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Chemotherapy

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Failures in Therapy

Date: August 30, 2003

by Chaya Venkat

Sure Things That Somehow Didn't Work Out

Mesoamerican ruins

There are many reasons why promising therapy approaches often do not work out in practice, some to do with the basic biochemistry of the disease and the immune system and some to do with economics or the vagaries of our healthcare system. We will deal here only with the science..

Of Mice and Men

Here is my take on why processes that work in mice do not always pan out in humans.

I think it has something to do with the natural life span of the two species. Cancer happens when a random mutation, an error in the transcription of the rules and regulations that govern cellular growth and death happens, due to genetic abnormalities, environmental factors, whatever. The longer the life span, the greater the chance that something will go wrong, just by happenstance. It is no coincidence that with the exception of a few specific cancers that predominate in children, most of the cancers in humans are age related.

The body develops very complex and inter-related ways in which to distinguish "self" and "non-self" organisms within the body. The function of the immune system is to destroy the "non-self" without attacking the "self". My guess would be that the mechanisms that control immune functions in humans would be a lot more complex than those in mice, evolved that way over the millennia because there is more need for complexity in longer lived humans. A therapy that works in mice may not work in humans because the cancer may be able to use a mechanism present in humans that does not exist in mice, to get around the therapy. Taking the argument one step in the other direction, cancer cell lines in lab cultures are a lot less complex organizations, and what works in a petri-dish in the lab does not always work in mice! I know this is a simplistic view, and I am not sure it is the most important reason, but it seems right to me.

Another thought: if a mouse's tumor disappears completely, we would say it is "cured", even if it dies a couple of years later, at the end of its natural span. Since we live a lot longer, the results of the experiment are judged more rigorously. Not only should the tumor disappear, but it must not return for a very long period of time, often measured in decades, before we call the therapy a cure. As we all know, even "PCR Negative" means a few thousand cancer cells may still be around. (PCR negative just means that if the cancer cells are still around, they are in numbers that are below our ability to detect them. But on the other side of the coin, it does not mean that there are any left in the first place.) How long will it take for them to grow back into a detectable tumor, if they chose to do so? If you were a mouse, you might die of old age before the cancer has a chance to grow back, and you could care less about it. The story is different if you are a  person with a long life to live. The yardsticks are different.

Etodolac - A Shell Game?

When one of our members asked about the potential of etodolac in treating CLL, another of our members came up with an article in Blood of April 2002 addressing the effects of etodolac on clearance of leukemic lymphocytes in B-cell CLL. The article is entitled "Enhanced clearance of leukemic lymphocytes in B-cell chronic lymphocytic leukemia with etodolac". Here is the URL: Blood Journal etodolac article.

You might be amused, (or angry, or shocked or frustrated) by this story. Etodolac (a common pain killer like most NSAIDs, such as aspirin etc) was touted at one time as a possible miracle drug in CLL. The accidental observation that WBC counts in patients went down significantly when Etodolac was administered was the basis of this excitement. This could be shown repeatedly: the lymphocyte counts went down every time the drug was administered, and returned back to old levels in just a couple of days after the drug was stopped. I understand there were clinical trials conducted in Europe with live CLL patients, but I have not seen any detailed reports based on the results of these clinical trials. 

To cut to the chase, Etodolac does not kill any lymphocytes. None. Period. So what causes the drop in lymphocyte counts in blood CBC? Very simply, it was later discovered that Etodolac re-distributes the white blood cells in their various compartments. It moves them out of the peripheral blood stream and into the spleen and lymph nodes. Stop giving the drug to the patient, and the white blood cells go back to their normal distribution, and the CBC numbers look the way they did before the whole experiment. 

I don't think any of us are naive enough any more to think that just shuffling the CLL cells from the blood into the spleen or lymph nodes is any kind of a "cure". Sure, your blood WBC results will look better, but that means nothing, the cancer cells have just been moved elsewhere, to potentially more difficult to treat locations. Fortunately, the effect of Etodolac seems to be short lived, and therefore none of the patients in their clinical trial were likely to have been harmed. 

The Blood article that John has dug up confirms this analysis. I also found a lengthy and complicated patent filed by these guys that claims "chemotaxis" (ability to move  specific cells from one site to another by means of chemical 'bread crumb trails'). 

There have been rumors circulating that new clinical trials are being considered in this country, using Etodolac as maintenance therapy for patients in first remission after standard therapies. This makes no kind of sense to me. It might make gullible patients more relaxed, I suppose, if they see their peripheral blood CBC numbers stay stable and unchanged. But if all Etodolac achieves is moving the CLL cells to the spleen or lymph nodes, no real therapeutic effect has been achieved, this is no more than a shell game. 

In my lay-person opinion, Etodolac as a drug for CLL makes no sense at all. I would recommend staying away from any clinical trials involving it. 

CD40 Ligand and Bryostatin: Drugs That Make CLL Cells Harder to Kill?

Two therapeutic approaches in CLL that I have trouble understanding are Bryostatin and Gene Therapy via CD40 ligation. I have given below some relevant links. You can read our entire review of the Gene Therapy protocol la UCSD on this website.

