Say hello to the “Gold Standard” CLL therapy

We discussed just a single subject at our workshop yesterday, everything about FCR that you wanted to know (but perhaps were afraid to ask).  The marathon session lasted more than three and a half hours.  It was obvious we had a motivated crowd that was there to learn, ask questions and share their thoughts.  I hope this on-line version generates as much interesting discussion. This is a very long article, reflecting as it does a very long workshop.  Don’t worry if you cannot read all of it at one sitting. It will be here on our website whenever you need it to refresh you understanding of this important therapy option.

It took a lot of work to put together all the information in this talk.  I used background material from more than a dozen published articles, coupled with my own editorial comments and evaluation of the data.  Many of these articles are listed at the end of the presentation, in the reference section.  Please send me a personal email if you wish to read the articles for yourself and would like my help in locating them.

I realize geography and time constraints made it impossible for many of you to attend.  Perhaps next year we can hold these workshops at other locations – provided you guys are willing to do your bit and organize them.  CLL Topics is thinly staffed with limited manpower resources.  We count on our membership to do a lot of the heavy lifting and I have not been disappointed thus far!

Welcome to our second CLL Workshop. I am Chaya Venkat.  Most of you know me by now – warts and all.  So, rather than wasting time talking about me, lets talk instead about something much more interesting, this drug combo called FCR.

Unless you are an extraordinarily indolent (“smoldering”) CLL patient, or you happened to be diagnosed with this disease very late in your natural life and can therefore afford the luxury of “running out the clock”, at some point you will need therapy to control your disease.  When that time comes it is almost guaranteed you and your oncologist will consider FCR as one of your major therapy options.  Most oncologists have accepted FCR is the modern day “gold standard” for treatment of CLL. I think it  is time you understood the reasons why that has happened.

Is FCR a slam dunk choice for you?

I believe in patients making therapy decisions with their eyes wide open.  There is a lot to know about FCR.  Dozens of learned articles have been written about this important chemoimmunotherapy protocol.  Most of them are written by expert researchers and meant to be read by other experts.  If you are just a garden variety innocent patient going about your business, the level of jargon in these professional reviews is usually pretty intimidating.

So, here is an example of what we try to do at CLL Topics and Updates:  we strip away the jargon, convert the “Expertese” into plain English and give you a cheat sheet that you can consult down the road when you are faced with these crucial therapy decisions.

I want to let you into a little secret:  it is not that smart people know a whole heck of a lot more than  mere patients like you and me. It is just that they know where to find the information when they need it.  The Internet has leveled the playing field a great deal, giving  “little people” like us a better shot at making smart decisions even if we did not go to Harvard Medical School

Over the last decade, FCR has gradually become the “Gold Standard” of CLL therapy options.  I have to confess I was not an early fan of FCR.  I thought it was a pretty aggressive combination (I still think it is), and its claims of vastly improved response rates a matter of grade inflation.

But over time I have changed my mind about  this therapy option.  I still believe it is not an “easy” therapy option, it is no walk in the park for majority of patients.  But to give the devil his due, this combination has proven to be a powerful and very valuable bullet in our fight to deal with this dreadful cancer. Later on in this talk we will talk more about why FCR’s claim to the label of “gold standard” has become justifiable, based on well conducted and credible clinical trials. The seminal work done at M. D. Anderson has been validated by other groups working elsewhere.  In particular, I am impressed by the study done by the German CLL group comparing FCR against FC. This was a beautifully balanced two arm study that gives us valuable apples to apples comparison.  And FCR was better than FC on all counts. Wow indeed.

FCR stands for combination of fludarabine(“Fludara”), cyclophosphamide(“Cytoxin”) and rituximab (“Rituxan”).  Earlier articles referred to the combination as “RFC”.  Same thing no difference, a different way of scrambling the alphabet omelet.

Of these three components, fludarabine and cyclophosphamide are  conventional chemotherapy drugs that have been around for a while.  Like most chemotherapy drugs, they are powerful drugs with toxicity to match.  No one would use them as recreational drugs just to get a high, not unless they were just sprung from the loony bin.  But for patients with CLL, both of these drugs have been the very important in controlling the disease. Both drugs have been around for many years.

Fludarabine is justly famous for causing T-cell counts to crash, which may in turn make you more vulnerable to opportunistic viral infections – such as a painful case of shingles, or dangerous case of viral pneumonia.  There is also concern that fludarabine may increase risk of autoimmune disease. For that reason, it is contraindicated for patients who have  AIHA (autoimmune hemolytic anemia). From the patients’ point of views one of the good things that can be said about this chemotherapy drug is that you will most likely retain your luxurious head of hair after therapy – that is, assuming you had lots of hair to begin with.

Cyclophosphamide has its own version of immune suppression.  A recently learned snippet:  cyclophosphamide kills T-regs, a set of T-cells that exert regulatory control over the behavior of other T-cells.  You should be aware that large doses of cyclophosphamide are particularly toxic to the bladder and urinary system.  What that means is that you should stay well hydrated (drink more than your usual share of water) and visit the facilities often. The idea is not to let your bladder marinate with all the drug byproducts sloshing around there, just because you are too lazy to get up and go.

Both fludarabine and cyclophosphamde are very good at killing CLL cells and they seem to work better in tandem than each by itself.  Unfortunately, they are not “smart drugs, in the sense that they are not very good at limiting their killing rampage to just CLL cells.  A lot of other perfectly innocent and healthy cells get killed in the process – a case of collateral damage unavoidable during indiscriminate carpet bombing warfare.  Red blood cells, platelets, neutrophils etc all take a hit during therapy with these drugs.  Even more important, there may be some damage to the precious blood stem cells in your bone marrow.  Since these blood stem cells are necessary to repopulate all the other cell lines at end of therapy, losing too many of them can be very dangerous – one reason why such potent chemotherapy may be contra-indicated for elderly patients with limited bone marrow reserve to begin with. All in all,  both of these drugs are quickly administered and rather easy to tolerate, not counting pesky little things like hematological toxicity, infections, loss of bone marrow reserve etc down the road.

What has changed the CLL scene is the advent of Rituxan, the first monoclonal antibody  to come along in the early 2000s.  This is not a chemotherapy drug. Rituxan is an immunotherapy drug – a monoclonal antibody – a smart drug that can tag and target B-cells (CLL is a B-cell cancer), making them more ‘visible’ and susceptible to attack by the patient’s own immune system.Rituxan targets the CD20 marker that is present on all mature B-cells and no other cell line.  The combination of FC+R is therefore called a chemoimmunotherapy combination.

The million dollar point to remember is this:  this  smart drug makes all the other drugs given along  with it work better.  Rituxan cannot do a whole lot of heavy lifting by itself, but it makes it  easier for its side-kicks to carry  out the job of killing cells, once they are tagged by Rituxan.  Think of Rituxan as the drug that paints a huge red bull’s eye on B-cells, making the job of F and C that much easier.

Thank your lucky stars you were diagnosed with CLL in this new era of monoclonals.  Make no mistake about it, average life expectancy of CLL patients has increased over the last decade. Chemoimmunotherapy remissions last longer, toxicity is reduced as we decrease the dosage of chemotherapy and increase the immunotherapy component; and most important, patients are living longer with better quality of life. Most of that improvement can be attributed to the contribution of these new generation immunotherapy drugs. Rituxan is  just the first in this series of smart drugs.

FCR therapy was pioneered at M. D. Anderson, Houston.  They are the ones that started the ball rolling all the way back in 1999, they have done the largest clinical trials with this combination. It is only fair that we discuss the protocol they used in their studies.  I used their seminal and recent paper in “Blood” (April 2008) as the basis for most of the protocol details I discuss here.

