Date: February 9, 2006
by Chaya Venkat
Here is a quotation from one of our favorite CLL experts, Dr. Terry Hamblin, "Every treatment that I know will make the immune system worse". I agree with that statement in general terms but, at the expense of sounding like our former president Mr. Clinton, I respectfully suggest the specifics depend on the exact meaning of the words “treatment”, “immune system” and “worse”. Please allow me to explain: in my view the situation is not quite so bleak and there are exceptions to this statement. Unlike our usual articles that are studded with learned abstracts, this article is 100% editorial comments from yours truly. You might want to have several pinches of salt handy.
I love analogies, lame or otherwise. Let us say the Department of Homeland Security receives credible information that a nest of the most dangerous terrorists has holed up in a suburban house, planning and plotting how best to infiltrate the country so as to carry out their lethal attacks on the population at large. This is obviously time-sensitive information, if Homeland Security dithers around trying to figure what to do, the terrorists would finish their meeting, slink out of their safe house and blend in with the general public. If that is allowed to happen, they would be very hard to nail down later. We will next hear from them only after it is too late. Time is of the essence, we hope that the authorities will not sit on their hands, that they act promptly and decisively. A surprise attack by well trained swat team to take out the terrorists, poison gas pumped into the house to kill them, perhaps a ‘smart’ laser guided bomb to blow up the whole house; the best choice may be to do all of the above, just to be on the safe side. A few innocent citizens may get killed in the process, casualties of friendly fire. Some of the older residents may get sick from the poison gas seeping out of the target house. Some of the neighboring houses may sustain damage because even smart bombs are not 100% accurate. But if the “overkill” strategy gets all the terrorists out of the picture once and for all, makes sure they cannot spread out, no one is going to complain. The few collateral casualties are to be regretted, but no one is going to say the price was too much given the safety of the nation was at risk.
This is similar to a diagnosis of a localized and early stage tumor, say in breast cancer. Here, too, time is of the essence. If the tumor is not dealt with right away so that each and every cancer cell is eradicated, chances are the malignant cells will metastasize, and spread through the lymphatic system to the far corners of the body. Metastasized cancer is much harder to deal with, just as it is harder to find terrorists when they have spread out and blended in with the general population. This is the reason why diagnosis of solid cancers is most often immediately followed by therapy. The “watch & wait” strategy does not make sense in these cases. It is also reasonable to bring on the big guns, several of them, to make sure all the cancer cells are caught in the cross fires and none of them survive. Typically, the tumor is excised by surgery, any residual cells burned by focused radiation and the stragglers poisoned by targeted chemo-immunotherapy combinations. Multiple approaches and “non-overlapping toxicities” — the belt-and-suspenders approach — makes sense in treating localized cancers. Since we have not yet advanced to the Star Trek level of sophistication and precision, there is often some collateral damage. Surgery leaves scars, radiation and chemotherapy are never 100% targeted and therefore cause generalized toxicity, people lose their hair. You get the picture. No one would indulge in any of this if he/she did not have cancer, but given the choice of dying soon because of the cancer or the prospect of getting cured by aggressive therapy, most of us would choose to go the route of aggressive therapy, get a hat or ‘rug’ to cover the bald head until the hair grows back.
At the heart of many of the misconceptions about CLL and how best to treat it is the fact that this cancer of the immune system is quite different from localized ‘solid’ cancers that oncologists are used to dealing with, such as breast cancer, lung cancer, colon cancer, etc. Paradigms that work for these localized cancers do not work for CLL. Frankly, in many cases, they may be exactly the wrong thing to do, a case of the “cure” being worse than the disease.
Here is how the analogy would look for CLL. Homeland security is aware that there is a general sense of dissatisfaction among a segment of the law enforcement officers, and this is spread through out the country. These are not your average bomb-throwing terrorists per se, but they are malcontents that do not do their jobs right, mouth off and spread discontent through their constant bitching and moaning. It is hard to pin-point them exactly, since they look just like their innocent colleagues. Unfortunately, their poor attitude is infectious, soon enough other officers stop doing their jobs and sit around complaining as well. While these malcontents and their side-kicks / new converts lounge around mouthing off, bank robbers and murderers roam the city with no one to challenge them. The longer authorities wait, the worse it gets. As if this is not enough, there is always the chance that one of the malcontents may stew in his crazy ideas long enough that he goes over the top, goes "postal" or morphs into a card-carrying member of the tribe of terrorists. Pretty soon, this tough guy becomes the leader in his ‘hood, more and more of the hoodlums start imitating his take on things - and we now have a serious problem on our hands. Evolution is a fact of life, even malcontents evolve over time.
