remissions!

First blogiversary

Yesterday marked the first anniversary of CLL Diary. One year and 57 posts later, I am amazed that I still have anything to say.

When I started this blog I didn’t know how it was going to work out. I figured I would just tell my story as I went along, pretty much stick to the subject of chronic lymphocytic leukemia, and let it go from there.

I am pleased with the response I have gotten. I know the blog has been useful to many of you, both from your comments here and in private e-mails. (It has also occasionally annoyed somebody, but what good would it be if it pleased everybody all the time?) There have been more than 15,000 visits to CLL Diary during the past year, and the number has increased steadily over time.

One effect this blog had was to inspire others to take the plunge into the blogosphere, most notably Dr. Terry Hamblin, whose Mutations of Mortality is a must-read for CLL patients. My friend Steve Madden also started his own blog, then went on to found CLL Forum, so he can be forgiven for putting the blog on the back burner. John Wagner, another friend and fellow patient, maintains an excellent blog, and there are other fine examples that I am pleased to share with you -- see the links on the right side of this page.

One thing I swore to do when I started blogging was to be honest. This is not always easy. Who wants to admit that their supposition was wrong, their choice mistaken? There is a certain degree of personal exposure that comes with this territory and it is not always comfortable. But if this blog is to be of value, it has to tell the whole story. If this shows me to be someone who absorbs new information and changes his mind, someone who experiences self-doubt, someone who undergoes the downs as well as the ups of life with CLL, then so be it. I have never claimed to have the truth in a bag. I am simply one person struggling with a disease that threatens to take my life.

Earlier this year I bold-faced my disclaimer, which you can see at the bottom right: “I am not a doctor and I do not play one on the internet.” I think this point needs emphasizing. I am a fellow truth-seeker, someone on the same journey you or a loved one may be on. I have no medical training. I am a guesser. At times I may be an educated guesser, but I am only that.

Dr. John Byrd told me in June that “CLL is a long journey.” It was interesting to hear an expert put it in those terms but his words resonate with me. For most of us it is, indeed, a long journey. When doctors call CLL “the good cancer” they are grading on a curve. Many other cancers bring about ends that are far more abrupt. (I recall my chemo-room neighbor Lynn, who had pancreatic cancer and whom I wrote about this past year.) CBS newsman Ed Bradley lived for 18 years with CLL. I am only guessing here, but I believe I have lived with it for 10. There is no good cancer when it happens to you or someone you love; but the decade or two that most CLLers are granted are lifetimes compared to the spans allotted to many of our compatriots, which can often be measured in months.

When it comes to my CLL journey, the future holds both wonders and monsters a lurking. I have wandered along for three years now using single-agent Rituxan, which is still sort of effective but is, as decorators might say about dated furnishings, a bit tired. During this time HuMax-CD20 has been developed and is nearing the marketplace. Other targeted therapies of promise are in the works. We can never know when a stroke of luck, or a stroke of genius, on the part of a researcher somewhere will lead to a new lease on life for us all. More likely, hard work will lead to incremental progress, and I am grateful for anything that will help.

While science progresses, so does the disease. It is reducing my immunoglobulins, perhaps starting to clog up the marrow, turning my once fine immune system into an old clunker that is barely roadworthy. The spectre of more frequent infections lurks, and with it a change in consciousness: I am not immune, and when I pick up a bacterium or a virus I am in danger. This is not something to look forward to, this slow decline. But I am still in the beginning, or at least the early middle, of my journey. Hope is my walking stick, even as I suspect that the climb is unlikely to get easier from here.

Medical matters are only part of this trek. Part of it is emotional, part of it spiritual. I have suffered the initial shock, the fear of dying before what I had always thought of as my time, the joy of remission, the disappointment when a test brings bad news. I can get depressed about all this, and I can live in la-la land and forget about it for awhile (road trips are wonderful for that). But most of all I just put one foot in front of the other and keep plodding away. This is one reason, in addition to my conservative approach to treatment, that I have chosen the tortoise as a metaphor for my approach to CLL.

Another way of coping, another part of the journey, is reaching out to fellow patients and their caregivers. I have always been an empathetic person, probably too sensitive for my own good. As a CLL newbie, I learned how difficult -- how terrifying -- the start of the journey could be. As I made my way, I felt the need to reach out to others who would follow in their own paths, whose earths had also been shattered one day by a phone call, or a doctor leaning forward in his chair and saying, “You have leukemia.”

This blog and my other activities in the CLL community -- I am a moderator at CLL Forum, which now has more than 1,000 members, and I also serve on the board of directors of CLL Topics -- allow me to help as best I can, to share the fellowship that only those of us fighting in this war can know, and to learn from others. Indeed, this blog is the product of a community of knowledge.

And so this blog is a spiritual act, and also a way of coping, of focusing on what to do, of sharing our common experience.

There is a further spiritual dimension that steadies me as I put one foot in front of the other.

In my life I have walked to the falls in Yosemite and paused below their streaming thunder on a starlit night; I have walked through the damp coastal redwood forests of California, smelling the incense of pine and hearing the call of crows; I have walked across the red earth of Sedona below spires of rock on which petroglyphs have been etched by travelers of centuries past; and I have walked on ancient paths in France, shaded by trees that have stood for centuries and looked down upon passing knights and priests, peasants and kings.

My CLL journey is made easier by recognizing, above all else and in spite of everything, the beauty of the spherical cathedral in which we are privileged to live.

Will you marrow me?