There are a lot of details.  Try not to get frustrated.  There is no pop-quiz at the end of this workshop that you have to ace.  This presentation will be on our Updates website, along with the text of my comments. You can refer to it whenever you need to refresh your memory.  That is the nice thing about Internet sites like ours.  We are not like the daily newspaper with short shelf-time.  Since we began publishing Updates January of 2009, I have written just over 90 articles.  They are all still relevant, still available to you when and if you want to read them, at your leisure.

We will be discussing drug dosages of F, C and R; the sequence of their administration in each cycle; how many cycles are usually prescribed and why; what other medications are given ahead of time to protect the patient, what drugs are given prior to infusion to reduce infusion related side effects, what drugs may be needed down the road to control adverse effects experienced by majority of patients.

Last but not least, I will give you my two cents on things you can do to maximize effectiveness of the therapy while reducing the possible adverse effects.  You are not a passive lab rat in this process.  You are a savvy patient looking out for your own welfare.  The more you learn, the more you participate in the process, the better you will do.  It is just that simple.  Motivated and organized patients are far less likely to fall victim to unforeseen complications and hospital errors.  Lord knows mistakes are made even in the best run institutions.  Remember, it is your skin at risk in this game.  How well FCR works for you is heck of a lot more important to you than anyone else.  If  the details are not important to you, why else should anyone else care about them?

The M. D. Anderson trial recruited 300  CLL patients over the period of 1999-2003.  That makes it a large study and that in turn makes the results credible.  Unfortunately, it was a single arm trial. There was no built-in control group that exactly matched the patients  in this trial.  We must compare these results against historical results of how other groups of CLL patients fared when other therapies were used.  It is not quite the same thing.  There are subtle differences, not-so-subtle built in researcher and institutional biases etc any time we consider single arm trials.  Fortunately, FCR clinical trials have now been conducted at many other prestigious institutions and while there are slight differences, the general findings at M. D. Anderson have been replicated elsewhere.  In particular, the recent German study comparing FCR versus FC has made it amply clear that addition of “R” to “FC” is indeed a no-brainer.

These were “naïve” patients – that does not mean these guys were wet behind the ears innocents willing to be sold anything – the word “naïve” refers to their chemo status.  These were patients who had never been treated for their CLL, this was their very first CLL therapy.  If you prefer, you can classify them as “chemo virgins”.  Turns out it makes a huge difference whether or not patients come into the FCR therapy in a virginal state or after they have flirted with other therapy regimens before.  We will discuss that point in greater detail later on.

As you can see, a range of dosage is specified for each of the three therapy drugs.  As researchers learned more about this combo, it is only to be expected that they would fine-tune the drug dosages.  The general trend has been to increase the amount of Rituxan while reducing the amounts of fludarabine and cyclophosphamide.  The role played by Rituxan has been shown to be even more significant that originally thought, hence the increase in its dosage.

Remember, it is always a question of maximizing rewards while reducing the toxicity costs of any of these combinations.  Variations on the theme such as “FCR Lite” have explored this concept by adding on long term Rituxan maintenance to front-end FCR combinations with increased emphasis on Rituxan.  Now that FCR has become an accepted mainstream therapy, it is reasonable to expect local hematologists and oncologists will further tailor the drug dosages to match requirements of individual patients.  It is a good idea to discuss these details with your doctors before you start FCR therapy.

I would like to bring to your attention the units used in the drug dosages – mg/m2.  Most of you know that “mg” stands for milligram or a thousandth of a gram.  But the term “m2” deserves explanation.  Expanding it, “m2” stands for “meters square” and it stands for the body surface area of the patient measured in square meters.

Think about it.  It makes sense to tailor the amount  of any drug given to patients depending on the size of the patient.  A petite woman patient standing 5 feet tall and weighing 100 lbs should get a smaller amount of drug than a hefty 6 foot tall guy weighing twice as much.  Researchers have developed a nifty equation for calculating the body surface area (BSA)of patients using their weight and height.  Click on the link to visit a site that will do the calculation for you, if you plug in your weight and height.  Most people of average build have BSA of around 2.  As an example, if you are of average build with a BSA of say, 2.1, Rituxan dosage of 375 mg/m2 means you should be getting a total of 375 X 2.1 = 787.5 milligrams of the drug.

If you are about to start therapy, I suggest you ask your doctor for the drug dosages he plans to use, ahead of time.  Using the website we cited above, calculate your own personal BSA, depending on your weight and height.  Do the math, figure out exactly how much of each drug you should be getting at each infusion. Write this stuff down in your therapy journal and make sure you get the correct dosage when you are actually in the infusion chair.  Just one more precaution to take and easy enough to do if you are organized ahead of time.  Twice in my husband’s career as a  CLL patient I was able to catch dosage errors before they were administered to my husband. Every little bit helps.

Most CLL patients are advised to commence taking a drug called allopurinol about a week ahead of start of therapy.  If your doctor does not mention it in the weeks leading up to start of FCR therapy, I strongly urge you to bring it up and discuss it with him.

When patients undergo powerful therapy regimens such as FCR, the hope is that the drugs will kill the pesky CLL cells easily and in large numbers.  After all, that is the whole point of the exercise, kill off the cancer cells in your body, right?

But there is a little detail that can turn this very desirable cancer cell killing into a very dangerous situation for patients. It is called “Tumor lysis syndrome”.  In simple terms, when any therapy kills cancer cells in large numbers, the dead and dying cells create a lot of debris that has to be disposed of by the patient’s body.  One of the by-products of dying cells is uric acid.  Normally, uric acid is disposed of by your kidneys. It gets dissolved in the water you drink and disposed of as urine.  But uric acid is only slightly soluble in water and when too many cells are dying too fast, out stripping the capacity of the  kidneys to dispose of this toxic by-product, uric acid can build up to alarming levels in the blood.  Have you ever lived in a large city during a garbage strike, especially during the summer months?  The smelly garbage bags pile up on the curb, pretty soon there are all kinds of roaches and rodents feeding on the garbage and life gets miserable awfully fast.  Some thing like that happens when there is too much cellular debris for your kidneys to handle.  Sudden and massive spike in uric acid can cause kidney damage and even kidney failure – and death.  At the very least your chances of developing kidney stones goes up.  Kidney stones are nothing more than undissolved uric acid. Another nasty disease associated with excessive uric acid is gout.

People with large tumor load (high WBC, very enlarged lymph nodes etc) are most at risk.  As you can imagine, people going into therapy with  less than healthy kidneys are even more at risk.  Allopurinol makes the process of getting rid of uric acid a bit easier, thereby reducing the risk of TLS. Unfortunately, significant minority of patients develop allergic reaction to allopurinol – they may develop a rash or a serious case of itchiness.  Another drug (“rasburicase”) has recently become available for such cases.

Many of us are familiar with Benadryl as anti-allergy medication.  Some institutions also use Tagamet as a pre-infusion medication. Tagamet is often used for stomach acid control, but here it is used because it is an anti-histamine. Steroids such as prednisone are also used sometimes.  All of these medications serve the purpose of  preventing  excessive “allergic” reaction to Rituxan.   Tylenol is given for the usual reason, to prevent any fever.  All in all, the side effects of Rituxan are similar to mild flu like symptoms – most of the time and in majority of patients.  But there are always exceptions to the rule, some people have more extreme response to the mouse juice.  The trick is to go slow, take things easy, make sure the patient is monitored carefully – especially the first time. Here is a bit of actionable advice:  make your Rituxan infusion appointments for early in the day.  As you can imagine, infusion nurses are less likely to be thrilled with sticking around for a long drawn out infusion that started late in the afternoon.

