CLL Prognosis

Many CLL patients identify themselves by their prognostic markers when writing in social media outlets.  "Diagnosis age 63, unmutated, trisomy 12, treated FCR age 67, still in remission 2 years later"  is the sort of "tag line" I've seen people write.  For individuals who visit social sites frequently it is a way to tell your story in a few words.  For individuals who are new to CLL, it can all seem very confusing.  Well it is about to get a whole lot more complicated for everyone very soon.

A lot of what follows is very technical but I wanted to get it all written in one place.  I hope patients actually read and re-read this material several times.  For people who are prone to sleeping every time they read one of my posts, here are two videos I did with Brian Koffman in Sept 2013 that goes over the same material in video format:

Part 1: New Prognostic Markers
Part 2: Another on New Prognostic Markers

I've been wanting to write this post for a while but a recent paper has really brought this to the forefront of management of our CLL patients.  Unfortunately the names are strange and I worry this post may fall toward the technical side - sorry.  I will create a separate post that specifically defines many of these terms.

Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia

For people who have read all my posts on FISH testing, you are probably aware that it is an antiquated technology that has served us well for 20 years but needs desperately to be replaced. Sequencing technology has advanced incredibly quickly and is now poised to refine our understanding of CLL risk groups with new molecular detail.

While most patients are aware of the incredible advances in CLL therapies (ibrutinib, CAL-101, GA-101, ABT-199), fewer are aware of the really important advances in molecular markers that have been recently discovered.  Once these are rolled out to the general public we will be able to understand with much more precision how a patients disease will behave.  Pretty soon, folks will not only be talking about 13q, 17p without also talking about BIRC3, SF3B1, and NOTCH.

In the last 24 months, genomic sequencing has been applied to cases of CLL with pretty remarkable results (see New England Journal of Medicine article or Journal of Experimental Medicine article)

Several key findings have emerged from these data sets.

1) CLL has a relatively simple genome.  While some "smart cancers" (cancers that quickly gain resistance to our treatments and are far more aggressive) like small cell lung cancer may have 50,000 mutations per tumor, CLL (a comparatively dumb cancer - which is typically slow, responds well to most treatments, does not gain resistance all that fast) may have fewer than 100 mutations per case and only a small fraction of those (around 10-20) affect important proteins (the enzymes that make all things happen inside a cell).

2) Certain mutations seem to be observed fairly commonly in CLL and have some defined prognostic or predictive value.  For instance BIRC3 turns out to be a really bad thing to have - it is the new 17p.  NOTCH probably is one way to get to Richter's and helps sort out the trisomy 12 cases, SF3B1 makes you resistant to fludarabine chemotherapy.

3) Certain mutations are seen early in the disease, while others seem to accumulate with time.  Furthermore, some of the ones present later on are actually present early but only emerge through "clonal selection."

4) Some cases of "familial CLL" (ie those cases that run in families) have an unifying genomic explanation that point toward things we already knew were important.


With all of this new information, it was only a matter of time before someone took on the herculean effort to figure out which of these were most important and what they all mean when you analyze them simultaneously in a large group of patients (1300 of them to make this model).

The old risk groups were:
High risk: 17p changes (home of the p53 protein)
Intermediate risk: 11q changes
Low risk; normal cytogenetics & trisomy 12
Very Low Risk: Isolated 13q changes

Unfortunately, there is a lot of biologic diversity that FISH testing misses since it only looks at large chunks of missing or added DNA.  Using sequencing technology (think microscope compared to telescope) as an adjunct to FISH we can now help sort all of these out.

The new risk groups
Very high risk: 17p deletions, p53 mutations, or BIRC3 mutations (10 year survival 29%)
High risk: 11q deletions, SF3B1 mutations, NOTCH mutations (10 year survival 37%)
Low Risk: Normal cytogenetics, trisomy 12 (without NOTCH mutations) (10 year survival 57%)
Very low risk: Isolated 13q deletions (10 year survival same as age matched controls).



