Friday, September 14, 2012

What is FCR?

FCR is a combination of three drugs that are each active in CLL – fludarabine, cyclophosphamide and rituximab.  Although the regimen has been used in mantle cell lymphoma and other NHL’s it is primarily a regimen used in chronic lymphocytic leukemia.  If there is such thing as a “standard regimen” in CLL, FCR is probably it.  For a regimen considered to be a “standard” there is a lot of emotional debate among academic physicians about how broadly to utilize this regimen.

I had the privilege of presenting the initial “patterns of care” data set at American Society of Hematology 2011 Annual Conference.  Put together by many of the leading minds in CLL research, this study attempts to determine just how American patients with CLL are treated in the “real world” (ie. 90% community practice, 10% academic).  The findings were surprising.  I invite you to review the 2011 data set linked here and draw your own conclusions.  In short, many US physicians hesitate to use FCR - even in the populations where clinical trial evidence suggests it has most impressive activity.   

Several years ago at a major scientific meeting one of the most important characters in CLL research was asked to give his three favorite CLL regimens.  His answer was, “FCR, FCR, FCR.”  Just a few years later though, we are hearing of the exciting new therapies including ibrutinib, CAL-101, ABT-199, new antibodies etc.  It was therefore profound to hear the "father" of the regimen state recently, “We are going to get rid of FCR.”  While I am optimistic about the future, we live in the present.  FCR is a very effective regimen and for all its flaws - it provides some of the most durable remissions we can obtain in this disease and in some cases people have even questioned if a minority of patients might be cured.

Much credit belongs to the MD Anderson team for developing and advancing FCR.  Many of the regimens created at MDA regimens follow a theme – “if a drug works, put it together with any other drug that works and pack as much punch into a single regimen as you can.”  FCR is pretty close to the maximum amount of chemotherapy you can put into a single regimen.

It is important to note however that the average patient who travels to MD Anderson is not the same as the average patient seen in most community practices.  If you have the means, resources, insight, and physical ability to travel to Houston you are not the “typical” patient with CLL seen in the community.  Consequently, what can be done well there does not always reflect what can be done elsewhere (ie. the input influences the output). 

None the less, the German CLL research group in the CLL8 study compared FC to FCR and published one of the first studies that showed an improvement in overall survival in CLL based upon front line therapy choice in a disease that can often last many years.  Multiple other research consortiums use FCR as the standard from which to try to build, modify or compare.  With so many votes of confidence from so many smart CLL docs, the discussion about what regimen to use should often include FCR even if the unique clinical circumstances result in a different final answer.

I thought I would start by giving a brief description of each of the drugs.  For purpose of this post, I will go in reverse order because I need to spend the most time talking about fludarabine.  So I will describe RCF….

R=Rituxan. Rituxan is an antibody. You make antibodies to fight colds, flu, e.coli, etc. Instead of a naturally occurring antibody, this one is "engineered" to bind to the outside of a lymphoma/leukemia cell and alert the immune system to go after it. See my other post "Building a better CD20 antibody." People can often have "infusion reactions" with the first dose (chills, shaking, shortness of breath, rash, etc). If you actually measure "b-cells" in the blood while administering the antibody, you can see them disappear from the blood during the infusion. As those b-cells go away they release little hormones that cause the symptoms. Often the symptoms do not recur with subsequent doses as the B cells are gone. Overall, most people tolerate the drug extremely well and are not even aware they are getting a very effective anti-cancer treatment. Those patients with side effects can often be managed by extra tylenol, benadryl, steroids, etc.

C=Cyclophosphamide. This is an old school chemotherapy that has been around for quite a few years. It binds to DNA in the nucleus of the cancer cell and prevents effective replication of the cells genome. Those cells that divide more rapidly are more sensitive to the treatment. Therefore cancer cells and normal bone marrow are most affected. It lowers healthy blood cells as well as bad ones. Fortunately the good guys recover more quickly. It can also cause nausea but our nausea medications are so good, that is rarely a problem. There can be bleeding in the bladder but I have given a ton of cytoxan and I've never seen it as a problem.

Fludarabine is what is known as an “anti-metabolite.”   It earns this name by functioning as a “purine analog.” In order to explain this I have to make a quick diversion to basic cellular biology -  I promise to be brief. 

Recall, DNA is the basic “master plan” for all the genetic material a cell needs for daily living as well as replication.  It contains all the “codes” to lead to the production of all the proteins the body needs.  Proteins are the actual engines, enzymes, building blocks, etc. that do the work in the cell.  Between DNA and proteins is a molecule fairly similar to DNA called RNA.  RNA is the intermediate step between DNA and proteins.  Most of the work of protein building happens in a part of the cell known as the cytoplasm whereas the DNA stays hunkered down in the nucleus.  RNA is the “messenger” that takes the protein building instructions from the nuclear DNA to the protein assembly lines in the cytoplasm.  Both DNA and RNA are made up of a series of 4 basic building blocks.  These are two types of purines and two types of pyrimidines.

Fludarabine is just a modified version of one of the purines you already use billions of times every day.  It is similar enough to the “A” molecule in DNA and RNA that the cell can’t totally tell the difference.  Therefore, as your cells happily go along the way making or fixing DNA or sending RNA out to the cytoplasm, they can mistake a fludarabine molecule for an “A” molecule.  The “chemotherapy twist” here is that the modifications of fludarabine cause the DNA or RNA molecule to be synthesized wrong (premature chain termination, mis-matches, etc) and fall apart.

If there is one thing most cells are good at, it is making sure their DNA is just right.  We spend a ton of energy making sure we don’t have mutations in the basic blueprint of our cellular DNA.  All sorts of very important molecules such as p53, ATM, BRCA-1, PARP, etc  are there just to make sure our DNA maintains structural integrity.  If those proteins get wind that the DNA has been mutated, they try to fix the error.  If the error can’t be fixed, the cell is programed to die.