FCR is a very immune suppressive therapy.  True, it does a good job of killing CLL cells.  But it also does a number on red blood cells, neutrophils, platelets etc.  Anemia (loss of red blood cells), neutropenia (reduced neutrophil counts)  and / or thrombocytopenia (reduced platelet counts)  are common and vast majority of patients develop one or more of these during the course of the 6 months of therapy and for as much as a year afterwards. Anemia makes you feel tired all the time and long lasting neutropenia can cause increased risk of infections.  Thrombocytopenia can increase risk of bleeding. Growth factors such as Procrit (for increasing red blood cell production) and Neupogen (neutropphil production growth factor) are among the reasons why it is possible for majority of patients to finish all six cycles, since they help the patient recover essential blood counts.  But growth factors are potent medicine and it makes sense to use them prudently.  More is not necessarily better, as we discussed in several articles referring to thedark side of epo drugs.

The standard of care is to try and protect the patient from infections, before they happen.  Prevention is a whole lot easier than treatment after the fact. Of particular concern are pulmonary infections that accelerate into a more dangerous case of pneumonia.  Overuse of broad-spectrum antibiotics has spawned a host of drug resistant bugs.  But if you are elderly or have had prior bouts of pneumonia and have other risk factors for developing it, you should discuss this carefully with your doctors.  Bactrim is often used, sometimes at reduced dose to prevent PCP (penumocystis carini infection) – but be aware that some patients are allergic to this drug and in that case another antibiotic is prescribed. Unfortunately, most CLL patients do not mount sufficient response to vaccines and therefore cannot benefit from pneumonia vaccines.

Viral reactivation is a big issue.  Once infected, most of us harbor tell-tale remnants of a variety of viruses in our body for the rest of our lives. The worst offenders in this category are the various members of the Herpes family of viruses. Under normal circumstances these trace levels of viruses are kept under check  by your immune system.  But  both CLL and therapies used to treat it – such as FCR – do a real number on your immune competence.  Of particular importance is the drastic reduction of T-cell counts during therapy. Dr. Terry Hamblin described the T-cell competency of CLL patients undergoing therapy to be similar to those of AIDS patients.

T-cells are the frontline troops for controlling viral infections.  The window of opportunity while you are going through FCR therapy may be all that is needed to precipitate a bad case ofshingles – herpes zoster.  Fortunately we now have a number of very good anti-viral drugs that can prevent viral reactivation.  Best practices protocols recommend use of drugs such as acyclovir (“Zovirax”), famcyclovir (“Famvir”), valacyclovir (“Valtrex”)  for prevention of herpes zoster reactivation. Many people have been on daily use of such anti-viral drugs for many years for control of oral or genital herpes, with remarkably low toxicity.  Be sure to discuss these prophylactic medications with your doctor ahead of time, especially if you think you are at high risk of shingles attack.

With the exception of the very first cycle, Rituxan is usually administered as a single dose on the first day of each 28 day cycle.  Fludarabine and cyclophosphamide are given on days 1, 2 and 3. The you go home and recover from therapy for the next 25 days. Different protocols are used for the very first cycle of FCR by different institutions.  The aim in each case is to introduce the patient to Rituxan ever so slowly and carefully, so that there are no over-the-top immune reactions to it.

The standard FCR therapy protocol calls for 6 such 28 day cycles.  We are talking of 6 months of therapy, give or take a few days.  It is a good idea to stick to the schedule, unless ill-health or badly tanking blood counts mandates the cycles cannot be given every 28 days – or the patient gets less than the 6 cycles.  Very often elderly patients or those with significant other health problems need to have the cycles customized to suit their specific requirements.

That brings up an interesting question.  Many patients write to me asking why they need to have more cycles of FCR when their blood counts are perfectly normal after the first couple of cycles.  This is not a trivial question and it is one that we should discuss thoughtfully.

For starters, it is not enough just to have “normal” blood counts.  What about lymph nodes, including the ones you cannot see staring back at you as you shave, or feel by poking around?  What about the bone marrow, spleen etc?  CLL is a very disseminated disease.  From day one, it has access to every part of your body, every nook and cranny that blood can travel.  Getting fixated on blood counts is a rookie mistake to make and it will cost you dearly if you make therapy decisions based solely on blood counts.

If your doctor declares you have a “CR” remission (clean blood counts, no nodes or spleen that he could feel by poking around) after your third cycle, should you quit at that point, just say no to the remaining three cycles?  Aha.  Not so fast. In the next slide we will discuss the changing definition of complete response.  As we have gotten more sophisticated technology (pcr, four color flow cytometry etc), we can detect remaining CLL cells at a hundred fold increased sensitivity.  Is your CR just a garden variety old fashioned CR or is it one of the new fangled MRD negative remissions?  MRD stands for minimum residual disease.  If you are MRD negative at end of therapy, your remission is likely to last a lot longer than if you were in just plain vanilla CR remission.  Hanging in there for the long haul and finishing all six cycles may get you better clearance of the CLL cells, a deeper remission that lasts a longer time – which means you don’t have to worry about what to do for an encore any time soon.

But on the other hand, no one would want to expose their bodies to more chemotherapy than they need, just for the heck of it.  Or you may have developed health complications, toxicity etc to the point where you are ready to cry “uncle!”  and quit half way through.  Please refer to an earlier article: “How much chemo is too much?” where we discuss the pros and cons, how to judge when you have had just enough chemo for maximum impact  but not too much.

This is a complicated slide.  But I will walk you through it and it is important that you understand it.

The horizontal axis is time from start of therapy.  The vertical axis is the amount of CLL you have in your body.  We are using an arbitrary scale here to illustrate the points.  Most patients facing therapy have many zillions of CLL cells in their bodies, way up at the top left hand corner of the graph. Now let us see what is likely to happen as the patient is treated.  We are comparing the effects of single agent chlorambucil, or fludarabine, or FCR.

Starting at time zero and moving to the right as therapy proceeds, chlorambucil dutifully reduces the number of CLL cells, killing as many as 99% of the cancer cells and  perhaps bringing them down all the way down close to the 10,000 mark on our arbitrary scale.  In most cases, response after chlorambucil  is not good enough for old fashioned “CR” (complete response, defined as normalized blood counts, no swollen nodes or spleen felt upon physical examination – your doctor poking around).  Not too many people got full CR after chlorambucil and the remaining cancer cells quickly multiply – as you can see in the quick upward drift of the red curve.

Fludarabine is more powerful than chlorambucil.  Many more patients have sufficient CLL cell kill that the green line dips below the old fashioned definition of CR.  The tumor load is reduced a lot more than with chlorambucil, but it is far from zero.  Since we did a better job of killing off more of the cancer cells, more patients get “CR” on their charts, and it takes a little longer for the green line to bounce back up – the remission lasts a bit longer – but relapse is inevitable and too soon for comfort in most cases.

We now have much more sensitive ways of detecting remnants of CLL cells in the body.  Polymerase chain reaction (‘pcr”)  is one such technique. Four color flow cytometry is another.  Whatever the technique used, we can now detect minimum residual disease (MRD) with greater sensitivity.  That defines a new goal for patients – old fashioned garden variety CR is not good enough any more, we aim to get MRD negative remission.  Notice we have just upped the ante by a hundred fold, in going from CR to MRD negative remission.

Possibility of getting such a deep clean out after FCR means majority patients get CR, and a significant percentage of these guys do not show any CLL cells even with our most sensitive methods – they are in MRD negative remission . Are the MRD minus guys cured? Is CLL killed, once and for all, never to show its ugly face?

