Saturday, April 21, 2007

Low-dose Rituxan

As readers of this blog know by now, I am currently being treated with low-dose Rituxan, 20 mg/m2, every Monday, Wednesday, and Friday. The plan calls for this to continue until my white blood count is normalized or until I reach a plateau at which Rituxan no longer appears to be effective.

That “m2,” by the way, stands for per “meter squared,” which means the dosage is calibrated to my body surface area, a calculation involving my weight and height. When they hook the bag up to the IV pole, it actually contains 42 mg of rituximab. The standard dosage would be 375 mg/m2, which I have had often in the past, and which usually translated to about 750 - 780 mg per bag once my body mass was factored in. So, even a math dunce like me can see that it will take somewhere on the order of 18 infusions of low-dose Rituxan -- six weeks’ worth -- to equal one dose of standard-strength mouse juice. I’ve done five weeks so far.

If less can achieve the same or better results as more, there are obvious advantages to using less. These include reducing the possibility of creating disease resistance to the drug, fewer infusion reactions, and reduced chances of unwanted side effects such as delayed-onset neutropenia and potentially dangerous skin problems. Plus, depending upon how much you and your insurance are paying, it costs a lot less. The only loser is the manufacturer, Genentech.

On the other hand, it is important to remember that Rituxan is still Rituxan, and that its use as a single agent is not a panacea for chronic lymphocytic leukemia. Rituxan-induced remissions are not terribly deep nor durable. There is no reason to think that low-dose Rituxan remissions will last any longer than those at standard dose. As one doctor put it to me, “I have used low-dose rituximab a couple of times with no clear evidence of long term effect yet.”

Early word on low-dose Rituxan’s effectiveness

Still, if Rituxan is your poison, low-dose -- hereafter referred to as LDR -- may be worth considering. Here is the early data, some anecdotal, some from pilot studies:

One patient has posted her experience online, pointing out that her absolute lymphocyte count (ALC) dropped from 137k to 4.6k after eight weeks of LDR at 30 mg, given intravenously three times a week. She had used standard-dose Rituxan in the past.

A pilot study conducted by Dr. Ron Taylor (photo below) and other researchers at the University of Virginia, during which patients were given LDR by IV three times a week over four weeks, showed results ranging from stable disease to complete response (link at end of post, along with lots of other links). Not surprisingly, the complete responses were achieved in patients with the highest levels of CD20, and both were, it is interesting to note, 17p-deleted cases.

Another patient experience, detailed in a CLL Topics Alert, shows the more middling, “stable disease” end of LDR response -- the patient’s counts had been rising, almost doubled in the month before LDR began, and were stalled by LDR, but not reduced. After four weeks of subcutaneous injection of LDR, 20 mg three times a week, his ALC went from 44.7 to 46.0. Are his results a matter of his state of disease, his CD20 expression, or could the sub-Q method of administration be less effective than IV?

There is now a clinical trial underway, using a flat 20 mg of LDR, to help answer the question of LDR’s effectiveness in a larger cohort of patients than Dr. Taylor’s original pilot study. After all, the proof of any theory is in the patient pudding. The bottom line is not how elegant the theory, but how concrete the result. Your donations to CLL Topics are helping fund Dr. Taylor’s laboratory analysis of the trial data.

It should be noted that LDR can also be accompanied by nasty infusion reactions, so adequate premedication (usually Benadryl, Tagamet, Tylenol, and a steroid such as Solu-Cortef to reduce the inflammatory response) is a must. I know of one patient whose first infusion of 20 mg/m2 was a near-disaster, exacerbated by her doctor’s refusal to adequately premedicate her, which borders on malpractice. I do my LDR infusions with no premeds, but I have had standard-dose Rituxan 25 times in the past, so I know my limits and my tolerance. Even then, when the nurse ran the bag through a little too quickly one time, I got a chill and broke out in a sweat. LDR is not a license to forget about precautionary measures, and this also includes pre-treatment allopurinol and drinking lots of water, both of which help protect the kidneys from tumor lysis, which can happen when millions of cells die at once.

My experience with LDR

In my case, so far, LDR is bringing down the white count. As you may recall, I also had 72 mg of methylprednisolone daily for a week, which did an excellent job of debulking me, and which has been gradually tapered and is now at 4 mg a day. The importance of the steroid in my particular treatment cannot be overemphasized. Its addition to the protocol was triggered by the onset of autoimmune hemolytic anemia (AIHA). The hemolysis soon stopped, and my red counts have since been recovering, slowly but steadily.