Every once in awhile a piece of paper crosses your desk that you know is going to have a big impact on your life.

When a fax arrived in 2005 with the results of my IgVH mutational status test, I knew the information it contained was going to tell me if my battle with chronic lymphocytic leukemia would likely be an easy one or a hard one. The news was bad -- unmutated -- which means treatment and retreatment and perhaps, in a last roll of the dice, a stem cell (“bone marrow”) transplant.

Another momentous fax occurred just recently, while I was undergoing my latest round of Rituxan treatments, on which I will report in the near future. With IV pole in tow, I was returning from the bathroom to my recliner at the infusion room of my hem/onc’s office. There, on the little swing-away table attached to the chair, on which I usually rest crossword puzzles, had appeared another fax, stapled with four pages.

This one was from the National Marrow Donor Program (NMDP). As readers of this blog may recall, Dr. John Byrd advised me to have my HLA typing done, followed by a preliminary search of the worldwide bone marrow donor database, of which the NMDP is a part. This database is a listing of more than five million volunteer stem cell donors and cord blood units in 43 countries.

Finding donors is really an ethnic matter and I am an ethnic mutt. Half of your HLA tissue types come from your father, half from your mother. My father’s side is Russian Jew and my mother, now deceased, was adopted. I never knew her background for sure, but some digging years ago led me to the conclusion that she was probably Irish, or certainly of British Isles stock. Historically, there has not been a lot of intermingling between lassies from Limerick and Jewish hoteliers from Novosibirsk. And Ashkenazic Jews, while whiter than white, maintained their own communities for centuries and are rather distinct, biologically, from other Caucasians in Europe. All us white folks may look alike, but we’re not.

My prospects are still better than those of any number of ethnic minorities. African-Americans, for example, have less of a chance of finding a match, so much so that the NMDP is trying to encourage more African-Americans to become donors. It currently costs $52 to join the registry and be tissue-typed, but there are discounts for what they call “needed minorities.”

What the search is all about

Even before I met with Byrd, I had been gathering that a stem cell transplant could be in my future: If you are younger than about 60 and have progressive CLL, which comes with being unmutated, you may well need a transplant when all the alternatives have been exhausted. Stem cell transplants can give you a new lease on life, literally.

They are risky, of course, and can end in death; but the good news is that in the majority of cases they can provide lengthy remissions and even cures. It is a true roll of the dice, and the odds are improved if you have a matched universal donor, or MUD, someone who is not a relative and who matches your HLA tissue type in as many ways as possible. (Indeed, even people with the worst CLL prognostics can be cured by such transplants, which are known as allogenic; the success rate is not as good using cells donated from relatives, and even less when one undergoes an autologous, or self transplant, in which you donate your own stem cells.)

HLA stands for Human Leukocyte Antigens, which are proteins on the body’s cells. Obviously, if you undergo a transplant and the new cells don’t match the old ones well enough, the body says, “Hey, are you trying to kill me?” and rejects the cells. Thus the need for as good a match as possible. The less perfect the match, the more the odds of success are reduced.

Having your HLA typed and doing the database search is the first step when you need a transplant. But it is also helpful to know the results if you are formulating a long-term treatment strategy, one in which a transplant may become an issue down the road.

Getting some idea of whether there may be a good donor match if and when the time comes can influence your treatment choices. For example, if there is likely to be a match, you may want to save some big chemo guns for your pre-transplant remission, when it is important to get as much clearance of the CLL cells as possible. Campath is one drug, for example, that is used to mop up after therapy, making you as free of CLL as you are likely to get. If it appears there may be no match at all, then you might take a different tack on treatment, perhaps consider using Campath earlier on as part of a program to stall disease progression. All these things vary with the individual, of course, but you get the idea.

Getting it done – cheap!

The good news is that anyone with $165 and a cooperative doctor can learn their basic HLA type and have a preliminary search done.

The place to start is the NMDP’s Office of Patient Advocacy. I cannot say enough good things about these people. They will answer all your questions and send you enough printed material that it might, if stacked end to end, reach the moon. I have spoken to case workers from the office on three occasions, and they have helpful, pleasant, and professional each time.

One of the most useful things they did was recommend Tepnel Labs for my typing test. Since my current health insurance plan does not cover HLA typing (or transplants, for that matter) I am an out-of-pocket player. City of Hope wanted $1600 to do the test. Tepnel will do it for $165. They send a kit to your house, you swab the inside of your cheeks, then return the packet to them by FedEx. After about a month, Tepnel sends you a report listing your HLA typing, which is completely incomprehensible. At your doctor’s request, the NMDP can then run what is known officially as a preliminary search of the donor database, matching your incomprehensible HLA codes against those of others. There is no charge for this. And finally, one day when you are distracted doing something else, a potentially life-changing piece of paper arrives.

It should be emphasized here that the preliminary search is just that, preliminary. It is done by what is known as low resolution typing and on what are regarded as the six most important markers (A, B, and DR, and we each inherit a double set of these).

If you go ahead with the transplant search -- this is known as a formal search -- the pool of potential donors will be narrowed. Your transplant team will request a test on higher resolution, which could reduce the field, and they may look for a stronger match -- a 6/6 might work, but a 10/10 is even better. And matching isn't everything; matters such as infectious disease histories can come into play. For example, if you are negative for the cytomegalovirus and your potential donor is positive, it may not be a good idea to use that donor’s cells. This next step in the search process can cost $30,000 or more, and the transplant itself can run between $300,000 and $400,000. (At this point, yours truly will be working as the world’s most churlish Wal-Mart greeter, if that’s what it takes to get insured for a transplant.)

