Selecting Therapy in CLL

The CLL landscape continues to change very quickly.  I have previously written about picking a first line therapy, but my post from 2013 has become quickly outdated.

I recently had the opportunity to participate with a group called "Clinical Care Options" on a decision support tool that allows you to plug in a variety of variables that are central to picking out a treatment regimen and then seeing what therapy would be selected by a handful of experts.

To use the tool, you have to register for an account - but I thought it would be worth it for a number of patients who are at the point of picking out a particular therapy.

Here is a link to the tool

I also serve on the CLL Steering Committee for Medscape.  We have recently conducted several taped interviews discussing how to pick therapy in both the front line and relapsed / refractory setting.  Here again, you need to sign up for an account - but worth it if you want more color commentary regarding the tool outlined above.

Here is the link for the frontline video with me and Steve Coutre

Here is the link for the the relapsed / refractory video with Stephen Schuster, Matthew Davids and Amy Goodrich

I would like to predict that these will remain relevant tools for the foreseeable future but I am happy to report that they will only be valuable for another 12-24 months before the world changes again.

I tried to embed these tools directly on the blog but unfortunately was not able to do so.  I hope you find them helpful.

Thanks for reading / viewing / tooling.

Can CLL be cured?

Question for you -

What is better, 10+ years free of CLL in exchange for 6 months of chemotherapy or 10 years of a pill taken daily?  Go one step further: what if the chemo not only got rid of the disease for 10 years but actually cured some patients?

We are incredibly fortunate that there are new therapies approved by the FDA that are non-chemotherapy based - but we should be careful before abandoning something that can be extremely effective for some patients just because it is called "chemo."

Everyone desperately wants to find a cure for CLL so we need to be vigilant and avoid excessive optimism.  The idea of "curable CLL" is debatable among the researchers who study the disease.  For the purposes of this post, I need to be very clear that the difference between very long term remission and cure can become a little blurry.  At what point is a patient with no signs of leukemia considered "cured?" 

I am always careful to define "remission" when I am in the clinic.  To me, it means, "we can't see the cancer but we know that it is there."  That is very different from a cure, where one would assume it isn't.  The only thing that really distinguishes between the two is the test of time.  How much time needs to pass before you say it is no longer a remission but indeed a cure.  In CLL we have never really talked about cure before, so I guess the answer is "a long time."

When carefully identified patients are treated with FCR chemo-immunotherapy, a decent fraction of them may not have any evidence of their CLL for over a decade.  Two studies have now shown statistical outcomes to suggest that some of these patients may be cured (link here and here).  

Frequent readers of my blog likely know that I have periodically taken a skeptical view of the FCR regimen.  The multitude of new drugs such as ibrutinib and idelalisib have forced us to fundamentally re-think the best ways to treat the disease.  After the widespread introduction of bendamustine and rituximab followed by the newer agents, the enthusiasm for FCR has been steadily diminishing.  Database analysis would indicate that it is only utilized in the front line management of patients with CLL in about 20-35% of patients,

I think it is human nature to embrace things that are new and exciting - especially when that means moving away from chemotherapy.  Yet as pendulums swing away from FCR 14 years after it was initially introduced, we may be ignoring some of the most impressive arguments in favor of the regimen that are only just now becoming evident. 

The "chemoimmunotherapy regimens" such as FCR and Bendamustine-rituxan have constituted our treatment backbone for a number of years.  Please see my prior blog post about choosing between the two.  With the new non chemotherapeutic targeted drugs that are coming, there is likely to be quite a "turf war" over what regimens are right in which circumstances.  While the new drugs are primarily approved in patients with relapsed disease, there will be considerable interest in moving them to the front line setting.  Indeed, I've already had quite a few patients ask me if starting with one of the new drugs up front makes more sense than chemotherapy.  I think that in some cases the answer may be yes, in other cases no.  In many cases it is too early to tell.

So where is all this going?