One effect the steroid had was pushing CLL cells out of the spleen, nodes, and marrow, doubling my WBC to 364k at one point. Then, almost as quickly as it doubled, it dropped: to 271k after another week, and to 95k after another. LDR was only one factor here, I think. Another is the steroid itself, which has lympholytic (lymphocyte-killing) properties and very likely some synergy with Rituxan. Another significant factor was probably the ramping down and end of an infection that likely had precipitated the AIHA, and which had been driving my white count upward even before the AIHA set in. As any CLL patient who has gotten a cold knows, your count will go up and then down again when the cold is over. My supportive meds -- Bactrim, diflucan, augmentin, and acyclovir -- no doubt had something to do with the end of the infection.

Since my white count fell below 100k, the LDR has been dropping it steadily, from 95k to 81k three weeks ago, from 81k to 67k two weeks ago, and from 67k to 49k last week. At this rate, my count should be normalized in about three weeks. I say “should,” because as we go lower, we encounter a greater chance of reaching a plateau point, where the effectiveness of Rituxan ends and cells shorn of CD 20 begin. (Back in October, when I did standard-dose Rituxan three days a week, that plateau point was 22k, achieved after just five infusions.)

The bottom line today is that the steroid and LDR combination has worked better than I had hoped -- so far. That is the operative phrase: “so far.” The bulk is largely staying off and the count is going down. If I can get a normalized WBC and have reduced the bulk by a substantial amount, it will have been a successful treatment experience.

Whatever the end result -- whether I get as good as I’m hoping, or whether the counts plateau at a higher level -- the question comes up of how durable the result will be. The count is not everything; indeed, in a patient prone to bulkiness like me, it is less important than the nodes. Many patients who have used steroids to debulk report that the nodes come back within a month or so. It will be interesting to see if that happens in my case. The steroid dosage is now so low that it is doing little to hold back activity in the nodes. I have noticed a very minor uptick in one node on the side of my neck, and I get the impression that even as my counts continue to drop with LDR, the nodes will gradually begin their return.

So, I am left to wonder: Where will I be a month after treatment ends? Will the nodes be back to where they were before I started? Will they be a shadow of their former selves, indicating that the treatment has ramped the disease down to a good degree? How long might they be held in check before retreatment is needed?

As we all know in CLL, there are no easy answers, and different patients get different results with the same protocol. As the Romans used to say, experientia docet -- experience teaches.

Planning my encore

So, what do I do for an encore? It depends, to a great extent, on how my treatment plays out. But doing nothing until the disease gets as bad as it was before I started would not be wise. Those days are over. In my case, the “just let it go until you hit the wall” approach brings with it infections and AIHA, which are not worth the risk. Getting mashed against the wall like a bug on a windshield is messy and unpleasant, to say the least.

One option is to do another cycle, as it were, perhaps giving my body a month’s rest and then using a four-day course of steroids to debulk again, followed by more LDR. Chemotherapy often runs in cycles of up to six go-arounds of treatment. Would more cycles benefit me? Would I be able to gradually erode the disease through this method?

If it works, then I might be able to adopt a new “low-tox” route of disease maintenance: Repeat this process every so often -- say every four months -- to keep the disease in check. Add periodic IVIG to boost my immunity against infections. Take maintenance acyclovir, one 400 mg pill a day, to control the herpes virus (my titer for this was high recently). Acyclovir may also help against the Epstein-Barr virus, which I know I have floating around in my system, as I had infectious mononucleosis as a child. An EBV titer test has been taken, and the results are pending.

Another option, depending upon how deep a remission I get, is to consider following this treatment with Campath consolidation. Having unmutated, 11q-deleted CLL means the disease will return faster than it would in many other patients. Would using Campath at this point in my CLL career be worth the risks that accompany this important, highly immunosuppressive monoclonal antibody? I will be studying the ins and outs of Campath over the next month or two. Stay tuned.

What about other chemo drugs?

My thought on FCR is that it is still best saved for transplant conditioning, by which time it will probably be FCH (as in HuMax CD20) and likely a more effective regimen than FCR. While I have accepted the likelihood of having a transplant at some point, I see no survival advantage to doing it now, as opposed to putting it off for as long as reasonably possible. I am only 50 and have a ten-year window to accomplish the task. And so far, by the way, I have no signs of marrow failure.