My results

As I shuffled back to my chair, I knew what awaited me, since my doctor and I had been talking about it recently and we expected the results any day. I sat down and settled in, careful not to kink the IV line, and picked up the fax.

Out of five million adult stem cell donors in 43 countries, a total of 17 were potential matches on 6 of 6 points. On 5 of 6, the total was an additional 668.

This was good news. The sea is not swimming with donors for me, but I do have a pondful; there are enough potentially perfect matches that I might find a decent one when the time comes. People drop out of the database -- reasons include pregnancy, flying anvils, reaching the age of 60, which is when a donor’s cells are not considered to be useful any longer. And new people join. But I can reasonably assume that, if and when the time comes, there will be between 10 and 20 potential 6/6 matches for me -- perhaps more, as the number of donors has only grown over the years.

There are those who come back with hundreds of matches, and those who come back with zero. In a subsequent conversation with a NMDP patient advocate, she described my results as “hopeful.” However, the pool is still small and it is possible that no 10/10 donors will be found. A cord blood transplant remains another option, and the NMDP will report those matches to you as well. I had no 6/6 but hundreds of 5/6, and in cord blood transplants you can get by with a 4/6 if the cords are large.

At least I now know that a transplant is a realistic option for me. You cannot roll the dice without having dice to roll.

RESOURCES

The National Cancer Institute has a presentation that walks you through the basics of stem cell transplants, complete with plenty of big cartoon pictures to illustrate the main points.

UPDATE

If you know your HLA typing, the National Marrow Donor Program now allows you to run a preliminary search for 6/6 matches in its registry. I just ran mine and found that I am up to 22 potential 6/6 matches, an increase of five in about a year. For more information, go to this page.
-- September 21, 2007

The midterm elections

I pretty much stick to CLL in this blog. I try to avoid politics because it is divisive, and because I think we CLL patients need to put our common cause first and all else second. (If you want to see a great example of this, go to CLL Forum, where conservatives and liberals coexist in good-natured friendship.)

But it is in the spirit of our common cause that I am now venturing into, ahem, politics.

On Tuesday, November 7, American voters will go the polls to choose 435 members of the House, a third of the Senate, and any number of governorships. In Arizona, we are also voting on 19 ballot propositions. In Sedona, we are even electing the board that oversees our fire department. There’s a whole lot of votin' to do!

The purpose of this post is to urge you to vote Democratic. Not because Democrats are perfect and Republicans are evil. Not because of the mess in Iraq and George Bush’s insanity, which is defined as doing the same thing over and over and expecting different results. Not even because it is time that we had some checks and balances in our government, which our founders intended, as opposed to one-party rule.

I am urging you to vote Democratic because, as the slogan goes, the ass you save may be your own. Ask yourself: Which party is more likely to fund medical research? Which party is more likely to insure access to health insurance?

If you answered “Republican,” BONK!

Did you know that George Bush has proposed a cut of $40 million in funds for the National Cancer Institute in 2007? And that the NCI funds the CLL Research Consortium? The Consortium's 4-year grant from the NCI has expired. My understanding is that this funding has not been renewed. And while the Consortium isn’t going away, it’s not getting much help from the government anymore, nor will it with Bush and the GOP calling the shots.

In April, acting NCI chief Dr. John Niederhuber gave a talk at MIT. “The NCI’s stagnant budget," it was reported, "which was about $4.8 billion in fiscal 2005 and fiscal 2006, doesn't keep up with inflation, so the funding actually amounts to a deficit, Niederhuber admitted.”

In October, from another report on Bush’s $40 million cut:

“That funding cut, argued Martin D. Abeloff, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital in Baltimore, will have a devastating effect on the progress of research of new cancer drug therapies.

“In an era when death rates for breast, colon, and lung cancers are declining and new targeted therapies for rare cancers [such as CLL] are on the 'cusp' of development, he said, 'this couldn't be a worse time' for a decrease in NCI funding.

“Many 'world-class scientists,' Abeloff maintained, already spend much of their time on writing grant proposals rather than on essential research activities.

“And their 'reward,' he lamented, is that less than 10% of those grant proposals get funded.”

Now, which party is more likely to restore that $40 million? Which party is more likely to increase funding for cancer research? Yes, the party that has traditionally taken an interest in health care and social programs. Vote Democratic and restore the $40 million; vote Republican and make Bill Gates’ multi-million-dollar tax cut permanent.

Let’s look at another issue: access to health insurance. Some 50 million Americans are without it. What have the Republicans done about this since Bush took office? Nothing. What will they do? Nothing. And if you're having trouble paying skyrocketing premiums? Nothing.

The Democrats are not going to turn our health care system into a government-run nightmare (as opposed to the privately-run one that we have today). Bill Clinton learned the hard way that powerful interests will block any attempt to establish a national single-payer system. But Democrats will make reforms, they will try to address the imbalances, and if they have the votes they will eventually insure that all Americans have access to insurance coverage.

Pre-existing condition such as CLL preventing you from getting care? The GOP doesn’t care. A longstanding Democratic proposal has been to let people in their 50s buy into Medicare. In 2004 John Kerry wanted to let people buy into the same federal program that senators and congresspeople get. If Mark Foley comes down with CLL, he’s covered, even now that he has quit his job. What about you?