CLL is biologically heterogeneous.  Two patients who look very similar can have very different outcomes with treatment.  Understanding that biologic heterogeneity is essential if you want to make the best choices on behalf of the patient.  At the extremes, I think there are some patients where we need to make every effort to give effective chemoimmunotherapy and others where starting with a targeted agent makes more sense.  Between those two extremes there is a lot of uncertainty.  Over the next several blog posts, I hope to make that spectrum clear.

Let me start by coming back to the question that I began this post with:  If you could get six months of chemotherapy and have 10 years free of disease and not require any treatment, would that be better than taking pills every day for ten years?  What if I upped the ante and asked if that same six months of therapy cured a decent proportion of molecularly defined patients?  Would chemotherapy be preferable to pills in that circumstance?   What fraction of patients would need to be cured?  Would 20% be enough?  What if it was 60%?  If 80% could be cured, would that make chemotherapy better than pills that are not thought to result in cure for anyone (yet)?

Let's start by defining "cure."

When we evaluate the performance of a new drug or a regimen, we plot the efficacy on a "Kaplan Meier" curve.  On the "Y axis (up and down)" is a variable such as overall survival, or progression free survival.  On the "x-axis (left to right)" is time.  At time point zero the curve should be at 100% but then it keeps going down every time someone has an "event" such as disease progression or death.  If a disease is really bad or a treatment really ineffective, the curve goes down very quickly toward the  x-axis.  If a disease is mild, or the treatment very effective, the curve stays very "flat" and doesn't drop from 100 much. 

People who look at Kaplan Meier curves a lot get really excited when they see a "plateau."  A plateau happens when you do some sort of treatment that is likely to cure a subset of patients.  As time goes on, all those patients who are not cured either relapse or die until you are left with those patients who no longer have the disease and the events stop happening.  When this happens, the curve may start at 100, slowly drop down to the percentage of cured patients (20%?-40%?) and then stays flat - or reaches a "plateau."  If a plateau persists with updates of the data, researchers start to ask if those patients who are no longer relapsing are cured of their disease - particularly if you test them with MRD testing and they remain negative for CLL.  Of course if you follow all patients long enough, it will always go down to zero as patients die of other causes, but few studies follow patients that long and a prolonged plateau is suggestive of something very important when considering a treatment.

At ASH 2012, the MDAnderson group put out an abstract entitled, "Is CLL still incurable?"  This provocative question was asked in response to an apparent plateau in their long term follow up of the original 300 patient sample treated with FCR.  After following their original group of patients treated back in 2000-2003 for thirteen years, a group of them still appear to have no evidence of any active CLL.  That is a very impressive result for a therapy that only lasts six months.

Many researchers however regard data from MDAnderson with a degree of skepticism.  It says a lot about a patient if they get on a plane and fly down to Houston for an opinion.  It says even more if they do that every month for six months to get treated.  Such patients necessarily have a degree of affluence, fitness, and education that makes them different from the average CLL patient.  Multiple different studies have shown that such variables strongly influence outcome.  It ends up being a biased sample set.  Indeed, the average age of patients in the study was 57 years old while the average age of a patient requiring treatment for CLL in the United States is typically 74 years.  That is a massive difference.

I have to admit, I was somewhat dismissive of the 2012 abstract on that basis - until the Germans gave an update of the CLL8 study which compared FC (fludarabine / Cytoxan without rituximab) versus FCR and evaluated outcome on the basis of molecular risk factors.  They show that after six years of average follow up, several groups of patients start to achieve a plateau.  Over the ensuing two years of follow up, if a patient has not already experienced a progression, very few such patients appear likely to do so.

Is this a cure?  It is still probably too early to tell for sure.  All Kaplan meyer curves are prone to becoming "unstable" the farther out in time that you go.  Since fewer patients of the original cohort have been followed that long, single patient changes in status can have disproportionately larger effects on the curve than happens earlier in the follow up.  Furthermore, bias influences become larger if there is a subset of patients with "better" follow up data.  I am very interested though to see if this curve remains flat with subsequent follow up.  It appears to mirror the single center MDA experience but in a multicenter population where the data is more reliable.