Chlorambucil is another option, as is cyclophosphamide, which is considered to level the playing field for 11q patients. But I would have to investigate how much one of these drugs would meaningfully add to what I am already doing.

Meanwhile, back at low-dose Rituxan Ranch

The whole theory behind low-dose Rituxan has to do with CD20 shaving and complement, a subject that Dr. Taylor has been studying for several years. We all know that Rituxan is a man-made antibody that affixes itself to the CD20 “fingers” on B cells. In cancers such as non-Hodgkins lymphoma, where there is a lot of CD20 per B cell, Rituxan works pretty well. In CLL, there are fewer fingers, and therefore it is less effective. (HuMax CD20, Genmab’s new anti-CD20 monoclonal that will probably be on the market in a year or two, requires fewer finger to work well, and may be able to do in CLL what Rituxan does in NHL.)

Briefly, the idea behind CD20 shaving is this: One of the ways in which cell-kill is achieved when Rituxan is used is by complement-dependent cytotoxicity, or CDC. The body’s complement system provides a fundamental level of immunity, and includes those mighty cell-chomping macrophages, which look like something out of a science fiction movie (photo below). In a process called phagocytosis, those macrophages, along with granulocytes, kill “invaders” such as Rituxan-tagged B cells (and innocent little red cells, when things go haywire in AIHA). But they become overwhelmed by the sheer number of Rituxan-B cell complexes when a lot of Rituxan is used (Taylor et al are still trying to define “a lot,” but is appears to be somewhere above 30 mg, definitely above 60 mg, and therefore includes standard-dose Rituxan). At a certain point, rather than killing the cells, the cells are sent to the liver, where they are shorn of their Rituxan-B cell complexes but not killed. In other words, the body has taken a shortcut to solving the problem. Et voila -- what returns to the bloodstream is a B CLL cell, minus its CD20 and any Rituxan that was attached to it. You have now officially shot yourself in the foot, or somewhere worse. Yes, CD20 may grown back over time, but there is no doubt that this process is a setback in treatment that is better off avoided. You don’t want to end up feeling like the cat in the photo at the end of this post.

Complementary medicine

Beyond this, there is evidence that the massive cell-kill process initiated when Rituxan is used also depletes complement. It recovers, but not immediately, rendering diminishing results in the interim. Early in his research, Taylor looked at this end of the problem and asked: What if we give the patient more complement? In a 2002 abstract, Taylor and colleagues concluded: “We suggest that if an anti-tumor mAb such as Rituxan requires robust Complement (C) activation for therapeutic efficacy, then insuring an adequate level of C activity in a patient, by supplementation with either fresh plasma or a purified C component such as C2, may provide an important approach for improving the therapeutic efficacy of a C-fixing mAb.”

This sounds logical, and an abstract presented at ASH in 2005 by Israeli doctors showed that this worked in one patient: a woman who had been through the chemo mill, including fludarabine and cyclophosphamide as well as Rituxan, and who was barely responsive to therapy anymore. Her doctors gave her two units of fresh-frozen plasma followed by 400 mg/m2 of Rituxan on day one, and the same amount of plasma followed by 275 mg/m2 of Rituxan on day two. They described her response as “dramatic,” and this included “marked reduction of lymphadenopathy” and resolution of other symptoms.

“To the best of our knowledge,” the doctors concluded, “this is the first description of a case where successful induction of dramatic and rapid improvement of both clinical and laboratory parameters in a patient with advanced CLL previously resistant to Rituxan-containing chemo-immunotherapy was achieved by combining Rituxan therapy with fresh frozen plasma as a source for complement. This observation has to be verified in additional patients in order to confirm the approach of potentiation of Rituxan effect by providing increased amount of complement in order to augment CDC.”

So, why not go this route? Well, I tried to get my second hem/onc, Dr. Chopin, interested in it back in 2005, and she looked at me like a deer caught in the headlights. The fact is that it is impractical and experimental. Using lower-doses of Rituxan, so that complement does not become overwhelmed in the first place, is far more practical, as well as more cost effective.

