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.
5 Years Since I started on Ibrutinib for my CLL (chronic lymphocytic leukemia) in a Phase 1 Clinical Trial at Ohio State - May 5, 2017 marked 5 years since I swallowed my first 3 capsules of PCI-32765, now better known as ibrutinib or Imbruvica. I still take 3 battleship grey ca...
1 week ago