There was a famous moment in TV history, on the show Happy Days, when Henry Winkler’s character Fonzie is on water skis and literally jumps over a shark. That scene symbolized, to many fans anyway, the show’s decline, a desperate attempt to grab ratings.
“Jumping the shark” has since come to signify the moment at which something has obviously outlived its usefulness, or strayed so far beyond its original welcome that it is now tangential and obsolete. Besides TV shows, the phrase is used for music groups, celebrities, movies, and even politicians. It could be argued, for example, that Bill Clinton jumped the shark with the Monica Lewinsky affair (no bad pun intended!) The American people seem to have decided that George W. Bush jumped the shark with Hurricane Katrina, although a substantial number of us would trace that moment back to the invasion of Iraq.
Allow me to use the phrase in medicine. In my case, anyway, single-agent Rituxan has jumped the shark. Readers of this blog will recall that I was diagnosed with chronic lymphocytic leukemia in September 2003. I was already at Stage 2, with swollen spleen and nodes. After much research and discussion, I had eight weeks of single-agent Rituxan starting in January 2004. I had four weeks starting April 2005. I had eight weeks starting in October 2005.
All this Rituxan has allowed me to play for time, which is what my original goal was in using it. I feel fine, my platelets are stable in the 160s and my hemoglobin is 15. Rituxan has reduced my oversized spleen, which does return to moderate enlargement between treatments. It has been effective on small nodes, but has never done much for those beyond 2 cm. (My largest ones are in the 3 to 4 cm range; I have never gotten the huge ones characteristic of some patients.) My disease today appears to be about where it was when I was diagnosed.
So far, so good. But my bloodwork tells another story. As of last week, when I visited my oncologist for my three-months-after-the-end-of-last-Rituxan-infusion checkup, my absolute lymphocyte count was 38,000. It took seven months for it to reach that point following my first Rituxan cycle. It took four-and-a-half months to reach that point after my second. Now we’re down to three.
Peripheral blood numbers don’t tell the whole story, of course, but there is no sign that Rituxan’s effectiveness on my bulky disease is getting any better. The bulk, decently reduced after my first Rituxan, has essentially found a plateau. As my oncologist said last week, “You’re bulky, but you wear it well.”
She also said “I think we have to add something to the Rituxan next time.” I hate to say it, but I have to agree with her.
I could continue to use Rituxan as a single agent, likely with diminishing results, and always risking some of the rare but serious side effects -- skin problems, delayed onset neutropenia, and so forth. Up until now, I have been lucky in not having any signs of the above. And Rituxan has continued to work well in my peripheral blood during all three courses -- my ALC bottomed at 2.2 the first time, 4.6 the second, 5.1 the third.
But given its value in combination therapy, I see no point in using it up completely, jumping and rejumping the shark as it were. It am fairly confident that it still has enough oomph in my case to work well in combination with something else.
When I began to play for time more than two years ago, I hoped a shiny, happy “something else” would come along, a choice so obvious that all I would have to do is sit back in my chair like Jean-Luc Picard, glance at my oncologist, and say, “Make it so.”
Alas, progress has been slow but steady. While there has been nothing that really puts a dent in the disease, there have been many new wrinkles.
In a couple of years we will likely have Humax CD-20, a fully humanized monoclonal antibody, that could replace Rituxan in CLL, and which may (or may not) prove to be somewhat more effective. It has been fast-tracked by the FDA and is currently in trials. (Rituxan has never had Phase III trials in CLL, and so as common as it has become in CLL treatment, it has never received official FDA approval. Humax is seeking that approval, and if it gets it, bye-bye Rituxan. Start thinking “HF” and “HFC.”)
There are some interesting trial possibilities with HSP-90 inhibitors but they are just that, possibilities, and they may not be viable in addressing my case of CLL. Nonetheless, I will keep my eyes open.
Another wrinkle has been R + HDMP (High Dose Methyl Prednisolone), the trial in chemo-naïve patients at UC San Diego. To better these remissions, some patients received Campath afterward to clear up residual disease. Anecdotal reports and one published report indicate some early success with this protocol, and it is not mutagenic. But it is highly immunosuppressive, and the long-term effects of all that HDMP are not known, as is the duration of remissions received.