Non-standard standards

How did 375 mg/m2 get to be the standard dose for Rituxan in CLL? There appears to be some question about this. One suggestion is that this was an arbitrary dose, determined by how much was on hand in an early study and how many patients needed to be treated. Another explanation is that it is based on a pivotal trial of Rituxan in patients with relapsed indolent lymphomas such as low-grade NHL. In this trial, the results published in 1998 by McLaughlin et al of MD Anderson, dosages of 375 mg/m2 once weekly for four weeks were used. This formed the basis for the use of 375 mg/m2 in the 2001 CLL study by Byrd et al -- it is directly cited -- in which patients were given Rituxan three times a week. This was in an effort to make up for the difference in effectiveness, as it were, between CD20 expression in indolent lymphomas and CLL. (Dr. Byrd still uses this protocol, and this is the one I tried last October until a plateau was reached, so the results in my case were rather disappointing.)

The larger point is this: There may not always be a truly logical reason behind the dose-selection of drugs. If the story about arbitrary dosage of Rituxan is true, that certainly raises a red flag. Even if the 375 mg/m2 is based on results in NHL, that may not hold water as a logical step in CLL. Low-dose Rituxan is no less logical than any of the above, and may be supported by better theory. So if it seems “weird,” it is certainly no less “weird” than the “standard.”

Another example is FCR therapy. It appears from reading CLL Topics that the FCR “lite” protocol currently in trial at the University of Pittsburgh may be every bit as effective as the regular-strength FCR protocol pioneered at MD Anderson. One would like to be a fly on the wall at meetings where dosages are determined. Is there a dartboard in the room? Do our famed researchers use “paper, scissors, rock” to decide how much fludarabine to give?

I’d like to think, of course, that the soundest of science is backing these choices, but I have a feeling that educated guesswork is every bit as common. However dosages are determined, the bottom line for us patients could not be more important. Thousands of us CLLers may have been unnecessarily overusing Rituxan for years, until a light bulb went off in Ron Taylor’s head. We shall see, of course, how brightly it shines and where it leads us.

Reading up on LDR

For those who want to examine LDR in more detail, here are some useful links that I have assembled.

Dr. Taylor does a nice job of explaining CD20 shaving in layman’s terms in a short piece he wrote for the UK CLL Support Association entitled Shaving and Rituximab: Targeting the Sharks. Chaya Venkat of CLL Topics does her usual excellent job of translating medicalese into English in the article CD 20 Shaving with Rituxan. An earlier article of Chaya’s, Role of Complement in Rituxan Therapy, is also worth reading and contains the complete abstract of Dr. Taylor’s early work suggesting that the addition of complement to Rituxan may be useful.

Dr. Taylor and colleagues have published three abstracts you might want to read. They are:

Pilot Study of Thrice-Weekly Low-Dose Rituximab (RTX) in Chronic Lymphocytic Leukemia (CLL): Decreased CD20 Loss Via "Shaving" and a Novel Strategy for Enhanced Therapeutic Targeting

A Pilot Study of Thrice-Weekly Low Dose Rituximab (RTX) in the Treatment of Chronic Lymphocytic Leukemia (CLL) Suggests Enhanced Therapeutic Targeting Compared to Standard Dose Regimens

Thrice-Weekly Low-Dose Rituximab Decreases CD20 Loss via Shaving and Promotes Enhanced Targeting in Chronic Lymphocytic Leukemia

Here is the clinical trial now underway at the NIH, which is apparently still recruiting patients, so those of you with a hankering to visit Bethesda, MD may wish to consider it:

Lower But More Frequent Dose Rituximab to Treat Chronic Lymphocytic Leukemia

The Israeli abstract -- Successful Induction of a Rapid Improvement of Both Clinical and Laboratory Parameters in a Patient with Advanced CLL by Combining Rituximab with Fresh Frozen Plasma as a Source for Complement. A Novel Therapeutic Approach? -- is only available online by logging into ASH and looking up their 2005 conference. Registration is free and it is abstract #5030.


Chris Dwyer said...

Thank you David or this excellent, balanced report on your treatment. It is great to hear that is is working better than you expected 'so far'.

Chris Dwyer

Anonymous said...

Thanks, David, this is an excellent piece: clear, sensible and very instructive. It brought together a lot of material floating around in my mind. It will help me to make decisions when time comes.

Andy Gach

Anonymous said...