No such luck.  As you can see in the blue line representing FCR therapy, even people reaching MRD negative status will eventually relapse.  But it will take a lot longer before the few CLL cells still left behind can regroup and grow back into detectable levels.  Another way of saying the same thing – the remissions last longer and MRD negative remissions can last many years without patients needing therapy again.

Now let us go back to that question of whether patients should stop FCR after the first couple of cycles because they are in  old fashioned CR stage.  What do you think will happen to them?  They are more likely to be following this green line, relapsing a lot sooner than if they had stuck to game plan and got their best possible remission, perhaps a full fledged MRD negative remission.  Moral of the story, do NOT count your chickens before the eggs hatch.  Why would you go through all the hassles of FCR and then pull your punches too soon, therefore relapse too soon?

What does a real CURE look like on this chart?  Look at this black dotted line, where the CLL cell count goes to honest ZERO.  That is a cure.  No CLL cells left behind to grow back, no chance of a relapse.  Our technology cannot reach that goal – not yet.

How about these gold dotted lines?  These are  the next best thing to a CURE and they are within our grasp today.  These gold lines represent what may happen after a mini allo stem cell transplant.  Patients can hope to get really good clean out, CLL cells killed to the same extent as powerful combinations such as FCR. In fact combos such as FCR are used in the pre-conditioning regimen of mini-allo transplants.  But there is a second chapter to the story.  Stem cell transplants replace your no-good, asleep at the job, cancer loving immune system with a brand new immune system from a healthy donor.   The idea is that graft-versus-leukemia kicks in, the new immune system goes on the warpath mounting an effective immune surveillance that keeps the last few CLL cells from growing back.  As long as an active immune system is keeping the cancer from growing out of control, bashing its head every time the CLL tries to stage a come-back, the patient is CURED for all practical purposes. Please read the many articles we have on the subject of mini-allo transplants both on this website as well as our flagship website  www.clltopics.org

There are some things you can control, some things outside of your control..You did not ask for this CLL diagnosis, you did not ask for the high risk prognostics and the need for FCR therapy.  But here you are, and it is up to you to do the best you can to increase your chances of a healthy and durable remission after the FCR.

First thing I want to ask you to do is have a frank and detailed discussion with your doctor about all the other medications and supplements you take. That includes the daily vitamin tablet, the odd green tea capsule, statins, blood pressure medication, Viagra, hormone replacement, nicotine patches, Chinese herbal concoctions – I mean all of the stuff you take.

The reason for this is quite simple and we discussed it in a recent article on Updates, titled “Take care of your liver”.  Everything you put into your body winds up in your liver, for detoxification.  The more load you put on your liver, the harder it becomes for it to do its job properly.  A dysfunctional liver can kill you a whole lot sooner than CLL.  All the stuff you were taking earlier may have been working out just fine, liver trundling along and doing its job. But now you are looking at massive doses of chemotherapy drugs, known poisons.  Your liver has to handle all that.  Besides, the whole point of FCR is to kill the zillions of CLL cells in your body.  When cells die, they create a large amount of debris that can become toxic unless it is carted away and disposed of properly.  You would not want to fumigate your roach infested apartment and then leave the dead roaches just lying around, would you?  The same logic applies to getting rid of debris created by dead and dying CLL cells.  If you want to make sure your liver is not over-loaded in the process, you may have to cut back on what else you are asking it to do.  This is particularly important in the case of patients with heavy tumor load – very high white blood cell counts or large lymph nodes.  The garbage accumulation can be even more extreme in their case.

There is no doubt that FCR does a huge number on your T-cell counts.  Almost all patients have drastically reduced number of these fearless virus hunters.  Lack of sufficient T-cells means you are more at risk of opportunistic infections as well as brand new infections.  You should be especially on the watch for pulmonary infections.  Pneumonia is the single biggest killer of CLL patients. Prevention is far better than taking care of the infection after it has taken root and established squatters’ rights in your lungs.  Make the life style changes you need to make to avoid getting infected.

We have already discussed the role of active patient participation in reducing / avoiding hospital errors in drug dosages etc.  I am the first to admit this is a little hard to do for patients undergoing heavy duty chemotherapy and not feeling quite perky in the process.  A stiff dose of Benadryl can knock you out as well. This is where it really helps to have a friend or significant other to watch out for you.  Written notes and instructions to yourself or your friend will make things a lot easier to keep things under control.  Make sure the infusion nurse spells out for you each and every drug you are getting, as well as the dosage you are getting.  Most nurses welcome a polite but involved and informed patients since it makes their job easier.

Most of us are familiar with swollen feet and ankles when we sit for many hours in cramped airline seats.  The swelling is due to pooling of lymph in lower extremities.  Did you know there is a full fledged lymphatic circulation that matches blood circulation over every inch of your body?  The big difference is that while blood circulates in your body by means of an active pump (your heart) pushing it around, there is no such active pumping going on for lymph circulation.  What makes lymph fluid to flow around your body and not become a static pool someplace is the movement of your large muscles.  Think of it as muscular squeezing of the lymph vessels to move the liquid around.  It makes sense to me that it is particularly important not to become a total couch potato when you are undergoing chemotherapy.  You want that lymph fluid moving around nicely, get the drugs circulating well into all the nooks and crannies of your lymphatic system.  Have you heard of something called the “Lance Armstrong Effect“?

Exercise will also make you feel a whole lot better.  It may not always be possible to work out, especially if you are suffering from therapy related anemia.  Just do the best you can, no one can do more than that.

Staying well hydrated (water, not junk colas please!) is important, for pretty much the same reasons we discussed above with reference to your liver. In this case it is also your kidneys you are trying to protect.  By the way, drinking a lot of water and then being too lazy to get to the bathroom until your bladder cries uncle is not a good idea.  Wheel that infusion pool with you, but get to the john and get rid of all the drug by-products etc in your urine every couple of hours while you are getting infused.  This is a good habit to make several weeks before, during and after getting therapy.

One last item related to T-cell depletion.  Many experts believe that T-cells (and NK cells) are involved in active immune surveillance, keeping an eye out for incipient microscopic clusters of cancer cells and killing them right away, before they grow much larger and develop real fangs.  T-cell depleted patients (such as CLL patients, AIDS patients, people undergoing chemotherapy) are much more prone to skin cancer.  Last thing you want is to get a nice remission from the CLL but then have to face aggressive skin cancer.  Stay the heck out of the sun, take vitamin D3 supplements with proper monitoring and your doctor’s permission and don’t forget to schedule regular dermatological check-ups. Dark skinned people don’t get a free pass either.  In fact, they are more likely to get dangerous melanoma – instead of less dangerous squamous cell carcinoma or basal cell carcinoma.

I am always preaching the importance of weighing risks and rewards before you make therapy decisions. Let us talk about what we can expect b y way of remission after FCR, followed by the cost side of the equation.

The statistics are fortunately quite robust, both because of the large scale studies done at M. D. Anderson and the more rigorous double arm studies done in Europe.  We can get a sense of how many people are likely to respond, how long the remissions last etc.

But I want to point out one thing.  Statistics are developed from the experience of large groups of people.  They are very important in giving us a lay of the land.  They do NOT however, define exactly how you as an individual patient is going to respond.  Think of statistical information as the handicapping of the various horses in a horse race.  It makes sense to look at the information before you make your bet.  But does the handicapping information guarantee that the best rated horse is going to win the race?  No, it does not.  All it does is give you the odds on how a given horse is likely to perform in the race.

In other words, the FCR statistics are important information to understand but they do not guarantee with absolute certainty how you yourself will respond to FCR therapy.  Your mileage may vary, depending on your specific medical situation.