As we have discussed before, in the recent phase - II gene therapy trials at UCSD, a deactivated adenoviral vector is used to transfect the patient's own B-cells with CD40 ligand. (It is confusing, but just remember this bit: the "soul mate" for CD40 is CD154. They form a perfectly matched pair that fit together like yin and yang. Sometimes, CD154 is just called "CD40L", short form for "CD40 ligand". Sort of like calling me Chaya, or Mrs. Venkat, or P.C's ligand or P.C.L. All mean the same thing. For you new members, P.C. is my husband, the reason why I mess around with CLL in the first place.)

The abstract below seems quite emphatic. Even if you do not want to wade through the alphabet soup of acronyms, the message is clear in the two quotes below: 

"CD40L and Bryostatin decreased both spontaneous and drug-induced apoptosis in most B-CLL specimens tested". 

"The potential anti-apoptotic properties of CD40L and Bryostatin should be taken into consideration when employing these agents in clinical trials involving patients with B-CLL". 

The Burnham Institute is hardly a fly-by-night or slouch outfit. It is in fact a member of the CLL Research Consortium. The Institute does some very important theoretical research and its publications are often the basis of clinical research undertaken elsewhere. This abstract is dated 1999. The "Blood" article I have referenced below suggests CD40 ligation may inhibit the effectiveness of Fludarabine was published in 1998.

What gives?

If there is this level of confusion and uncertainty or controversy among the experts conducting these research clinical trials, I despair of laypersons like us ever being able to make sense out of this stuff. How is it possible that one prestigious research group is studying the deliberate ligation of CD40, and another is studying the prevention of such a ligation, and both groups are trying to do these exactly opposite things in order to kill CLL cells? Today has not been my day, for a variety of reasons, and this article reflects the confusion I feel.

Blood Journal article on CD40 and apoptosis: Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood 1998 Aug 1;92(3):990-5

Abstract

Br J Haematol. 1999 Sep;106(4):995-1004.

Bryostatin and CD40-ligand enhance apoptosis resistance and induce expression of cell survival genes in B-cell chronic lymphocytic leukaemia. 

Kitada S, Zapata JM, Andreeff M, Reed JC. 

The Burnham Institute, Program on Apoptosis and Cell Death Research, La Jolla, CA

Modulating signal transduction pathways represents a promising approach for altering the biological behaviour of haemopoietic malignancies. B-cell chronic lymphocytic leukaemia (B-CLL) cells were treated in vitro with CD40-ligand (CD40L) (CD154) or the protein kinase C modulator Bryostatin-1, exploring the effects on: (a) sensitivity to apoptosis induction by chemotherapeutic drugs (fludarabine, dexamethasone) or anti-Fas antibody; (b) expression of apoptosis-regulatory proteins (Bcl-2, Bcl-X, Mcl-1, Bax, Bak, BAG-1, Flip, XIAP); (c) expression of cell surface co-stimulatory antigens (CD80 [B7.1]; CD54 [ICAM-1]; CD70); and (d) expression of immune modulatory receptors (CD27, CD40, CD95 [Fas]). CD40L and Bryostatin decreased both spontaneous and drug-induced apoptosis in most B-CLL specimens tested. Apoptosis resistance was associated with CD40L- and Bryostatin-induced elevations in the anti-apoptotic Bcl-2 family protein Mcl-1. CD40L also induced striking increases in the levels of the anti-apoptotic protein Bcl-XL in B-CLLs. CD40L stimulated increases in the surface expression of CD40, CD54, CD69, CD70, CD80 and CD95, whereas Bryostatin induced expression of CD40, CD54, CD69 and CD95 but not the co-stimulatory molecules CD70 and CD80. Despite elevations in the expression of CD95 (Fas), anti-Fas antibodies failed to induce apoptosis of CD40L- and Bryostatin-treated B-CLL cells. This Fas-resistance was associated with increased expression of the Fas-antagonist Flip in CD40L-treated, and with elevations in the caspase inhibitor XIAP in Bryostatin-treated B-CLLs. The potential anti-apoptotic properties of CD40L and Bryostatin should be taken into consideration when employing these agents in clinical trials involving patients with B-CLL.  

PMID: 10520003
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The Buzz About Bryostatin

Here is an interesting recent interview on Medical News Alert, Cancer Channel, entitled "One-Two Punch for Leukemia – Full-Length Doctor's Interview". The opening blurb is catchy, it says "In this full-length doctor's interview, John Roberts, M.D., explains how a new combination approach makes leukemia more susceptible to treatment". You can read the whole interview at this URL: Cancer Channel Story. If this link fails to respond, a keyword search on www.ivanhoe.com might be of assistance.

Guess what, folks, this was all about the Bryostatin plus Fludarabine clinical trial described in ASH abstract No. 1495, NCT00005580. The good doctor missed his calling, he should be running for elected office. If you read just this electronic report of his interview (hot off the presses, dated December 2, 2002), you could be forgiven for thinking this particular combination of Bryostatin and Fludarabine was the best thing that ever happened to CLL patients. As in the ASH abstract, in this interview, too, he offers the judgment that the results are encouraging enough to continue with the next phase clinical trials. The wording was careful, but boy, was the spin doctored (pardon the pun) just right! Not mentioned was the fact that the Phase-1 trial results were disappointing, to say the least. 