That is the basis for fludarabine activity – mess up the DNA/RNA and count on the cell to take itself out of the picture.  For a variety of reasons, your cancer cells are more sensitive than your normal cells. 

Put all these together and you have FCR!  The combo is very effective.  In studies, the median (50% do better, 50% do worse) time previously untreated patients both remain alive and without disease progression (Progression Free Survival aka PFS) is about 5-6 years!  At 10 years, 1/3 of patients still have not relapsed.  Not bad.  If you could opt for 4-6 months of therapy and not have to deal with the disease for another 10 years, I think most people would think that is a good wager (even if only 1/3 get that sort of benefit).  Current guidelines suggest that if your initial remission duration lasts greater than two years, you use the same regimen again when the disease comes back.

For most patients FCR is a moderate hassle (3 days of treatment every 28 days for 4-6 months) but the average person doesn’t feel too sick.  With FCR, you keep your hair, nausea isn’t often that big of a deal, fatigue is fairly common but not overwhelming. 

There are problems however.  T-cells are also pretty sensitive to fludarabine.  Since they are the “brains” of the immune system, FCR can really lower the immune system.  I often give patients preventative antibiotics against both the chicken pox virus (which causes shingles in adults) and an odd lung infection known as PCP which is otherwise only seen in patients with very low immune function (such as HIV).  You also have to watch out for reactivation of a virus most of us carry but rarely notice called CMV.  It can cause a whole host of strange problems.

Another issue is definitely age.  FCR gets harder to tolerate the older you are.  In the MD Anderson studies, the average age was in early to mid 60’s whereas in typical practice most patients are in their 70’s.  Those several years can make a huge difference.

Kidney function declines as a function of age.  Fludarabine gets removed by the body through the kidneys.  The same dose given to a young patient has a very different effect than it would on a patient in their late 70’s.  When given as a single agent, beyond age 70, it isn’t really clear that fludarabine works as well as old fashioned chlorambucil (a commonly utilized standard in Europe that is neglected in North America)  – at least in part because the side effects are worse.  Occasionally you see someone get really wiped out bone marrow from fludarabine based therapy.  Often it is only in retrospect that you identify that their kidney function was getting a little borderline. 

Long term, there is concern about the effect on the bone marrow.   After several cycles of fludarabine based treatment, it is not uncommon to see it take longer and longer for the marrow to recover to full strength.  Furthermore at its extreme, FCR can give rise to another big marrow problem called MDS which can even become a much more aggressive version of leukemia.  There is even a significant proportion of patients who pass away while in remission from their CLL from a second cancer.  It is not clear if this is related to FCR but it is definitely worrisome.

Those are the clinical concerns – then there are the biologic concerns.

I mentioned above that there are a lot of proteins responsible for making sure DNA is intact.  Two are of particular relevance for patients with CLL.  P53 is called the “guardian of the genome” and it is thought to be the main problem when somebody has 17p deletion because that is where p53 lives in the genome.  The other is the ATM protein which lives on chromosome 11q.  The ATM protein on 11q is responsible for fixing double stranded DNA breaks.  These two familiar proteins are often missing in patients with relapsed or refractory disease.  If someone has a FISH result that shows they have most of their cells lacking a copy of 17p they get very short durations of benefit from FCR compared to patients lacking the abnormality.  Although the published response rates to FCR exceed 90%, I had a memorable patient with 100% 17p deleted stage 4 disease not even budge in response to FCR. 

Recent technologies have made significant advances in our ability to detect if someone carries cells with p53 abnormalities.  I have written in other posts about clonalevolution in CLL.  It turns out that if you look hard enough 1/5 patients may have cells with a p53 abnormality at diagnosis even if it does not show up on their FISH panel.  It may be that only one out of several thousand cells actually has the abnormality – but it is there early on.

Now treat that patient with FCR and get rid of all the sensitive cells and you may find that what you have left are the ones that are resistant.  Even if you have a “complete response” that does not mean you may not have some resistant cells lurking – we just don’t see them very well with conventional testing.  When that patient’s disease comes back, it may be that the “resistant clone” has become the dominant.  Therefore, they may not have been 17p at diagnosis but they are at relapse.  

While 17p disease at relapse is still not the majority of patients, it is a disproportionate amount of the patients who we really struggle to get back under control and may be well served with a transplant or one of the novel agents that seem to be less influenced by 17p.

There are some very passionate feelings out there among thought leaders about the role of FCR and I need to tread carefully here.  FCR is a VERY EFFECTIVE regimen that most younger patients tolerate very well.  In a younger, good performance status patient lacking 17p at diagnosis, I think it is felt to be the treatment of choice.  In patients > age 65 I might consider alternatives unless they are very fit with good kidney function.   With newer drugs that “king of the hill” status is eroding but things never move as fast in science as our patients want.  Investigators are hoping to “replace” FCR but we have a ways to go before we are there.

We are very fortunate to have a bunch of tools in our tool shed when it comes to CLL.  The newer agents really look to be like a dramatic step forward in terms of both efficacy and tolerability.  I am optimistic that CLL treatment is going to move away from drugs that damage DNA as a basis for efficacy very soon.  We do not know what we will find in terms of resistance to the newer agents but I anticipate we will see less 17p/11q upon relapse.   Since so many new drugs are winding their way through the system, I don’t think we are too far from providing targeted treatments that may allow some patients to never get traditional chemotherapy.

That’s all for now.  There is a lot more I should probably write about the topic but perhaps it will serve as a motivation for more posts on the topic soon.  Perhaps next I will write about the patterns of care I mentioned above….

Here is video link for Michael Keating perspective on the topic.