What to do? Nuking every police department in every city and thereby poisoning the whole country is hardly an appropriate solution. It might get the offending cops, but it will surely kill off major part of the population as well. Anyway, there is no guarantee that all of the malcontents will be killed by this process . They are too darn much like the average Joe Bloe walking down the street! This situation requires a more subtle approach. For starters, it is important to recognize this is not an immediate crisis that requires a knee-jerk response. There is time to think things through and come up with the most effective and least damaging solution. It may take hard work, courage, resolve and persistence to select and implement the right plan but speed is not the overriding factor.
I think you can see the parallels. Most of the time, a diagnosis of CLL does not require immediate and urgently scheduled therapy. “Watch & Wait” is entirely justified, to get a better fix on the lay of the land. Like our malcontents of the analogy, CLL cells are spread all through the body — there is no place in your body that blood and lymph do not circulate and therefore there is no place that is entirely safe from CLL. Without a localized enemy, it does not pay to initiate all-out war. The take-no-prisoners strategy does not work well for CLL in my opinion. Far too many innocent, healthy cells get killed by this process.
On the other side of the equation, waiting indefinitely is not a solution either, unless you are fortunate enough to have a very indolent, “smoldering” variety of CLL. As time passes, the tumor load grows and CLL cells gradually compromise other important cell lines. CLL cells are like bad cops lounging around. They do not do their jobs. As they flourish and multiply, they take up more and more space in the bone marrow, they suck up more and more of the nutrients and resources of the body. As it gets progressively more packed, the bone marrow has a hard time producing other vital cell lines. Even in patients with relatively slow-growing CLL, over time there may be a gradual drop in red blood cell, platelet and neutrophil counts. Over time other organs such as the liver and spleen may also get infiltrated, limiting their function and efficiency or causing them to behave in a destructive fashion.
Several articles point to T-cell and dendritic cell defects in late stage CLL patients. These cell lines are not cancerous themselves, but their function is compromised with increasing tumor load. CLL patients have obvious defects in their B-cell function and often have low immunoglobulins (“Ig” are secreted by plasma cells, which come from mature, healthy memory B-cells). The added burden of T-cell dysfunction leaves us wide open to a host of serious and sometimes life threatening infections. Squamous cell cancer and basal cell cancer can easily transform to more dangerous versions of skin cancer in the absence of effective T-cell function. CLL patients also have a higher incidence of other secondary cancers, probably also as a result of compromised immune surveillance. As in the analogy, diseases run rampant when the immune system is not working right. All too often, the wonky immune system starts attacking perfectly normal and necessary cell lines and this may result in a variety of autoimmune diseases such as AIHA (autoimmune hemolytic anemia), ITP (idiopathic thrombocytopenic purpura), rheumatoid arthritis, Crohn’s disease, psoriasis - the list goes on.
“Clonal evolution” is a fact of life in CLL. Cancer cells have unstable genomes to begin with, and over time it is entirely possible that new and more dangerous mutations are picked up. It is a jungle out there, there is a fight to survive even amongst cancer cells and only the baddest of the bad survive to breed more of their own kind. Even if you started with the more benign 13q deletion as your sole chromosomal abnormality, over time a new clone may be born, one with the more dangerous 11q deletion, for example. Since this new clone is harder to kill, it will gradually take over the turf and become the dominant clone in your body. It has been suggested that CLL cells that are IgVH gene mutated are more stable, less likely to develop more dangerous mutations via clonal evolution. This is one of the reason why IgVH gene mutation is a good prognostic indicator.
There is one more very simple reason why it is not a good idea to wait until the last bitter moment — “B-symptoms”. I have no idea why they are called this, and why they are “B” rather than “A” symptoms. Whatever they are called, they are no fun and take a big chunk out of your quality of life. Overwhelming fatigue, drenching night sweats, frequent infections and unwanted weight loss are but some of the unwelcome symptoms in late stage CLL patients. In some if not all, lymph nodes and organs such as the spleen and liver grow big. Even if you don’t care whether or not you look like a chipmunk with the enlarged lymph nodes along your jaw-line, sometimes these nodes can be downright painful and they can press against vital arteries or nerves.