Last but not least we will discuss what happens to patients after they relapse following FCR

Response to therapy is diced and sliced into several categories, depending on how good the response is.  I know, a bunch of jargon, but it is important jargon and you are better off knowing what it all means.

CR stands for complete response or complete remission.Unfortunately, it is not what the English words imply, complete response in the sense you are done , CLL is defeated once and for all and you can forget all about this awful cancer. CR is defined as clean blood test counts (WBC, ALC in normal range, no anemia, no neutropenia, no thrombocytopenia – i.e., red blood cells, neutrophils, platelets are all in the normal range), your doctor cannot feel any swollen lymph nodes or spleen no matter how diligently he pokes around.  Old fashioned CR does not depend on CT scans.  So, you could still have enlarged nodes buried deep in your gut and beyond the reach of your doctor’s poking fingers.  You could also have residual CLL in your bone marrow.  Old fashioned definition of CR does not require bone marrow biopsy.  But I must point out more and more expert centers are requiring a BMB and / or CT scan to stage their patients more accurately at the end of full course of therapy.

A nodular PR is  a CR for all practical purposes, just that the patient still has a few nodules of CLL clusters in his bone marrow. If the doc had not insisted on a BMB you would not even have known about it.

PR stands for partial response. Some centers further parse that into PR-i and PR-d.  In the case of PR-d the patient has achieved only a partial clearance of CLL, does not meet the definition of a CR because there is still remaining disease as can be seen in white blood count or still enlarged nodes. PR-i on the other hand refers to someone who meets all the requirements of a full CR, but cannot be given that grade because he is a little low on red blood cells, or platelets etc.  He has one or more cytopenias that have not yet resolved.

Until FCR came along, it was very rare to get 72% of people into CR state remission.  You will notice the first column adds up to 95% (taking into account rounding of decimals), a whopping 95% got some kind of remission.  Only 5% of the patients failed to get at least a partial remission from FCR.  Some of these unfortunate 5% had “stable disease” meaning things got no worse, while some had “progressive disease” meaning the CLL continued to grow even with everything FCR was throwing at it, and some of these patients died during therapy.

How long did the remissions last? As you would expect, the deeper the remission the longer it lasted. For people who achieved a CR, at 85 months past completion of therapy half of them were still in remission.  Folks, that is a wonderfully long 7 years!  Going down the column, people who had residual disease after completion of therapy, those with PR-d, half of these guys  had relapsed by month 19 – a year and half.

How about survival? How many people were still alive after completing FCR?  Again, the guys who got  CR did best.  At the 6 year mark, 88% of them were still alive.  At the other end of the spectrum, people who got only a PR-d, with obvious residual disease, less than half of them were alive 6 years later.

Moral of the story:  the better the quality of your remission, the deeper it is, the longer it will take the CLL to grow back and the longer you will stay in remission and the longer you will live.


Now that we have had a little peak at what FCR results look like, we will go on to discuss what makes this the new gold standard. We will look back to when chlorambucil, fludarabine and cyclophosphamide were the only available drugs, Rituxan was not available.  We will compare FCR versus these old standards and see how far we have come.

People get all flummoxed by survival charts. I will walk you through a couple, show you how to read them.  It is no big deal, once you have figured out how to do it.  I will also take this opportunity to remind you once again not to get bummed out by general statistics.  Each patient is an unique individual and  your particular prognosis depends on many things.

But I thought I would give the punch line right here. The jury is in.  It is no longer a question open to debate.  If you need therapy, you are better off getting FCR compared to single agent F, single agent chlorambucil or F+C combination.  Compared to strictly chemotherapy regimens such as F, FC of chlorambucil, the chemoimmunotherapy combination of FCR is better on all counts. It is nice to have a clear-cut verdict for a change.

There are a few cases where FCR is contraindicated and something like single agent chlorambucil may be a better choice.  We will be discussing this in greater detail  later in this presentation.

 

I said I was going to help you understand how to read survival curves.  It is almost mandatory for clinical trial articles to have graphs like this.  They look scary, but actually they are quite easy to read, once you know how.

The horizontal axis is months since end of therapy.  As you can see, the scale extends to 108 months or 9 years – quite a long period to have followed these patients.

We have three curves here, color coded for your convenience.  The top line in blue is for FCR.  The  green line in the middle represents patients who got F+C; some of them also got mitoxantrone – but for the purposes of this discussion I am going to ignore that little dogleg.  The bottom line in red refers to patients who got single agent fludarabine.

The vertical axis is the percentage of patients alive.  At the start of the monitoring process all the patients are alive and all the curves start at the 100% point.  As the months go by, some of the patients don’t make it and all three curves start dipping downward, reflecting the fact that fewer of the patients are alive as time goes on.

To compare these three therapy options, let us look in detail at the status of all three patient groups at say, 6 years out from end of therapy.  We draw a vertical line going straight up, starting at the 72 month mark (6 years).  As you can see, the dotted black line meets each of the three curves at different points.  We now draw horizontal lines from the point of intersections and going towards  the left, to get the percentage of people still alive at the 6 year mark we chose.  After 6 years, roughly 78% of the FCR patients are alive, about 60% of the FC patients are alive, but only 54% of the single agent fludarabine patients are alive.  I did not put the statistics on this chart in order to keep it uncluttered, but this difference between each of the three curves was statistically significant – in other words, the difference is real and not just due to happenstance. 

CLL tends to be a confusing disease with few clear-cut nuggets of wisdom.  This is an exception.  FCR has been proven to be better than single agent F or F+C on all counts – no ifs and buts.  If you are a CLL patient looking to make therapy decisions and your doctor recommends FC as the frontline therapy, you have a couple of issues to consider:  is he up to speed on this latest stuff?  Is he trying to save money for the insurance company by not using the more expensive Rituxan combination? Is he paying sufficient attention to what is likely to be in your best interests?  Last but not least, should you vote with your feet and get yourself another doctor who does not have these problems? There are a few exceptions, cases where FCR is contraindicated – and we will discuss them later on.

FCR is the clear winner, compared to FC.  But let me add this caveat since our website is read by patients all over the world.  Rituxan is not (yet) available in every country and not every patient can afford to pay for it.  If these are the pragmatic but bleak realities you and your doctor face, then the decision to use FC becomes more understandable.  We can only hope that as time goes by and patent protection goes away and the door opens to cheaper generic versions of Rituxan this important monoclonal antibody becomes more widely available without costing an arm and a leg.  One of the reasons why we pushed so hard for FDA approval of ofatumumab (Humax-CD20, Arzerra, another anti-CD20 monoclonal like Rituxan) is in the hope that once competition heats up prices may come down.  We can only hope it will happen soon enough to matter to patients reading this article today.

Let us look at some more detailed analysis of FCR versus FC.  The previous slide compared FCR results based on a single arm study with historical data from patients who had FC or F.  That is not really a kosher comparison since the groups could have been different, biasing the results.

So, we ask the question: in a head to head comparison, do patients undergoing FCR chemoimmunotherapy live longer than those getting plain vanilla chemotherapy of FC – without the magical “R”?  In one word, the answer is YES.

An excellent randomized phase III clinical trial done by the German CLL group leaves no doubt on this front.  The overall response rate was higher, more people got the coveted “CR” response, the remissions lasted a whole lot longer (52 months versus 33 months!) and best of all, at little over three years post therapy, a larger percentage of patients getting FCR were alive, compared to those getting just FC. 

The higher percentage of deaths in the plain chemo arm is almost all due to progressive disease.  It is also reassuring to note that the addition of R did not increase the percentage of deaths due to secondary cancers or treatment related mortality.  In other words, there is nothing here to suggest Rituxan adds significantly to the toxicity already baked into the FC cake, but its addition improves the remissions.  Improved benefits, no extra “cost” – just what we want to hear.