I’m not talking about people wanting free health care. I am talking about people who can pay being denied coverage for pre-existing conditions.

This is personal. I am self-employed and my insurer won’t cover stem cell transplants. What do you think my chances are of finding an insurer or a program that will?

Better under the Democrats.

RESOURCES

Advocacy page at the Leukemia and Lymphoma Society website.

The President's Club

During a recent visit to my hem/onc’s office I noticed that my medical file is now about the size of a phone book for a mid-sized city. It is larger than most of the other files that I see stuffed sideways into the open-faced cabinets arrayed in back of the reception desk.

And so it occurred to me that as a patient with a chronic disease who needs treatment regularly and who has a fairly long life expectancy, I am a cash cow in the cancer business. Most other patients at this office either beat their cancer, or don’t, and their files probably cover fewer treatments over a shorter period of time. Having chronic lymphocytic leukemia makes me a frequent flyer, so to speak, a prize customer.

So where are my rewards? I mean, airlines have private lounges for their best customers. Even Camping World has something called the President’s Club. Why not a President’s Club for CLL patients?

For example, I might enjoy a private infusion room -- nay, suite -- with a genuine leather recliner, none of that vinyl stuff. And why can’t my IV pole be at least gold-plated? Where, oh where, is my plasma TV? My private nurse? The dessert tray, fer chrissakes?

“Champagne with your Rituxan, sir?”

“Don’t mind if I do.”

Clink!

But no, I’m stuck in there with the hoi polloi, some of them using cheap, off-patent drugs. I am a Rituxan user. My insurance pays $5,000 a pop for this stuff; in the last three years I have brought this office around $150,000 in gross income. Yet the management is forcing me to root, raccoon-like, for bags of peanuts from an oversized communal snack basket. What is this, the Motel 6 of oncology?

In all seriousness, or at least partial seriousness, there are times when having CLL can be used to one’s advantage. After one recent Rituxan treatment, Marilyn and I went to our favorite hotel in Phoenix. I plopped my bandaged hand on the counter and announced to the twenty-something clerk that I had been doing chemotherapy and that I needed a quiet room in which to rest. This led to a free upgrade.

When Marilyn and I flew to Florida recently during the height of the gels-on-planes scare, we were able to bring a bottle of Purell hand sanitizer on board with us. This required showing the TSA guards a report stating I have CLL and am immune-compromised, which was backed up by me pointing to my neck and saying, “It looks puffy because I have swollen lymph nodes from my leukemia.”

Indeed, at the Miami airport one of the Northwest Airlines clerks fell all over himself being helpful and gladly agreed to give our bags priority handling even though we weren’t flying first class.

The best story I’ve heard came from a fellow patient in the infusion room, not a CLLer, who lost her hair to chemotherapy. While speeding down the freeway, she was pulled over by a cop.

“Officer,” she said, whipping off her baseball cap to reveal her bald head, “I am late for my chemotherapy.”

It worked, of course. No ticket.

Let that be an inspiration to you the next time Cytoxan does nasty things to your hair follicles.

And while I still wish I could get a complimentary foot massage while being hand-fed Godiva chocolates, I'll take what I can get.

The way of the tortoise, Part 2

It was Churchill, I think, who said that democracy is the worst form of government, except for all the others.

The same could be said of Rituxan and the other CLL treatments. Rituxan is imperfect -- effective in the peripheral blood, only mildly effective in the marrow, chancy in the larger lymph nodes. Other things work better, but at a far greater cost to the immune system. To put it another way, Mussolini made the trains run on time, but was it worth it?

Looking at my situation, the question is: “What really needs to be done?” Not “What could be done if I wanted to do the most possible?” This is an important distinction for a tortoise, or any CLL patient, to make.

So, what needs to be done? The lymph nodes need to be reduced, the spleen needs to be reduced, and the marrow needs to keep treading water.

I have written about my bothersome pelvic nodes. It has been a year since I last started Rituxan maintenance and I am getting rather chunky all over. (Only part of the blame can be placed on excessive consumption of Tire Tread licorice.) The discomfort in my lower left side will only get worse the longer I let things go.

So, how far do I let things go?

Letting things go was Dr. John Byrd’s suggestion to me, and at first I was rather taken with it. Letting the nodes go to 10 cm, double the size of the largest ones I have now. Letting my platelets and/or hemoglobin drop below normal. Letting my spleen get big enough to press on my stomach, making me feel full. Then using his protocol of Rituxan three times a week for four weeks, which he said would have a 40% chance of giving me a partial remission for 10 months. And, afterward, hope that something else would come along, maybe start thinking about a transplant, for which I would need RFC as preparation.

For awhile there I was tempted to put my head firmly in the sand and say “the doctor told me not to worry,” but then I started thinking. (Damned brain!)

The thing is, I am not so anxious to get a transplant. And I see HuMax-CD20 on the horizon. It should provide better disease control than single-agent Rituxan, which has itself probably kept me in Stage 2 and feeling pretty healthy for almost three years now. I can see myself going several more years controlling the disease with better monoclonals before even thinking about starting chemotherapy, let alone a transplant. This is called playing for time.

In Part 1, I talked about how science presents data, but is at a loss when it comes to value judgments. As much as it pains me to disagree with some of Dr. Byrd’s analysis, it has come to pass. Above all other considerations, I must make what I feel is the best value judgment, and I must remain true to myself.