If you are with me thus far, you will agree it is not a bad idea to hold your horses, wait a bit to sort things out before you plunge into therapy. At the same time, it may also not be such a good idea to wait until the last bitter moment either. That brings us to the crux of the problem: when, with what and how to treat CLL. Does all therapy damage your immune system and does the damage happen to the same degree? Here is where we need to parse the words carefully.
Two main groups of chemotherapy drugs are used in CLL. The older drugs were alkylating agents (chlorambucil - “Leukeran” - and cyclophosphamide - “Cytoxan”). More recently, we have added purine analogs (fludarabine - “Fludara” and pentostatin - “Nipent”). There are others as well, steroidal drugs such as prednisone, and several that are used more often in lymphoma than in leukemia, such as doxorubicin, vincristine and mitoxantrone.
Sticking to the big 4, all of them work by damaging the DNA of cancer cells to the point where the cell has no choice but die. They are all small molecules and quite effective in getting to the various nooks and crannies of the body, reaching the CLL cells whereever they may be. The problem lies in their very nature. Inevitably, the DNA damage does not limit itself entirely to CLL cells. Normal cells get damaged too and, as they die under the onslaught, the result is toxicity to various organs in your body. The biggest hit is taken by the rest of the immune system cell lines, such as neutrophils and T-cells, leaving patients vulnerable to opportunistic infections. Even more worrisome, some of the erstwhile normal but now damaged cells may survive in their mangled state and initiate new secondary cancers.
Are they all equally bad? It is hard to put this into a nice sound-bite. The devil is indeed in the detail. It is generally accepted, for example, that fludarabine gets better response statistics than chlorambucil but the profound T-cell depletion and neutropenia (loss of neutrophils) caused by fludarabine is more extensive than that caused by chlorambucil. Some researchers also suggest that pentostatin is less myelosuppressive than its sister fludarabine. Combinations of alkylating agents and purine analogs may be synergistic in their anti-leukemic action but such combinations are thought to be particularly damaging to the immune system and may even be responsible for triggering secondary myeloid cancers as well as the dangerous Richter’s transformation in a small percentage of patients. Almost invariably, the cancer cells learn to live with the damage inflicted by these drugs. Not just live, but thrive and evolve to become more resistant to any kind of therapy. “Fludarabine refractory” patients faced a grim prognosis prior to the advent of drugs such as Campath.
Very often when reviewing new chemotherapy combinations, I get the feeling we are trading higher response rates for higher levels of toxicity. Researchers experiment with various permutations and combinations of this alphabet soup, tweaking the dosages up or down to try and get the optimum "best response". There is no free lunch I am afraid. It may well be that the higher response rates are offset by more toxicity, to the point where there is no significant survival advantage between these various drugs and combinations. It is a pity that there are so few well designed phase-3 trials that do an honest apples-to-apples comparison of the various combinations. Phase II trials done in single institutions leave way too much room for institutional bias and selection bias. But I think the point I am trying to make is still valid — there are shades of grey here, not all chemotherapy drugs damage the immune system in the same way, or to the same degree. Getting over-aggressive in your short term tactics to get the deepest possible response may hurt you in the long term strategy of prolonging your overall survival.
The good news is that in the last few years we have discovered monoclonal drugs such as Rituxan and Campath. These are not your classic chemo drugs, they do not act by directly damaging the DNA. They are what I call semi-smart drugs, in the sense that they make some effort to target the CLL cells. Rituxan, for example, targets the CD20 marker expressed by all mature B-cells, not just the CLL cells. This means Rituxan therapy repeated often enough and over long enough time leads to profound B-cell depletion. Campath goes one step further, it targets the CD52 marker, which is expressed by several immune system cell lines, not just B-cells. This monoclonal can lead to profound loss of T-cell repertoire for several years after therapy! Is this damage to the immune system? You bet. But it is a different type of immune system damage, not quite the same mangling of the DNA that we see in old fashioned chemotherapy drugs. Sure enough, the loss of immune surveillance opens the door to opportunistic infections and T-cell controlled cancers such as skin cancer. But I would like to think there is less direct mutagenicity here, compared to DNA-damaging drugs.
Combinations of monoclonal drugs with chemotherapy drugs is now all the rage - chemoimmunotherapy . The alphabet soup grows with each iteration. Take your pick, there is FR, FRC, FRC+M, FRC+Campath, PCR, FluCam ... as many combinations as there are researchers out there willing to test them on us. Forgive me if I have not listed your particular favorite combo. Is it reasonable to think that in the progression of FR → FRC → FRC+M the degree of toxicity and damage to the immune system goes up as we add on more bells and whistles? In the absence of well-conducted phase-3 trials comparing these combinations head on, common sense suggests the toxicity and damage will increase as we add more drugs to the mix. It is also entirely possible that the response statistics will improve as well, as we go up this scale of aggressiveness.