There is an often quoted saying: lies, damn lies and statistics.

There is some element of truth in that.  All too often we see trials run by drug companies where they compare their drug against a particularly weak “standard therapy”, a straw-man comparison where they are guaranteed a win by the nature of the half-baked comparison.  We have taken note of such trials and criticized them on our website.   For example, a recent trial compared the new darling “Treanda” (bendamustine) against a particularly low dose version of chlorambucil therapy as the standard and declared Treanda a winner.  A lot of money rides on the success of these industry funded clinical trials, and it is easy to get taken in by the self-serving hype.

So, is the comparison of FC versus FCR more of the same, is it a straw-man comparison that gave an automatic win to FCR?  No, that is not the case. In its own day, FC was truly the most potent therapy there was, patients were grateful for this combo therapy as compared to single agent F or chlorambucil.

The chart above proves the point.  Three curves, representing the percentage of patients who remained in remission after therapy.  At the five year mark, roughly 38% of the FC patients were in remission.  But only 10% or so of the patients who got single agent F or chlorambucil were still in remission.  This is quite a difference, and by the way, as you can see from the chart, this difference between the FC and the other two therapies was obvious from day one.

 

Does everyone get a whopping long remission after FCR?  The answer is NO.  How long your remission lasts depends on how deep your remission was to begin with.

We talked about the old fashioned “CR” standard of a decade ago, which meant nothing more than that your blood counts looked OK and the doc could not feel any swollen lymph nodes or spleen with his fingers.  We now have much better methods to look for CLL cells, methods such as pcr (polymerase chain reaction) that are 100 times more sensitive than simple blood tests.

So, it is possible to categorize patients into three groups.  All of these guys got a “CR”.  But looking more closely using pcr technology, we can divide them into three groups.  First group (blue curve) are the really lucky guys, no trace of CLL cells could be seen even when we used pcr technology to go looking for them. These guys are said to be in pcr negative remission.  Another term used for such a deep remission is MRD negative remission – meaning the patients were negative for minimum residual disease.

The red curve represents patients at the other end of the spectrum, those who had CLL remnants at the end of therapy, traces that could be clearly seen by pcr testing.  The green curve represents the in-between guys, who did not quite make it to the coveted pcr negative status, but who missed the mark by just a little.

Once again, let us look at the 5 year mark and how these three different groups fared. 90% of patients who got a pcr negative remission to begin with were still in remission.  But only 42% of the pcr positive patients were still in remission, more than half of this group had already relapsed. 

Moral of the story: getting an old fashioned “CR” does not tell the whole story.  Folks who get really, truly, squeaky clean pcr negative remissions have the longest remissions as well.  Sort of common sense really, when you think about it.

 Let me point out a bleak aspect of this chart.  Even the folks who got pcr negative remission did not stay in remission for ever.  FCR does not CURE CLL.  People will relapse, inevitably.  It is only a matter of time.  Even the pcr negative curve (blue curve) dips down inexorably.  There is no point where it flattens out, no more people relapsing after that point.  It is clear that if we go long enough on the horizontal axis, wait long enough in time, eventually all the patients relapse.

But before you start crying into your beer, let us look at the other side of that coin. You are a healthy 75 year old guy, you went for FCR and got a pcr negative remission, and that set you up with a better than even chance of staying in remission for another 7 years or more, into your eighties.  Is that good enough?  We are all mortal, it is just a question of when.  Remission length of 7 years to a 75 year old guys is terrific news.  But to a 40 year old patient the same 7 year remission prognosis is not good enough, not by a long shot. 

 

Why do some patients get deep remissions and other don’t?  As you would expect, it has to do with their prognostics.  If you were lucky to begin with, if you had good prognostics going in, your luck will probably hold and you will also get a deep remission.  If on the other hand you had lousy prognostics going into FCR therapy,  you would be kidding yourself if you expected to get the best possible pcr negative remission.  It could happen, you could beat the odds, but it would not be something that you can bet on.

Most of you have heard of the IgVH gene mutation status test.  This is probably the single most important prognostic test. People with the mutated version of IgVH have good prognosis, those with the unmutated version have more aggressive disease.

This chart shows that indeed IgVH gene mutation status is a good predictor of how patients are likely to do after FCR therapy.  All of these guys got an old fashioned CR. There is clear difference between the good prognosis mutated group (blue line) and the worse prognosis unmutated IgVH gene group. At the six year mark, roughly 82% of the mutated IgVH group were still in remission, in stark comparison to more than half of the unmutated group who had relapsed. That fits with what we know of IgVH gene mutation status.  CLL cells with mutated IgVH are less likely to have babies quickly and grow back rapidly after completion of therapy – the remissions are likely to last longer.  The opposite is true of unmutated IgVH cells. Even if the patient got just as deep clearance of CLL cells, these unmutated IgVH CLL cells proliferate more quickly and the remissions fail sooner.

This is kind of a bleak analysis.  I would have liked to see an entirely different story, that FCR was so potent that it could turn the tables on IgVH gene mutation status and make even the poor prognosis guys get stellar remissions.  That is not the case.  How you respond to FCR depends on the prognostics of your disease, your overall health, and other things like luck that you don’t really control.


I use “cost” in quotes because I am not going to be discussing the dollar cost of FCR – even though that too is quite substantial and in some countries it is high enough to keep FCR out of reach of the general CLL patient.  I will be looking at the other “cost”, namely the cost of FCR in the toll it takes on your body.

“Cytopenia” is a general word to describe lower than healthy blood counts.  The three cytopenias of interest to us are anemia (too few red blood cells, too low hemoglobin, leaving us tired all the time), neutropenia (too few neutrophils, leaving us vulnerable to infections) and thrombocytopenia (too few platelets, increasing the risk of uncontrolled bleeding, possibly stroke, GI tract bleeding etc).

19% of patients undergoing FCR had persistent cytopenias of one kind or another.  28% had late, recurrent cytopenia, meaning they had episodes of anemia, neutropenia etc that resolved and came back again and again, for as much as a year after completion of therapy.  This is no small matter.  This is the hematological toxicity we were talking about earlier.  Prudent use of growth factors such as Procrit and Neupogen can help.  Careful monitoring of blood counts is necessary to catch the problems early on so that something can be done about them.

Infections are generally graded into four groups.  Grade – I infections are no big deal, just a case of feeling a little under the weather.  Grade – II is typically obvious infection but nothing much to write home about.  Grade III and IV are the serious stuff.  Often they require intravenous antibiotics etc to treat, which in turn may mean hospitalization.  When research papers talk about “serious infections”, they are talking about Grade – III and IV infections.  Recently someone pointed out to me that there is a further  Grade – V, representing patients who did not survive.  Talk about using jargon to cover real life situations.

10% of the FCR patients had serious infections in the first year.  That is not trivial  by any means and I will have more details on that in the next slide. Many of these were bacterial infections but a significant number were also due to destruction of T-cell counts which made it easier for viral infections to take hold.

Many of you have heard of Richter’s transformation.  This is when CLL (an indolent leukemia) morphs into a lot more dangerous and aggressive lymphoma.  Patients with Richter’s transformation have much shorter survival prospects and need aggressive therapy right away to try and control their disease.  We have discussed this topic before, here is the link to our earlier article on Richter’s transformation.

There was concern that combination of purine analogs (fludarabine) with alkylating agents (cyclophosphamide) can be sufficiently toxic to the bone marrow as to causemyelodysplasia - which in turn can lead to myeloid cancers. There were 8 cases of myelodisplasia  among this group of 300 patients who were treated with FCR.  Not a  hugely scary statistic, but not one to dismiss either.