I read Dr. Byrd’s single-agent Rituxan study. In it. 56% of patients at Stage I/II responded to the treatment; that number dropped to 42% of Stage III/IV. Similarly, there was a 56% overall response in patients whose nodes were 2 to 5 cm. That dropped to 40% among those with nodes from 5 cm to 10 cm.

In other words, if I wait until I am sick as a dog and do his Rituxan protocol, there is about a 40% chance it will work, which is exactly what he told me -- “work” being defined in the study as a reduction of 50% in disease bulk lasting for 10 months. If I don’t wait that long, the odds of it working are better.

Another point: Assuming I get that 50% reduction in bulk when my nodes are at 10 cm, that would put me right where I am right now. Given the discomfort from my pelvic nodes, I am not sure that this is the ideal baseline for a remission.

I also read Dr. Susan O’Brien’s single-agent Rituxan dose escalation study from MD Anderson. It told me two things: First, the more Rituxan you give someone, the better the response. Second, at dosages commonly given (375mg/m2 once a week for four weeks) one can expect perhaps a 9% reduction in CLL in the marrow.

Finally, and very, very important in all this, I know how I have responded to Rituxan the first three times I had it. It does very well in my peripheral blood and in nodes up to 2 cm. It is almost useless in nodes bigger than 3 cm. At times, prior to treatment, I have had very small declines in red blood cell count and hemoglobin and it has reversed those declines, indicating perhaps that it has some effect in my marrow. Rituxan sends my spleen, which has been as large as 10 cm below the costal margin, back under my rib cage. When it does this there is usually a bump up in platelets, which had probably been sequestered there.

The Rituxan maintenance idea

If Rituxan were not available and starting chemotherapy were the only option, I would avoid treatment until I was half dead. This is the traditional view held by treatment conservatives, and in a world of few choices, it made sense. But Rituxan is available, and it changes the game for some of us.

There is a hardy band of CLL patients doing single-agent Rituxan. I know of maybe ten through the internet and there are no doubt more. The patient who has been managing the longest on this maintenance (that I know of) has been doing it for about five years. Our choice is unorthodox and experimental, though not off the wall. (Among those who have said they think it makes sense for some patients are Chaya Venkat of CLL Topics, who has written about it extensively, and Dr. Terry Hamblin, who comments on it here. MD Anderson often puts older patients, past age 70, on Rituxan + GM-CSF, aka Leukine, because older people have a harder time with hard chemo.)

The Rituxan maintenance rationale is to keep the disease at bay with the least collateral damage. For most people (but not all) Rituxan is essentially toxicity-free. Most CLL docs don’t think it is worth using by itself given the middling remission it gives. As an academic exercise, they are correct that the depth of remission provided by Rituxan pales in comparison to that given by combination therapy or even individual drugs such as fludarabine. But my body is not an academic exercise.

As Dr. Hamblin famously asks, “What is the aim of treatment?” For me, the answer is to keep me going, nothing more, with the least collateral damage. I don’t care how unpretty my remission is -- that is not the point. Beauty is in the eye of the beholder, and I like looking into the distance and seeing all those beautiful unburnt bridges ready to be used if I need them.

I have used Rituxan maintenance three times thus far. (My first hem/onc wanted me to use fludarabine alone. My second suggested RFC but went along with the Rituxan when I objected. She later quit her practice and I am now on my third hem/onc, who is open-minded and whom I like.) My first treatment was starting January ’04, 8 weeks at 375mg/m2. Second was starting April ’05, 4 weeks at 500mg/m2 (along with some G-CSF (Neulasta) shots to try to boost the effectiveness, which appeared to have little effect). Third was starting October ’05, 8 weeks at 375mg/m2. So it has been a year since I last started treatment.

There is no control to my experiment -– no cloned version of myself who chose another path –- so I can only make educated guesses at what the Rituxan has done for me. I would like to think that I have been keeping the marrow from becoming impacted; Rituxan’s modest effects on it may be just enough. I have kept the node growth reasonable among the smaller nodes, at least. Rituxan has been effective on my spleen. My Rituxan maintenance system has probably allowed me to drag Stage 2 out longer than I might have otherwise.

Now is the time

The deal with Rituxan maintenance is that you are using Rituxan, and Rituxan works better on earlier-stage patients and those with less bulky disease. I could wait longer to treat and take pain meds for my pelvic node(s) -- and more and more of them as the problem grows bigger and bigger, literally -- but what about the marrow? If I were to wait long enough for it to crash, Rituxan’s 9% reduction in CLL will probably be too little too late. I will have boxed myself in, likely leaving myself no choice but to add stronger agents that I would rather avoid.

I meet three of the NCI guidelines for treatment: Spleen swollen greater than 6 cm below the costal margin, lymphocyte doubling time of less than 6 months, and progressive lymphadenopathy.

To recap my prognostics: I am IgVH unmutated; ZAP-70 positive as per the reliable lab at UC San Diego; I tested positive for the 11q deletion on 24% of cells in March; and I am CD 38 negative, a blessed 1%.

Prognostics only tell some of the story. Based on my experience since diagnosis in 2003, I know my disease is steady in advance and can be steadily pushed back. I do not have the wild over-the-top escalation that some patients with my prognostic markers have, and I have so far been spared the sudden onset of major surprises. Maybe that negative CD 38 is helpful in some way, or maybe the planets have aligned right, or maybe I just haven't reached the point in time when the disease starts to go berserk.

For all these reasons, I think it makes sense to treat now if that treatment is to be Rituxan maintenance.

Why not the rest?