Oh I'm sure researchers just made up doses! Maybe they used a Ouija board!

You insult researchers with your ill-informed musings.

Dosing is based upon animal studies, and then tested in the clinical trials.

I'm sure you have heard that the phase I trial is a dosing-safety trial, where the maximum dose is established. This means the dose is given in ever-increasing levels until toxicities become apparent.

Maybe there is science behind this after all!!!

Varying the level of doses has been tried many times before. Usually, higher doses are tried to see if they provide better results.

Now it may be true that the 'shaving' reaction is important, and Dr. Taylor has something. But don't insult other researchers by saying the idea to vary doses ONLY happened when a light bulb went off in His head!

Isn't rituxan a fairly new drug? Isn't it true that even Dr. Taylor is unsure how rituxan even works?

And maybe even you will grant that Dr. Taylor's trials are PART OF THE CLINICAL TRIAL PROCESS and PART OF THE SCIENTIFIC METHOD! Things are being learned every day. Even science!

How about that!

I'm not sure, but I'd venture a wage that the dumbest CLL researcher is a heck of a lot smarter than the average CLL patient. I know that these guys are smarter than I am. Maybe a few are even smarter than you???

Terry Hamblin said...

We are still experimenting with the idea of low-dose rituximab. I organized a meeting last year on the use of monoclonal antibodies in CLL. This was where Chaya first met Ron Taylor, and where Martin Glennie described the development of HuMax. There are other developments in monoclonal antibody therapy in the pipeline. Following that meeting we have organized a formal trial of low-dose rituximab in the UK. My own personal experience with it has not been as optimistic as David's but the only way to be sure of its value is to treat a lot more patients.

Going right back to the start of monoclonal antibody therapy in the 1980s we were aware of the potential loss of antigen from the cell surface as well as the possibility of the exhaustion of complement (which we saw in some of our early patients treated with anti-idiotype). It really is true that we gave the as much antibody as we could, only dependent on how many patients we wanted to treat and how much antibody we could produce. The doses that were estimated from animal studies proved to be very wide of the mark, and those calculated from first principles - number of target molecules on the cells, volume of distribution, etc - were equally wayward. Why is it that Alemtuzumab, which binds to CD52 and which is far more widely distributed than CD20, is given in so much smaller doses than Rituximab?

Terry Hamblin

Jenny Lou said...

Thank you for documenting your experiences with LDR. I think you know that with steroid use ending that your nodes will return, so take all those photos now! LOL...

David Arenson said...

I suppose patients undergoing treatment have a natural optimism about their treatment, but I have tried to present a balanced account of where things stand with LDR. Stable disease is the best some people seem to get out of it. My guess is that it may work as well as standard-dose for some patients, probably those with less disease and at earlier stages. Frankly, I don't know how well it will ultimately work in me; if I do get to a normalized WBC, I'll be a little surprised.

In response to anonymous who mentioned the ouija board, I am aware of the clinical trial procedure and how dosages are determined in Phase I. I suppose my attempt at being a little facetious may have failed. The point I was trying to make is this: Researchers often determine what is called the maximum tolerable dose through Phase 1 studies, and then apply it to patients in later phases. The question is: Is the maximum tolerable dose always the best one? Or might a lesser dose be sufficient, as is the case, apparently, in FCR lite? And as may be the case in LDR?

We have seen what happens with chlorambucil dosing -- Dr. Hamblin has pointed out elsewhere that it has not been tested against fludarabine at a comparable dose, and therefore may not have been given a fair shake in determining its effectiveness vis-a-vis fludarabine.

The larger point is that sometimes more, sometimes less, of a drug may be warranted than the "standard" that has evolved. As Chaya Venkat is ever fond of saying, "The devil is in the details."

Jan said...

Beautifully presented and greatly enjoyed.

Alan Knight said...

It may be almost two years since you posted this, but I am so very grateful that you did, since I am nearing a decision point on treatment. This is especially true since my local oncologist knew nothing---as in "zero"---about low-dose rituxin or "rituxin shaving" when I asked him about it.

As for the caustic criticisms I saw posted here, an old editor/mentor of mine used to say, "Non carborundum illegitimi" [don't let the bastards wear you down]. I am reminded, too, of a quote attributed to Robert Moses: "Critics are eunichs."

Keep up the good--and very valuable---work.

Alan Knight
Duanesburg, NY