Since infections were perhaps the single biggest issue on the “cost” side of the equation, I thought we should look at it in greater detail. The chart above is directly taken from the seminal 2008 M. D. Anderson article. This bar graph shows the percentage of infections in their 300 patient cohort. As we discussed before, all of these reported infections were Grade – III and Grade – IV infections, serious stuff and not just the odd case of sniffles.

First year there were just under 10% infections. Since this is a group of 300 patients, that adds up to 26 patients. Next to the yellow bar at the one year mark are 26 circles representing the 26 patients who suffered serious infections. 10 of these (color coded green) were bacterial infections. Ten (color coded yellow) were cases of shingles – varicella zoster reactivation. Six (color coded red) were various infections due to loss of T-cell counts – opportunistic infections that do not normally happen in people with healthy T-cell counts. Three of these 26 people died of their infections, represented by the red cross across their circle.

With each successive year the infection rate dropped. There were just 10 cases the next year and by the time the third year rolled around the case load dropped to onesies and twosies. It is interesting to see that the red circles – infections due to loss of T-cell counts – went away after the first year. To be expected, since T-cell counts gradually recover after end of therapy.

If your local oncologist does not believe in prophylactic medication to protect you against bacterial infections and / or protection against shingles attack, this may be a good graph to show him. Especially if you are prone to bacterial infections (pneumonia comes to mind) and have had prior episodes of shingles. Prevention is the name of the game.


The bleak news we must face is that no matter how good FCR is, it does not represent a full and honest CURE of CLL. Patients will relapse eventually, it is a case of when and  not if.  So, the question becomes important, what is life like after patients have relapsed following FCR induced remission?

Obviously, the answer depends to a great deal on how deep the remission was to begin with, how long it lasted.  Someone who got a terrific MRD negative remission that lasted a long 7 years and eventually relapsed probably has a good chance of getting another decent remission using salvage therapy. On the other hand patients who had shabby response and whose remissions failed soon after are in a much tougher situation. 

In a recent article we discussed “Life after FCR“, reviewing results from M. D. Anderson as they followed their FCR treated patients.  After relapse patients tried a variety of salvage therapies, including retreatment with FCR.  Also among the  list of salvage therapies are Campath containing regimens, experimental drugs such as flavopiridol etc. 

Median survival for the whole group was less than three years, no matter which particular salvage therapy was chosen. For patients who did not do so well after FCR (short remissions), the medial survival was just about 1 year.  “None of the regimens showed a significant survival benefit.” is the down-beat assessment of the authors.  Only 14 out of the full cohort of 97 patients survived more than 4 years.  Of these, a large majority (11 out of 14 – a whopping 79%) had chosen the transplant route.  That is the single most important bright ray of hope for these FCR relapsed patients looking to decide on their next choice. 

While these data are both startling and perhaps depressing, there are details to rember.  For starters, other drugs that were not available to these FCR relapsed patients are making their way through the pipeline, and there is always hope that the paradigm will change when new drugs become available.

 Second, since these 97 patients were by definition patients that were among the early relapsers after FCR, are we looking at a particularly high risk subset in the overall group of 300 patients who went through the M. D. Anderson FCR trial?  Stated differently, will life after FCR relapse look more encouraging if we wait long enough to look at what happened to all 300 patients in the MDA study and not just the guys who relapsed early?


My major concern about FCR is that it is an aggressive therapy.  That concern remains, even though I am now a great deal more impressed with the number and quality of remissions it can bring about.  The trial participants in the M. D. Anderson study were a tad younger than your garden variety of CLL patient.  Does age make a difference on whether or not FCR is appropriate for you?

The answer is YES.  As we get older, we lose more of our precious blood stem cells in our bone marrow – an unavoidable fact of life.  And as we discussed earlier, FCR toxicity is not limited to just CLL cells. It also causes massive cell death in other blood cells.  Among the unintended victims are blood stem cells.  If too many stem cells are killed, and the patient had a smaller number to begin with on account of being older, there may be too few stem cells left over at the end of FCR therapy.  Without sufficient number of blood stem cells – bone marrow reserve – it will be very difficult for the patient to grow back all the cell lines – red blood cells, platelets etc – needed for good health at the end of FCR therapy.  In other words, age is a definite criteria to take into account in deciding whether FCR is appropriate for you.

Advanced age is also likely to cause other medical comorbidities.  Cardiac health issues creep in, as well as increased risk of type-2 diabetes.  Kidney function may not be what it was when you were younger.  Why are these important?  Poor cardiac health means it will be that much harder for you to tolerate therapy induced anemia, when your heart has to work harder getting enough oxygen to the rest of your body.  Patients with active diabetes are more at risk of infections and FCR therapy can make a bad situation worse. Kidney function is important because many of the drugs used in FCR therapy are removed from your body via your kidneys.  Poor kidney function means the drugs will linger for a longer time in your body and may build up to dangerously high levels.  What this means is that if there are concerns about how your kidneys are working, that should be taken into account and your drug dosages revised downwards accordingly.


All the wonderful response statistics we have discussed thus far were based on using FCR in chemo-naive patients.  How does the picture look in the case of patients who have been around the block one or more times, been exposed to other drugs?  As always, the devil is in the details. How much chemo has the patient had, what kind of chemo, how many times, how long has it been since last chemo treatment – all of these are relevant to the discussion.  On general basis, more chemo in the patient’s case history means more refractory disease and poorer response to any future therapy – including FCR.

For a heady period in the early days of Rituxan many patients (including me) thought single agent Rituxan was the proverbial free-lunch.  It was assumed that since this was not chemotherapy, prior use of single agent Rituxan would not burn any bridges in terms of response sensitivity to chemo or chemoimmunotherapy regimens later on.  That is not the case.  Patients do develop resistance to Rituxan therapy – experts are still arguing about how this resistance develops, the exact mechanism of it.  But the fact of the resistance means someone who has had boat loads of Rituxan in his past is not going to get as good a remission to FCR, compared to how the same patient would have done if his body had never been exposed to this monoclonal antibody.


This data is courtesy of M. D. Anderson. Right at the bottom of this chart (green box)  are all the wonderful statistics we have focused on thus far, the case of chemo naive patients.  Compare that line against the top line of the chart, describing how 177 patients who have had prior therapy responded to FCR.  The overall remission rate plunged from 94% to just 73%, a huge drop.  Even more important, the remissions were poorer quality.  Only 25% of previously treated patients got a CR, compared to 72% chemo naive patients – almost three times as many.   The data then breaks out prior exposure into different groups.  Notice that exposure to single agent Rituxan (blue box) took a toll as well, not all that different than exposure to standard chemotherapy drugs such as alkylating agents or even F+C combo.  Of the lot, the guys who had been exposed to fludarabine and become refractory to it were in the worst situation.  Almost half of them did not respond to FCR and only 6% of them got a CR.  I am willing to bet the remission durations were equally short for this group of patients.

 


In the time remaining to us, let us discuss briefly the variations on the theme proposed to make FCR more effective or less toxic.

While FCR was pioneered at M. D. Anderson, FR was studied most closely at Ohio State.  It boils down to this: can we get as much oomph with just FR, leave out the cyclophosphamide?  Afterall, cyclophosphamide has quite a list of potential toxicities associated with it.  And there is that nagging question of increased risk of myelodysplasia when we combine alkylating agents (C) with purine analogs (F).