As readers of this blog know, I have explored Rituxan + HDMP and Rituxan + chlorambucil as possible options. But since my marrow is holding steady, I do not feel the need to jump to a stronger agent that might clear it better than plain old Rituxan.

I think both options do make sense for people who need better marrow clearance but who wish to avoid heavy-duty chemo combinations.

R + HDMP has been the subject of somewhat spirited debate in patient forums and among leading doctors as well. (I have recounted opposing views by Dr. Januario Castro and Dr. Byrd in this blog.) It is being pioneered in chemo-naive patients at UC San Diego, which has had generally good results with it, and I feel it is best done there, under their watchful and experienced eyes. I would not rule it out as a future treatment for myself under the right circumstances.

R + chlorambucil, advocated by Dr. Hamblin, appears to have good anecdotal results. My concern here is the possibility that alkalyting agents can be mutagenic. There is a study that lumps chlorambucil and cyclophosphamide together and reports a somewhat higher incidence of p53 mutations in patients who have received those alkalytors. While the chance may be small, especially at small doses, acquisition of a p53 (aka 17p) deletion is the last thing I want to bring upon myself. Still, under the right circumstances, I could see using R + low-dose chlorambucil.

My plan: festooning the shark

What I am opting for is the minimal amount of treatment I think I can get away with, but something a little stronger than I have had in the past.

Having a blog means sharing an evolving learning process. I was a little premature in March when I posted “Single agent Rituxan jumps the shark.” Since March, HuMax-CD20 has begun to loom on the horizon, and the likely advent of this promising new tool has changed the outlook for me, as discussed in Part 1.

The treatment plan ahead is single-agent Rituxan with some Beta-Glucan added, probably with a second step involving a steroid tweak.

I looked back at my prior experience with two courses of once-a-week-for-eight-weeks Rituxan. After week 5, I reached a plateau in blood counts and node reduction. Is there a way to improve on that dosing schedule? The O’Brien study showed that the more Rituxan you get, the better. (Yes, yes, Rituxan shaving may be a drawback, but there appears to be something causing it to work better at higher doses.) Byrd’s protocol uses more frequent dosing, three times weekly. By extension, even at 375mg/m2, that gets more Rituxan into you in a shorter space of time.

So, on the theory that more frequent dosing is likely to be no less effective than the once-a-week schedule -- and hopefully more -- I will be following the first half of Byrd’s protocol: six infusions of Rituxan at 375mg/m2 over two weeks. The decision to use half of Byrd’s protocol is made given my past plateau after infusion 5 and the fact that the extra Rituxan may 1) go to waste, or 2) be more than I really need right now, and 3) always carries the risk of developing disease resistance, which I want to keep to a minimum, since I will probably have to use Rituxan maintenance of some kind again before I can use HuMax. Hopefully the shorter, more intense schedule will lead to a more intense result. We shall see.

Added to the mix will be Beta-Glucan, which may have the benefit of boosting macrophage activity and thus the cell kill. Researchers at the University of Louisville in Kentucky are now accruing CLL patients for a Rituxan + Beta-Glucan clinical trial. The Beta-Glucan they are using is available commercially.

Failure to clear the larger nodes adequately –- I am not expecting miracles here, just a decrease in discomfort -- would lead to Step 2. After an interval designed to allow the body’s complement to recover from the Rituxan, I would receive a course or two of dexamethasone (Decadron), perhaps 20 mg daily for four days. The idea is to push the CLL out of the nodes and into the bloodstream, where Rituxan can get at it better. I have done some research on dex and it is lympholytic on its own –- that is, it kills CLL cells (though it is not a major player in this department).

The question of whether it would have synergy with Rituxan is another matter and there are no definite answers, it seems. It may, or it may tamp down macrophages and the CDCC (complement dependent cytotoxicity) and ADCC (antibody dependent cytotoxicity) that helps with the Rituxan cell kill. So after administration, there would be a wait of a week or two before doing two final rounds of Rituxan -– enough to clear the dex from my system without allowing the CLL to return in large numbers to the nodes. (The immunosuppressive effects of the dex may well continue for some time, despite the wait; sometimes there are no elegant options. Also, as I have skin cancer issues, I will also be monitored by a dermatologist.) Since Rituxan works best in the peripheral blood, it will hopefully kill off some of the formerly node-based CLL. Again, we shall see, but there is little downside in trying.

(As an aside, one reason not to frontload the dex is to avoid the possibility of tumor lysis syndrome, since I already anticipate significant cell-kill during the first week. Another reason is not to gum up the works -- I know I get my best response from Rituxan after the first two or three infusions, and I would just as soon let it do its thing before doing anything that might inadvertently dampen its effects.)

In the end, I am hoping for 8 or 10 or 12 months of CLL control, with the nodes knocked back further than when I started, a petite spleen, and any decline in the marrow arrested. And “control” is the operative word. Call my hoped-for remission incomplete, crappy, or whatever name you wish. As my father once said when asked many years ago why he wasn’t going to get rid of his clunky old 1967 station wagon, “It gets me from Point A to Point B.”

That’s my goal.

The way of the tortoise, Part 1

In March of this year I wrote a piece for this blog entitled "Single-agent Rituxan jumps the shark." In it, I said that Rituxan by itself -- of which I have had three courses over two years -- would no longer do the trick for me when treatment time came around again.