So who are these patients? It is interesting to know after the fact that some patients do very well, but it is far more helpful if we know before selecting a therapy if a cure is within reach.  It would likely influence how you think about treating such a patient. 

I previously wrote a post about the mutation status of the B-cell receptor, so called IgVH mutation analysis.  The new update from the German CLL8 study did an impressive job looking at the multitude of new prognostic markers in CLL.  They showed that patients with unmutated IgVH (bad), had a substantially higher rate of other negative prognostic markers (such as NOTCH, SF3B1, TP53 mutations) compared to those patients with mutated IgVH (better) to the tune of about 43% vs 24%.  We also know from recent publications that newer technologies (next generation sequencing) can find a much higher frequency of adverse markers as it is a lot more sensitive to lower levels.  These lower levels appear to be very important because they appear to confer similar overall prognosis.  I wouldn't be surprised if "next-gen" could identify an even larger split between the IgVH mutated and unmutated groups.

Turns out that those patients with the mutated IgVH did MUCH better long term than those with unmutated IgVH.  Indeed if the plateau in their data holds, it may occur in as many as 60% of patients with mutated IgVH whereas no clear plateau is seen in patients with unmutated IgVH. 

Is 60% chance of long term disease control (maybe cure) good enough to take FCR?  It is abundantly clear that not all patients are sufficiently "fit" to receive FCR and NCCN guidelines draw the line for full dose FCR at age 70.  Are there other variables that you can look at to remove "bad actors" within this subset of better risk patients?  If you focus on the "good risk" patients with IgVH mutated BCR and then exclude the patients with 17P or 11Q or bad molecular markers such as TP53, NOTCH1, SF3B1 mutations what is the long term disease control rate in that group - certainly a lot higher than 60% - probably closer to 80-90% chance of long term disease control - possible cure in this subset of patients.

These findings are very similar to those seen by the MD Anderson group.  In their study just under 40% of patients had not experienced any progression at the 10 year point. If you look at the associated table however, it was strongly skewed in favor of those patients IgVH mutated BCR 49% vs 11%.  They did not have access to FISH or molecular markers so that information is not available.  I find it compelling though that the numbers were very similar between the two studies.  It is also interesting to note that the change in the shape of the curve occurred right around the 6-7 year mark in both data sets.  This implies that if you fit this highly favorable profile and make it that far out, your chance or progression over the next few years seems very unlikely.

The point I wish to make is this.  The new drugs are very "sexy."  It is very appealing to think of  taking a non-chemo pill rather than chemotherapy, but if I am ever a patient with CLL and IgVH mutated BCR lacking 17P/11Q/TP53/NOTCH1/SF3B1 abnormality, I will absolutely take chemoimmunotherapy because there is a VERY GOOD chance I will not have to think about my CLL for many years, and based upon these two studies, I think he plateau in the survival curve is very provocative.   

This blog post was originally intended to also talk about what I would do if I had 17P deletion, IgVH unumtated BCR, or other high risk markers but the post became too long and unwieldy.  I will tackle those possibilities in upcoming posts. 

Thanks for reading.

Predicting outcome to therapy

There is an interesting article out today via pubmed that talks about the ability to predict response to chemotherapy in CLL (summary editorial here, actual article here).

As I've been talking about quite a bit, it involves knowing the detailed molecular genetics associated with an individual patient which you can now test for.

I wanted to briefly point out the difference between "prognostic" and "predictive" biomarkers.  First of all, a biomarker is any sort of test such as a blood test, type of scan, etc that correlates with a biologic behavior.  Ideally those biomarkers can help influence treatment decisions to make more personalized treatment decisions.

"Prognostic biomarkers" give a general sense of how a patient is likely going to do with their disease.  In CLL, you might look at things like ZAP-70 or CD38 to estimate how a patients disease is going to behave over time.  You might say that they are "high risk patients" or "low risk patients" for progression / survival etc. but it doesn't necessarily tell you if a specific therapy is going to be useful.