The million dollar question is this: will the higher response statistics translate to longer progression-free survival and overall survival? The results to date have been equivocal. As we have seen in the recent statistics of the RF therapy, the value of a CR depends on who gets it. Patients who were lucky in having good prognostics got longer remissions, while the remissions of patients with poorer prognostics did not last as long, even if they all got the same “CR” grade a the end of the therapy. We are just beginning to see a bunch of patients relapsing after one of these new “chemo-immunotherapy” combination regimens. Will these folks respond well to re-treatment, or will the bad news be that they have used up too many bullets right off the bat and have fewer good options left? Only time will tell. Looking into my less than clear crystal ball, my guess would be that the addition of monoclonals will improve the risk/reward ratio and get us a better bang for the buck compared to plain chemo combinations. But I think increasing the alphabet string and ramping up the dosage is not likely to be the best answer here. We need to come up the learning curve on how best to optimize the combinations without making them ever more toxic. In my layperson opinion recent efforts to examine “Lite” combinations are moves in the right direction.
Do you want to know which therapy is absolutely the worst in terms of damaging your immune system? Here is one that is downright guaranteed to destroy your immune system, lock stock and barrel. It is also the only therapy that is actually proven to cure (that is right, CURE, in the English sense of the word) a significant percent of the patients who undergo this therapy. Some of you may have guessed the answer already. It is called an allogeneic stem cell transplant, preferably a mini-allo stem cell transplant. The idea here is to get rid of your immune system entirely, replace it with a healthy one from a donor. Here is a case where damaging your immune system by conditioning pre-treatment is a good thing to do, because otherwise it will fight and reject the donor graft stem cells when they are brought in to replace your own cancer prone system.
I am an optimist, I really think there is a brighter future out there for CLL patients. I do not mean way out in the distant future, I mean in the very near term and soon enough to make a difference to many of you reading this article. That is why I think it is so important for us to understand the stakes, play this game to win. The short term tactics you decide on should not leave you out in the cold, when better choices become available for longer term survival strategy.
For example, we are already beginning to explore options of treating early stage and chemo-naïve patients with low toxicity drugs such as EGCG, to see if we can gradually control the rate of growth of the cancer. It is unlikely that this approach will decisively cure the CLL, in the sense of eradicating every single CLL cell in your body. But think about it a minute. Going back to the “solid cancer” mode and the take-no-prisoners strategy is not the right answer for us. CLL is fundamentally an indolent disease. If it can be controlled to stay dormant indefinitely, at the level it was when you were first diagnosed for example, what is not to like? Hopefully approaches like this will someday let you live out your natural life span, with few complications and hassles. When that happens, we have fine-tuned the definition of “treatment”, we are no longer shooting for treatment to cure CLL, merely get a long term truce. In terms of our analogy, every society has its share of malcontents, the trick may be learning how to improve general working conditions so that the complainers have less to gripe about and we accept a certain level of inefficiency as inevitable in a pluralistic society, learn to live and let live. Perfect societies where everyone is happy and there are no malcontents are only possible in fanatics’ dreams.
In the next few weeks I hope we will be able to announce the start of a new clinical trial, a very interesting custom-made vaccine against CLL. This approach has seen very impressive results in non-Hodgkin’s lymphoma patients, and we have been campaigning with the company to open similar trials for CLL patients. Once again, the idea is to take very early stage patients with low tumor load, where the CLL cells have not already established a huge presence, train the immune system in these patients how to recognize and kill CLL cells. Going back to our analogy, this is the equivalent of educating the law enforcement community how to detect and neutralize the malingering bad cops in their midst, before they become too much of a problem. Several companies are exploring the use of custom made patient specific vaccines in B-cell cancers. Some of them have been more effective than others. The good news is that they have all been remarkably free of toxicity with no discernable damage to the immune system of any kind. This gets as close to the proverbial free lunch as I can think! My optimism is not mere wishful thinking. As we pointed out in an earlier article, a good 3-4% of the general population out there has small clusters of clonal cells within them, cells that bear all the hallmarks of classic CLL. Yet the vast majority of these people will continue with their lives, blissfully unaware of the tiny clonal colonies. Very few of them will develop into full blown, clinically diagnosable CLL. In these lucky folks, their own immune system is able to identify and kill the malignant clonal cells. Even if the clones are not completely eradicated, the immune system is capable of keeping them under control, below the radar so to speak. It seems CLL patients need to learn how to do this trick, and the vaccines are designed to teach them that.