The search for what to do next led to my Doctor Quest, which I have described at length in these pages. I explored options such as Rituxan + high dose methylprednisolone (HDMP), Rituxan + chlorambucil, and even Rituxan + fludarabine, and I picked the brains of a few leading experts. This being chronic lymphocytic leukemia, of course, I got different and even contradictory answers. But in the process I have become more familiar with my case, what the criteria might be for treating it, and the options for that treatment. I also had a chance to mull over the conventional wisdom as well as some opposing viewpoints about depth of remission, long-term survival, and various other things that go bump in the night.

And now, here I am, ready to embark on a course of treatment. I will tell you what I have decided, and why.

I have decided who is in charge

Meeting with some top doctors, as well as some lesser lights, I quickly realized what so many CLL patients learn: four rabbis, five opinions. Or, as one world-renowned expert told me about my treatment timing and prospects, “There isn't a right or wrong answer. I could construct an argument for almost any approach.”

So the one thing I have learned in my Doctor Quest is that nobody knows my disease quite like I do. Or, as I wrote to a friend of mine, “After seeing all the experts and learning all I can, I have learned one thing: my guess is as good as anyone's and it is all a crapshoot.”

This is not hubris. I may be a fairly well-educated patient, but my knowledge of the disease pales in comparison to that of the experts. We patients need our doctors, and I have learned a great deal in my conversations with them. I would not want to be left to my own devices even if I could buy Rituxan at Costco and set up an IV pole next to the living room sofa. Doctors are needed not only for their expertise but also for their skill and experience at monitoring symptoms and managing complications that can blindside us. And not every patient has the time or inclination to make the effort I have made to get to know the lay of the land. Nor does everyone have the same personality type; some people would rather just pick a doctor they are comfortable with and follow that person’s advice. I respect that choice, which seems on the surface to be quite sensible.

For me, personally, it is not enough given the uncertainty that surrounds CLL. I am the recipient of a disease without consensus, a disease termed “heterogeneous” because it is about as individual as a fingerprint, and mine in particular is rather quirky. Understanding of CLL is in flux, old assumptions are being questioned, new treatment ideas go every which way. The experts are left to debate and disagree among themselves. And you and I are cursed with living in interesting times. I wish it were easier to be a patient, but it’s not.

In terms of how to put it all in perspective, someone named Andy once left a comment on this blog that offers sage advice:

“Nothing can substitute for common sense, especially when one's life hangs in the balance. Science is indispensable to the understanding of the pros and cons but when it comes to making a value judgment, science has nothing to say -- that's something many patients (and many doctors as well) fail to grasp.”

So, while I know that I will never have the scientific knowledge of a John Byrd or a Januario Castro, my ability to make the right value judgment is probably equal to anyone’s. And since my life is on the line, I had better become adept at it.

I have decided what makes common sense to me

The more I have learned, the more I am convinced that, as a rule, less is more when it comes to treatment. The least toxic route to disease control is to be preferred to nuking the sumumbitch and risking very real complications that I have written about many times, that CLL Topics has warned about many times, that Dr. Terry Hamblin’s blog has discussed many times, and that basically fall under one category: I done blowed up my CLL and my immune system’s all shot, too.

If there is one thing I fear more than death by CLL, it is becoming sickly and having a lousy quality of life, being in and out of the hospital, being at the mercy of every bacteria or virus that comes waltzing along. CLL means my immune system is in decline -- this is why our immunoglobulins drop -- but why speed up that process?

I said this was my view “as a rule.” There are exceptions. There are people whose marrow becomes impacted, whose platelets and hemoglobin drop to dangerous levels, whose nodes grow to enormous size, and who have no choice but to do something pretty drastic to clear the marrow and deal with the problem. I may be one of those people one day, and if that time comes, I will welcome fludarabine, cyclophosphamide, and god knows what else with open arms and open veins.

But now is not that time.

I have decided I am a tortoise

I know, you’re thinking “What has Dave been smoking? Does he also think he’s the Eggman, coo-coo-ca-choo?”

Let me explain about the tortoise and the hare and how it applies to CLL.

There is a school of thought, the conventional wisdom, that depth of remission leads to longer overall survival. This may make sense in many cancers, but does it hold true in CLL? One problem is that long-term studies are very difficult to do, and CLL is a long-term disease. A must-read is Dr. Hamblin’s “What is the aim of treatment?” series. In it, he posits that the acute leukemia model, in which a cure is the desired goal, may not be realistic in CLL.

“Most doctors who design clinical trials for CLL have trained as acute leukemia doctors, “ Hamblin writes. “Faced with a disease that may span decades they revert to type. Pharmaceutical companies are not much interested in a clinical trial that may last 20 years -- their patents will have run out. Current clinical trials, by common consent, have abandoned overall survival as an end-point; instead they have adopted “complete response rate” and “progression free survival” as surrogates. There are problems with both of these . . .”

Hamblin goes on to discuss this in detail, and I will leave it to you to read his thoughts (see “Resources” below) if you have not already done so. His views may be somewhat heretical on this topic, but that does not make them wrong.

The point is that there is not sufficient evidence, to my mind, that depth of remission will lead to longer overall survival for all CLL patients. The problem is that patients relapse from those deep remissions and are left with fewer treatment choices. Another big-name doctor told me that the weakest spot in CLL therapy is finding things that work on the fludarabine-refractory. And there is plenty of anecdotal evidence, at least, that some patients who get big remissions set themselves up for other big problems in the process, notably immune suppression that can lead to life-threatening complications.

So, will you live longer by running hard out of the gate, or by plodding along only as fast as you need to?