"Predictive biomarkers" on the other hand help with specific therapeutic decisions.  They can be either positive or negative predictors.  Patients with 17P deletion for instance do not experience durable benefit from FCR therapy so in essence it "predicts" an inadequate response to this treatment.  Patients with TP53 or BIRC3 mutations have similar negative outcomes therefore these are considered "negative predictive biomarkers."

On the other hand, some biomarkers may be "positive predictive biomarkers."  I am VERY interested to find out if CLL patients with NOTCH1 mutations derive unique benefit from new research medications that target that mutation specifically.  In other cancers like melanoma or lung cancer, the presence of BRAF or EGFR mutations are required before you can even use certain meds that have very high levels of activity in those specific settings but are useless or even harmful if a patient lacks the mutation.

This particular CLL paper looks at the German CLL8 study which compared FC to FCR and was the first paper to establish a survival benefit in CLL.  It offers a wealth of new insight into the newer prognostic and predictive biomarkers that have emerged in CLL.  We find out that patients with SF3B1 mutations respond well, but experience more rapid relapse.  Patients with NOTCH1 mutations don't derive benefit from the addition of rituximab to FC.  Patients with 17P deletion / TP53 mutation and IgVH unmutated CLL have shorter survival following FCR therapy compared to patients lacking these abnormalities.

Both the technical article and the associated editorial are worth the read.

Thanks

FCR versus BR in frontline CLL

The abstract I have been most eager to review in this years ASH meeting details the results of the German CLL10 study in which FCR (fludarabine, cyclophosphamide, rituximab) is compared to BR (bendamustine, rituximab) in the front line management of patients with symptomatic CLL.

Here is a link to the data

The data is based upon a planned interim analysis and concludes with the statement, "In light of these results, no firm recommendation of one regimen over the other can be given at the present time"

Why the balance?

It looks like FCR is better than BR in terms of depth of response.  While the overall response rate was identical between the two arms, the CR rate favored FCR (47% versus 38%) and MRD negativity (71% versus 66%).  This translated to a more durable progression free survival (85% versus 78%) at two years of follow up but not surprisingly the overall survival at this early time of follow up are equal.

While that may lead you to conclude that FCR is better than BR, it comes with a price.  4% of FCR treated patients died during treatment as opposed to 2% of patients who received BR.  That was in part because 90% of FCR treated patients versus 78% of BR treated patients had side effects rated grade 3-5 in severity (the higher the worse).  This was particularly evident in the rates of severely low blood counts which translated into a considerably higher rate of severe infections (40% vs 25% in favor of BR).

Not surprisingly, the outcome seems to have an age effect.  In the population less than age 65 with good performance status the progression free survival more strongly favored the FCR over BR but above age 65 it was a wash - totally equal.

One tragedy of this study was that there was an imbalance in the randomization that resulted in considerably more patients with an unmutated BCR ending up in the BR group.  This less favorable group may have handicapped the BR arm of the study making it appear worse when perhaps it was just that that arm had patients destined to do worse genomically.

Keep in mind that the average age at diagnosis is 72 and average age at first therapy is 74 years old.  I think a lot of the bias against FCR comes from experiences docs have treating patients with FCR that probably should have never had the combination of drugs because they were never likely to handle it well in the first place.

FCR is also pretty close to the limits of what a person can tolerate while BR seems to be a good platform for adding new drugs.  Drugs like idelalisib and ibrutinib combine very well with BR.  I suspect GA-101 would also be a good partner with bendamustine.  I wouldn't be surprised if some of the new combo treatments make BR much better while maintaining the better tolerability.

This study sheds very important new light on selecting first line therapy for patients with CLL.  How will I handle the data?  For patients above age 65 I will probably favor the BR therapy - particularly if I can do it in a clinical trial that adds a novel agent.  Below age 65 I will look very closely at parameters like renal function and medical comorbidities.  In the very healthy sub-65 year olds FCR will probably get my nod (unless I have a trial with BR with a new drug).  If I have concern about marrow or renal function, I would probably go with BR in this group.  Of course a close discussion with the patient will be very important.

Thanks for reading

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.