Saturday, October 14, 2006

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 a
t 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 n
eeds 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 exce
ssive 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 di
sease 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 talke
d 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 sing
le-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 to
ld 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 i
s 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 ma
intenance 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 co
nservatives, 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 choi
ce 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 acad
emic 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 re
ached 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 optin
g 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 add
ed, 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 s
chedule -- 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 d
ependent 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, a
nd 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.


Anonymous said...

Apart from the fact that you are designing your own treatment plan (with really nothing but your 'gut feeling' on what might work), what is the significant different between your plan using rituximab and dexamethasone, and using the high-dose methylprednisolone and rituximab? There is of course the high dose methylprednisolone and high dose rituximab which is being done at least at UCSD, perhaps elsewhere as well.

The theory behind the HDMP+HDR is the same as you describe your own plan.

As you know and I'm sure have recounted, the original HDMP+R (low dose rituximab) trial participants fared fairly well, especially those that followed with Campath at some point to 'consolidate' their response.

Aren't you proposing pretty much the same thing?

And what says the CLL treatment landscape will be significantly different in one year from today? I don't see it...

David Arenson said...

Last point first: The treatment landscape will be changed to some extent by HuMax CD-20. I would be shocked if it is not approved by the FDA by 2008 at the latest. Both alone and in combination, I expect it will add a lot to CLL treatment -- certainly enough to give us Rituxan maintenance folks a new lease on life, so to speak.

You could say that I am proposing Rituxan + steroid "lite." I do not see the point of taking on the added toxicity of HDR + HDMP given my current situation. Again, remember that my marrow is not a big issue; also that I have skin cancer problems and would therefore prefer a lighter touch when it comes to immunosuppressive therapy. Dr. Castro told me I might get 18 months from R+HDMP; getting somwhat less with less toxicity is an acceptable tradeoff for me.

Also, I do not wish to add any Campath at this time. The reason is because I want to reserve its use for pre-transplant conditioning, if it comes to that; also, it would be useful in reserve should I ever develop the 17p deletion on my own. Dr. Castro pointed out to me that people cannot use Campath indefinitely -- I do not see a compelling reason to start it now, given my age (50) and the (relative) strength of my marrow.

Finally, the treatment plan was designed in consultation with my oncologist and others. All treatment decisions come down to a gut feeling. One enters a clinical trial with a gut feeling that it may be helpful, even if it has not been proven. The Rituxan and steroid components of my plan have been used in CLL before. My combination, timing, and the addition of Beta-Glucan make it a bit different, but within the realm of realistic, tried approaches.

Deb said...

Good Luck David with this new treatment plan.I hope it buys you time until Humax is approved.Take Care.My thoughts and prayers are with you!


Anonymous said...

Hi David,
This HuMax-CD20 sounds very very interesting.
I am always waiting for your posts. I am now reading more
on CLL Topics (about HuMax-CD20), what a GREAT site!
Thanks for all you do and always be true to yourself! Being
true to yourself is sometimes so very hard, but in the end it
is worth it!
Carlin C.

Irving Putter said...

I agree with the protocol you propose.I am not convinced that Humax will be that more active for the large nodes.Steroids potentiate the movement of CLL cells from nodes to blood.HUmax may kill cll cells faster by more than 1 mechanism in blood thus pushing equlibrium to blood.The latter potential improvement may still be ratelimiting.Let the trials speak.
I would not wait to begin therapy.

Irving Putter

Anonymous said...

The latest news is that HuMax is being tried with fludarabine and cytoxan; perhaps it is not effective as a single agent.

The problem with waiting for new drugs is that it takes literally years to learn the best way to use a particular drug. For instance, rituximab is still in clinical trials to better understand the way to best use the drug. And this has been approved almost a decade ago.

Perhaps HuMax or another agent will prove its mettle more quickly; let's hope so. I am a bit disappointed they are using the drug in combination already, suggesting it just won't work as a single agent.

David Arenson said...

I heard Genmab's latest conference call and am pretty much up on HuMax statistics. From that, and what I hear through the grapevine, it appears to provide deeper remissions than Rituxan. It appears to do a nice job in many previously-treated patients. It appears to be a better node reducer, though the nodes obviously bounce back.

But it is a monoclonal antibody and, as such, will not provide as deep a remission on its own as it would in combination. Now, think of where the money is: Rituxan is commonly used in the US in RF and RFC. If HuMax can prove it provides a better response in these combinations, that opens up another major venue for HuMax to be used (besides refractory patients). From a business standpoint, Genmab's interest in this trial makes sense. Their willingness to take Rituxan on head-to-head in Rituxan's CLL stronghold also indicates they have a fair amount of confidence in their product.

Monoclonals as single agents are never going to be super-popular with docs as a frontline treatment precisely because the remissions are not so deep. This will always be the "afterthought" use of such drugs, popular as the concept is with patients. Eventually someone will get around to doing a trial of HuMax as a single agent in untreated patients, but that will probably be some time after it is approved for CLL.