Readers may recall that I have skin cancer issues, which is why I am leery of therapy that is too immunosuppressive, and which is one reason why I would like to avoid fludarabine until absolutely necessary. I am also Coombs positive, a candidate for autoimmune hemolytic anemia, and fludarabine has been known to catalyze it.
In considering what to do next, I am still looking at the long term. I want to retain the chance for one excellent, deep remission, possibly as a prelude to a stem-cell transplant, and would be tempted to reserve Campath, and perhaps fludarabine, for that effort.
I am IgVH unmutated -- I have a fast-growing disease -- but am CD 38 negative and have a “normal” FISH result. It appears that whatever chromosomal abnormality underlies my CLL, it is relatively benign. It is keeping the brakes on the unmutated part, at least as well as can be expected, and at least for now. So I am loathe to pick up another, more dangerous abnormality -- say the 11q or 17p deletion -- which can happen through treatment with certain drugs.
Two other options I am beginning to mull over involve Rituxan and alkalyting agents.
One is Rituxan and chlorambucil, the concept of which has received an endorsement from Dr. Terry Hamblin on the ACOR list. There have been no trials of this in CLL but, anecdotally, some patients have done rather well with it. My concern is that chlorambucil can cause marrow problems and can be mutagenic. But I am reaching the stage where I have to take more chances to keep my disease in check, and the concept of trying for a two-year-or-so remission with R + low-dose Cb is somewhat tempting -- especially as it may be repeatable and I can still “graduate” to fludarabine combinations later on.
A similar prospect is Rituxan plus cyclophosphamide plus prednisone -- R + CP -- the protocol being followed by John Wagner, who writes about it in his excellent blog. My concern here is the mutagenicy of the “C,” and whether it will be as effective as “Cb” in clearing the marrow and therefore in length and depth of remission. Sometimes vincristine is added to this protocol, for R + CVP, but vincristine is a known cause of peripheral neuropathy and I like my fingers the way they are, thank you.
Beyond these choices, of course, lie all the F acronyms -- RF, RF "lite," RFC, CFAR, etc. And the “P” for pentostatin, of course. There are some doctors who would look at my bulkiness and unmutated status and say that I should choose one of those. But I tend to look at my disease as half-full, so to speak: less aggressive than many unmutated cases, and present in a patient who feels fine, who has normal platelets and hemoglobin, and no "B" symptoms. If I ain't totally broke, I am loathe to try to overfix me.
Needless to say, my doctor and I have some mulling to do. For now, I am simply going back into “watch and wait.” I have ordered a new FISH and CD 38 test, part of the Quest monitoring package, to see if my disease may be ramping up. That will help bring the picture into a little better focus.
In the meantime, I am putting away the skis and leaving the shark alone. I am not the only patient who may be reaching this conclusion after a couple of years of single-agent Rituxan. I have friends with similar declining results, or increasing side effects.
There are those for whom Rituxan monotherapy will continue to do the job longer, people with different disease profiles, or people at earlier stages. In CLL, we all have to adapt to changing circumstances and find the right weapon for the right time. I'll keep you posted.
Speaking of jumping, I certainly jumped to some premature conclusions in this post; I think perhaps I had been listening to my doctor a little too closely. Sometimes it takes a while to sort things out, and blogs are real-time affairs, so one can see changes of heart and mind as time goes on.
Here I am, a year and a half later, still using Rituxan, now with occasional steroids to combat AIHA but with the added effect of knocking back the CLL. Facing the other treatment options squarely in the face made me realize that Rituxan, even if reduced in effectiveness, was still the lesser of all evils. As Winston Churchill once said, democracy is the worst form of government except for all the others. Think "Rituxan" instead of "democracy" and "chemo" instead of "government" and you see my point.
What I have realized since this post is that unless there is a specific, dangerous complication or problem that demands immediate attention, playing for time is of paramount importance. I can still hold the fort, albeit not quite as well, with ever-crappier, more inelegant Rituxan remissions. While many doctors and some learned friends might argue that I have continued to jump the shark to the point of indescribable boredom, I would point out that my show is still on the air, so to speak. Plus, the addition of steroids has given my Rituxan therapy new life.
How long can I continue this? At least a while longer, I think. Here, Sharky, Sharky . . .
-- September 23, 2007
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