My intuition says to bet on the tortoise.

The tortoise rewarded

Good things come to he who waits, or at least he who moves slowly. HuMax-CD20, the monoclonal antibody, has received fast-track status from the FDA and is now in Phase III trials. Everything I read and hear, officially or through the grapevine, is that this stuff puts Rituxan to shame. It adheres better to the CLL cell, it leads to better cell kill, and being fully-humanized it guards against some of the nasty allergic reactions that can accompany mouse-based Rituxan.

For those of us who have been saying “Do the minimum you need to do, avoid burning bridges if you can, keep your immune system as functional as possible to maximize the effectiveness of new drugs that may come along,” HuMax-CD20 is evidence of our logic, the proof in our pudding. I would be shocked if it were not approved for commercial distribution sometime in 2008, at the latest.

So, how does this tortoise get from here to there?

I’ll conclude my thoughts in Part 2.

RESOURCES

Dr. Terry Hamblin's three-part "What is the aim of treatment?" series:

Part I: http://tinyurl.com/qgd2f
Part II: http://tinyurl.com/rxnpt
Part III: http://tinyurl.com/rmjv5

The fog lifts on "chemo brain"

Now that I'm 50, I suppose I need to start worrying about um, er, what was it? Oh, senior moments.

Having chronic lymphocytic leukemia, I have another strike against me: the prospect of getting "chemo brain" from heavy-duty chemotherapy, should it ever become necessary. This is one of the hidden dangers of CLL and most cancer therapy, and yet another reason to avoid the alphabet soup treatments such as RFC. RFC+M, CFAR, et al until you have no choice and really need to use them.

Researchers tend to talk about "multiple non-overlapping toxicities" and doctors tend to use phrases like "well-tolerated" when describing some of these regimens. (I suppose whatever doesn't kill you is something that, grading on a curve, you can tolerate well.) But in plain old common sense English, pump your body full of stuff that destroys cells and don't be surprised if it does something in the brain.

Of course, chemo brain is one of those areas that is not really the subject of too many studies. After all, drug companies have little incentive to reveal yet another potential problem with their products. And researchers looking for a cure or effective control may feel their time is better spent on that rather than on tracking down amorphous side effects that can vary from person to person. Type "chemo brain" in quotes into PubMed and you get exactly three results (though there are other areas which better catalog the information available -- see "Resources" below).

It is on internet CLL patient forums that one hears stories about chemo brain: people becoming disoriented and not knowing where they're going when they're driving down the street, people who go to work and can no longer answer the phone and type into the computer at the same time. Some people seem to be spared these sort of effects, some have mild or transient cases, some have long-term problems.

Depression complicates matters

Chemo brain is a very real risk, though matters of depression and stress can lead to an impression of brain fog in some people that may not be entirely chemo-related.

A PubMed abstract of a 2003 study at the University of Indianapolis provides this analysis:

"Oncology patients often complain that their "mind does not seem to be clear." This subjective perception, sometimes referred to as "chemo brain," may be due to situational stressors, psychological disorders, organic factors, or effects of neurotoxic medications. Cognitive decline cannot only diminish quality of life, but can also interfere with a patient's ability to make decisions regarding complex treatment issues."

The authors of the study tried to quantify and clarify the results in 61 patients. They found this to be difficult, and concluded: "While the perception of cognitive impairment is common in cancer patients, there may be problems in interpreting the nature of these complaints, particularly in separating them from depressive preoccupation."

Certainly depression can lead to reduced clarity of thought and action. Many older people have CLL and may already be experiencing a bit of brain slowdown as part of the natural aging process. But chemo brain cannot be dismissed as a figment of the imagination. A study reported today by UCLA researchers finally pins down in hard science what many cancer patients have felt to be true all along.

New study: chemo alters brain metabolism

Entitled "Chemo has long-term impact on brain function: study," Reuters reported the following:

Chemotherapy causes changes in the brain's metabolism and blood flow that can last as long as 10 years, a discovery that may explain the mental fog and confusion that affect many cancer survivors, researchers said on Thursday.

The researchers, from the University of California, Los Angeles, found that women who had undergone chemotherapy five to 10 years earlier had lower metabolism in a key region of the frontal cortex. Women treated with chemotherapy also showed a spike in blood flow to the frontal cortex and cerebellum while performing memory tests, indicating a rapid jump in activity level, the researchers said in a statement about their study.

"The same area of the frontal lobe that showed lower resting metabolism displayed a substantial leap in activity when the patients were performing the memory exercise," said Daniel Silverman, the UCLA associate professor who led the study. "In effect, these women's brains were working harder than the control subjects' to recall the same information," he said in a statement.

Experts estimate at least 25 percent of chemotherapy patients are affected by symptoms of confusion, so-called chemo brain, and a recent study by the University of Minnesota reported an 82 percent rate, the statement said.

"People with 'chemo brain' often can't focus, remember things or multitask the way they did before chemotherapy," Silverman said. "Our study demonstrates for the first time that patients suffering from these cognitive symptoms have specific alterations in brain metabolism."

The article goes on, and this link will take you to the full text.

But the message is simple: chemo brain is real, and it is a risk. Yes, there have been no studies of it in CLL, but there is more than ample anecdotal evidence that some people are affected by it. For those of you who feel your body is crumbling but "at least I have my mind," take heed.

RESOURCES

The website http://www.chemobraininfo.org/ offers a fairly encyclopedic roundup of studies and other information.