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.
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.
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.
I've go to admit it's getting better: More good news about my CLL (chronic lymphocytic leukemia) - Most of my blog posts can be followed here. The full story of my CAR-T therapy, the incredible rollercoaster and the amazing results can be found there I...
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