Another option is FCR Lite.  In this approach, the researchers decreased the dosages of F and C, while increasing the amount of Rituxan used in each of the six cycles.  They also added a maintenance phase, where the patients got regularly scheduled infusions of just Rituxan after completing the normal six monthly cycles.

Another variation on the theme is PCR, where pentostatin (P) is substituted in place of fludarabine (F).  Pentostatin has been studied at great detail by Mayo clinic and it should come as no surprise to you that the PCR combination is pioneered at the same institution.  Pentostatin is also a purine analog, similar to fludarabine and has a similar mechanism of action.  But some researchers think it is a kinder and gentler version of fludarabine.

Last but not least is the replacement of Rituxan in FCR with Arzerra (ofatumumab, Humax-CD20).  FCO trials are happening as we speak at many centers.  The theory is that since ofatumumab hangs on to the CD20 marker on B-cells without letting go, it may work better than Rituxan and therefore FCO may work better than FCR – with no additional toxicity.  As a matter of fact, since ofatumumab is fully human antibody, it may pose fewer adverse effects than Rituxan with its share of mouse protein in it.  Just a couple of days ago I published an article on a trial at the NIH using  FC+O combination, with maintenance regimen of ofatumumab at the end of the six monthly cycles.  Only time will tell if this new approach will be “Better than the gold standard“.

There have been other efforts at further improving FCR.  For example, researchers have looked at addition of adding a second monoclonal to the list.  FCR + Campath has been studied extensively at M. D. Anderson.  This approach seems to have some value in very refractory cases but I am not all that comfortable with the high level of toxicity (mostly a huge big additional wallop of immune suppression courtesy of Campath) and this four letter combo (M. D. Anderson calls it “CFAR”) is not for everyone.  Another approach that failed to live up to expectations is the addition of lumiluximab (an anti-CD23 monoclonal antibody) to FCR.  Equally disappointing in my book  was the addition of mitoxantrone to FCR.  We have reviewed the clinical trial results of FCR+Lumi and FCR+mitoxantrone on our website, if you wish to read about them.


Unfortunately, we do not have any one-on-one comparisons of FCR versus FR.  The best we can do is compare two single arm studies, each of which looked at the two different approaches.  That kind of comparison is likely to have a lot of room for errors, since the two groups are not well matched, there are small differences in the protocols etc.  There is general consensus that cyclophosphamide adds to the toxicity and dropping it reduces the toxicity.  Duh.  But when it comes to how it impacts efficacy, there is more divergence of opinion.  One group suggests that since FC is better than F (as seen in the German trials), FCR should be better than FR.  Several researchers have also suggested that in the case of high risk patients  (especially those with 11q deletion by FISH) the addition of C  is necessary and FCR is a better choice for such patients.  Another issue to consider is that since FR is likely to be less toxic than FCR, dropping the “C” may be something worth doing in older patients with reduced bone marrow reserve.  Bottom line, this is a difficult choice to make and the available information is clear as mud.  Talk it over carefully with your doctors, make the choice that sounds best to you – and then do not second guess yourself.


I was very pleased when I saw a paper a couple of years ago, comparing FCR and PCR head-on.  I thought for a change we will get a straight answer to this question,  which is a better choice?  Does substituting pentostatin in the place of fludarabine make it a kinder and gentler option with no reduction in effectiveness?  I am sorry to say, the paper was a huge disappointment.  You can read more details on our prior review comparing FCR versus PCR

The trial used pretty much identical drug dosages to compare FCR and PCR.  The C and R portions of the protocol were the same.  F and P dosages were equivalent (it is standard to use approximately 1/5th as much pentostatin as fludarabine, having to do with the different molecular structures).  So far, so good.

Then we come to the reported and results and all hell breaks loose.  The statistics reported for FCR are so far out of kilter from what anyone else saw using FCR that I have no way of understanding these results.  If the results of the FCR arm of this two arm study are unreliable, how can we depend on the PCR part of the trial results?  All in all, this study and the paper that resulted from it was an exercise in frustration, perhaps a classic example of how not to conduct clinical trials.

A far more credible report on PCR (Mayo Clinic) was unfortunately a single arm study.  As always, comparisons of single arm studies with historical data can be difficult and has  built in mechanism for biased comparisons.  This paper failed to prove conclusively that PCR was indeed a kinder and gentler therapy for all the patients involved.  They were able to make the case that in a subset of elderly patients the replacement of “F” by “P” may have resulted in less toxicity.  So, if you fall into that category, it is important that you check it out, see if PCR is a better choice.  But speaking purely on statistical terms, subset analysis of a single arm study compared to historical norms is a bit of a stretch. 


Turning to FCR Lite as our next variation on the theme of FCR:  Dr. Kenneth Foon started this trial at University of Pittsburgh.  I understand he is continuing this research at his new location, Nevada Cancer Center.  I believe the FCR Lite trial is still recruiting patients, in case you are interested. We reviewed Dr. Foons article in the Journal of Clinical Oncology earlier on our website.

The concept here is to reduce the amount of F and C used, while dramatically increasing the amount of R used.  Both FCR and FCR Lite use the 6 monthly cycles format.  As you would expect, the overall amount of F and C used in FCR Lite is significantly lower (bottom two lines of chart above). More Rituxan is used in the monthly cycles and added on top of that is the regularly scheduled infusion of Rituxan in a maintenance phase after the six monthly cycles are done.  FCR Lite uses an overall 9,875 mg/m2of Rituxan, compared to a much smaller 2,875 mg/m2 for FCR – Classic protocol.


So, what is the answer?  Does FCR Lite work as well as FCR classic, but with lower toxicity?  If our healthcare and insurance systems can afford to pay for that huge increase in the amount of Rituxan (by far the most expensive part of FCR drug combo), is FCR Lite a better choice?  The answer is a thundering “maybe”.  We do not know.  Once again, we are left comparing  results from two separate single arm trials – not quite apples to apples comparison.  At the very best, this is a Red delicious apples to Granny Smith comparison.  Further more, the FCR Lite trial reports on only 48 patients, a small number, and these were monitored for 27 months – a short period of time.  We need to see larger scale studies and patients monitored for longer periods in order to have credible data that we can compare against FCR classic.  But even with this level of information, I think it is safe to say that the FCR Lite protocol reduces the risk of neutropenia – not something to sneeze at.  Neutropenia in turn translates into risk of infections.  The  reduction in neutropenia is to be expected, given the FCR Lite protocol uses smaller doses of F and C.

Thanks for sticking it out, listening (reading) to this very long presentation.  As I said earlier, you don’t have to know all this stuff and pass any pop quizzes.  All you have to know is the general themes we discussed and, this is most important, realize you can look up the rest of the stuff anytime you want to refresh your memory.

Last but by no means least, I would like to honor the hundreds of CLL patients who participated in the clinical trials we discussed today.  But for their courage and generosity, we would still be shadow-boxing blind folded.  FCR would not have become the modern day gold standard.  Idealism and altruism are still alive and well, people still go out of their way to help complete strangers.  “Do it for the fat lady

You would think that would deserve an acknowledgment from the researchers who conducted the clinical trials.  The professional papers I reviewed in this workshop thank their sponsors, colleagues who participated in the research, even the secretary down the hall who typed the manuscript for publication.  Conspicuous by its absence is any “thank-you” to the patients who made the whole thing possible in the first place.  This is a pet peeve of mine, and I think it highlights  a deeply entrenched problem in our healthcare-system.  Clinical trial recruitment will languish until and unless researchers and research institutions accept patients are central to the whole process, treated as equal partners deserving respect and thanks.

So, let us remedy the shortcomings of the acknowledgment sections of the research papers.  Please join me in a nice round of applause to thank our guys who made this research possible in the first place.