A friend brought to my attention the logic behind the use of Bryostatin in CLL. It goes like this: CLL is presently not curable, mainly because it is so indolent and it is hard to target chemotherapy to cells that are lying low and not doing much of anything. There is another blood cancer, called Hairy Cell Leukemia (HCL), which is somewhat more aggressive, and has a better chance of being cured. It was observed in cell studies in test tubes (perhaps mouse studies as well, I do not know those details) that upon treatment with Bryostatin, CLL cells seemed to become "Hairy". Light bulb goes off! Eureka! We can convert the indolent CLL cells into the more aggressive HCL cells, and then cure the new disease!? 

Pardon me for being stupid, but this logic sounds a little weird to me. Come again, we want to transform the indolent CLL cells into more aggressive HCL cells? Even if it works, won't I be stuck with some cells that are HCL, and some that are the good old CLL I started with, and now I have both diseases? I doubt anyone thought there is going to be one hundred percent conversion of each and every CLL cell in my body to a HCL cell!! So now I have Hairy Cell Leukemia, which can **perhaps** be cured, and then I still have the old devil CLL to deal with. How is this a good strategy? What happened to the principle, "This above all, do no harm"?  

Actually as it turned out, the CLL cells did not really transform to Hairy Cell Leukemia upon treatment with Bryostatin, they just looked "hairy", without being HCL. I wonder what that means, do these patients now have a new and unknown version of CLL, or maybe two different diseases to worry about? Anybody tracking these "failures" on a long term basis?  As they say, success has many parents, failure is always an orphan. 

Some ideas sound great in the lab, great for researchers playing with cells or mice. But if the basic concept is spelled out as bluntly as this, which one of you would think this is worth risking your life for? And now that we have seen the depressingly mediocre results of the Phase-1 trial, which one of you will sign up for the Phase-2 version of the exact same protocol? Let me know, there is a bridge in New York that needs to be sold. 

To repeat what I have said in previous articles, I am all for furthering science, and patients participating in well defined and well documented clinical trials. But how about a little more transparency, straightforward communication minus the "spin", respect for patient rights? CLL is an indolent disease. Many of us will live quite a few years, with good quality of life, with no need for therapy of any kind. And when therapy is unavoidable, now there are more realistic options open to us than ever before, with well defined toxicity risks. No doubt this raises the bar on what is, and what is, not acceptable risk.  Clinical trial protocols need to take this into consideration. 

I guess my beef with this particular study, and that is too strong a word for my concern, is that even with these less than exciting results, the "spin" at the end of the abstract is that more trials are justified along these lines. How about calling a spade a spade, these are researchers and doctors, not politicians and lawyers that have to declare every new venture a thundering success. Clearly, not all clinical trials and reports are guilty of this, my comments are about this particular abstract.

Also, it was not clear from the description of the patient group that the CLL patients were indeed a far gone bunch with no other options. They were described as having "progressive disease", which is every patient with increasing WBC. The NHL patients, on  the other hand, were clearly spelled out as refractory and resistant to prior chemotherapy. If indeed the CLL patients selected for the study were also similarly handicapped, I would expect the researchers would have made that clear. If patients had other options, then the results of this trial were truly unfortunate. 

I am aware of the hope of transforming CLL to Hairy Cell Leukemia by use of Bryostatin, and that in fact the transformation did not happen along those lines. Would there be a follow-up of these patients who participated, to see if their un-anticipated transformation was not into something more aggressive and resistant than CLL? Anyone willing to take a bet against me there will be no long term study and monitoring results reported on how these patients fare down the road? 

My main point is this: medical jargon is hard enough to understand, but we accept it is a language that is necessary to communicate effectively between researchers, so we lay people will do our best to learn it, live with it. Boards like yours and mine will do our bit to explain the jargon. But there is no excuse for obfuscating statistics or "spin" on the results. 

I think every ethics committee out there will agree with me, transparency in reporting the results is a primary responsibility of the researchers, and patients who are volunteering for these trials have an absolute right to expect it. It goes to the heart of the whole concept of informed consent, consent that is truly informed. I see a lot of Phase II & III trials listed on the official sites, that are looking to recruit participants. Very few of them clearly discuss the results of the prior trials conducted using the same approach. A few give references to scholarly articles, that are written to communicate with other researchers, not patients. There seems to be a pervasive assumption that participation in clinical trials is a matter of trust and faith, not understanding. 

I recognize there are limitations on how much of the complex science we can follow, just because it is so complex. But the limitation should not be because of a lack of effort to communicate with patients. Trust and respect, these need to be two-way streets. Patients who participate in clinical trials are doing their community a huge service. They need every available resource in order to make informed decisions, and I for one believe strongly that they deserve the extra effort at straight forward communication. CLL Research and CLL Topics came into existence, as patient advocacy and education groups, for just that purpose.

 

 

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Pier

 

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