Down the road, I would like to see this approach expanded to include patients who have been around the block. If graft-versus-leukemia can eradicate the last traces of CLL in patients undergoing mini-allo transplants, why is it not possible to treat patients with heavy tumor load with preparatory regimens to reduce the tumor load and then finish the job with a well-timed vaccine and booster shots? In fact, in the earlier trials using these types of vaccines in NHL patients, that was exactly the approach taken. Preconditioning with standard therapy to reduce tumor load, followed by vaccine therapy to get rid of the last traces. I also found an exciting reference to aggressive mantle cell lymphoma patients who went through autologous stem cell transplant, followed by the same sort of vaccine therapy, with promising results. In case you have forgotten, autologous transplants by themselves are rarely curative. In this case the auto transplants were used merely to get the tumor load as low as possible and set it up for the vaccine to deliver the final blow.
While we wait for these new technologies to become generally available, how about patients who have already progressed beyond the early stages, people whose CLL has grown over the years to a substantial presence? It is not likely that “kinder and gentler” approaches such as EGCG will hold the line for you for long. If you are in this group, there are two paths to consider. The first one is to go slow, start with the least damaging therapy first. You have to accept that the remissions are not likely to be long, and you may need frequent re-treads. When and if the chosen treatment stops working, you can work your way up the chain, keeping in mind the goal of not burning any bridge before you have to. This is fundamentally a game of playing for time. Who knows, may be you can string it out until you die of old age, or perhaps better options will become available down the road.
The second path is a bit more aggressive, but very valid if you also happen to have poor prognostic indicators. Several highly regarded researchers have echoed this advice to me. In such cases, the best thing to do may be to get a good and deep remission right off the bat, knowing full well that this remission is not likely to last very long, and therapy choices will become very limited when the inevitable relapse happens. The idea is not to waste this first and best remission. Second and third remissions are rarely as deep. Mini-allo stem cell transplants are getting better by the day and they work best when patients go into them in deep remission. The treatment-related mortality statistics are dropping as we get better at fine-tuning the procedures and a surprisingly high percent of patients go on to live their lives free of CLL. The deal is get your ducks in a row, make sure you have things lined up so that you can go seamlessly from first therapy to deep remission to stem cell transplant to cure, without missing a beat. This is one approach where you can really reap the benefit of planning for it, getting your HLA matching done, finding the right donor, finding the right expert center where they have a lot of expertise in doing these kinds of transplants, making sure you have right insurance coverage, etc. Last but not least, survival after mini-allo transplants is hugely influenced by the general health of the patient. Your chances are much better if you are in otherwise fighting trim. This where it pays off big time if you get ready for the fight ahead by getting into good shape physically and mentally.
I hope I have made my case. Not all treatments are equally damaging to the immune system. Both the level of the damage and the type of damage depends on the treatment under question. In general, high response statistics obtained by more aggressive combinations also seem to cause more toxicity and damage to the immune system, and it is yet to be proven that these early response statistics translate into longer remissions or longer life for the patients. Even as we speak, lower-impact therapies are making their way into clinical trials, some of them targeting a long-lived truce while others are aiming higher, hoping to teach your immune system to reject the cancer all together. As stem cell transplants get better, we may become a little more relaxed about damage to our present immune systems, reassured that it may be possible to replace the diseased system with a healthy one from a willing donor.
I will leave you with this last thought. CLL comes in many flavors, and there has been an explosion in our understanding of this disease in just the last 5 years. How can you make the right choices if you do not know what you are dealing with? Truly, what you and your oncologist do not know can kill you.
Editor's Note: For those interested in reading our past articles on related topics here is a reading list. You will find some of these same themes running through many of these articles.
Death by Conventional Wisdom
Fludarabine Monotherapy Is No Longer the Gold Standard
Mitoxantrone plus FCR
RF Risks and Rewards
Rituxan plus Campath
Rituxan plus Short Duration Campath
Shopping for Therapies
Project Alpha Kickoff
17-AAg Clinical Trial
Genitope May Try Vaccine in CLL
Only Real Cure - For Now
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Topic: Therapy Choices