There are some really interesting observations contained within this.

1)  It is not a surprise that 17p deletion and p53 mutation are both really bad - we've known that for a long time.  They commonly run together (ie. most 17p deletions also have p53 mutations - but not all cases).

2) BIRC3 is a new kid on the block.  It has only been recognized for about 18 months.  Turns out it is really bad to have.  It confers chemotherapy resistance and is often very discrete from p53 alterations (i.e., if you have one, your probably don't have the other).  We've known for a while that p53 doesn't explain all cases of chemotherapy resistance - BIRC3 explains a lot of them.

3)  We have known for a while that 11q deletions often associate with bulky lymph nodes, unmutated B-cell receptors, faster growth kinetics, requirement for alkylating drugs (cytoxan, bendamustine).  It has often been considered a poor risk feature.  SF3B1 and NOTCH are totally new though and we didn't know where these fit in terms of hierarchy.  Turns out, they are about equal.

4)  Last year the relationship between NOTCH and trisomy 12 was identified.  About half of trisomy 12 cases carry a NOTCH mutation - particularly those with unmutated BCR (ie. cases with unmutated BCR and trisomy 12 have high frequency of NOTCH mutations - sorry if this gets confusing).  We have been aware that trisomy 12 was a bit of a wild card - some did fine, some did poorly.  Turns out that NOTCH mutations can sort the two apart.  Those with mutations do worse, those without mutations are now considered "low risk."  I am very eager to learn if the new NOTCH antibodies turn into personalized medicines for patients with the NOTCH (or even FBXW7 changes).

5)  Our good old friend 13q is still "good risk."  The surprise here is that 25% of 13q cases get put into higher risk categories when you do the mutation analysis.  They might have an SF3B1 mutation or BIRC3 mutation you would have otherwise never known about.  By carving out the bad players, it makes the good group even better.  "Matching age controls" does have some limitations because the model is built upon typical CLL cases.  There are probably not sufficient number of 42 year olds with 13q in the model to say that they necessarily match their peers.

6)  This model holds true no matter when you evaluate a patient.  In other words, if clonal evolution occurs and you go from very low risk to high risk by molecular definition - your clinical outcome changes too.

There are some important questions in all of this.

1) The most obvious is - how do I know what I am?  Right now - you can't easily tell.  There really are not commercial tests to sort this out - I'm trying to make one but seem to running into more walls than doors.  If anyone out there wants to finance this idea, let me know!

2) What defines "positive" for mutation?  For 17p by FISH we do not define a patient as positive until 20% of their cells are positive.  With ultrasensitive testing you may find 0.07% of cells have a BIRC3 mutation.  That patient isn't "positive" but I would be very concerned that clone may evolve in the future.  Do you therefore do anything different when you choose to treat them?

3)  This analysis may miss some of the subtlety of different FISH abnormalities.  We already know there are type I and type II deletions on chromosome 13 with different prognostic value.  We also know that the overall percent of cells with 11q or 13q makes a difference.  This model does not capture that degree of subtlety.

4)  Mutated vs unmutated is not included necessarily in this model - I would like to know if it "sub-stratifies" amongst the various different risk groups (although it is more common to see unmutated with 17p and 11q than the 13q cases so perhaps the model was just not big enough to take it all into account)

5) How do these markers hold up in the face of the new drugs.  ABT-199, ibrutinib, CAL-101, GA-101 are so remarkable.  Will traditional markers hold up in the "new era?"  It is important to note that this model is based upon cases that have already been followed for quite a few years.  Some didn't get rituxan with their first line of therapy.  Presumably none were able to take advantage (since it is an Italian study) of the new drugs.  By definition, this is a backwards looking model and does not capture what I see as a very optimistic future. For example, 29% 10 year survival for poor risk does not reflect the impressive durable control obtained in front line 17p patients treated with ibrutinib.


Though there are questions, the authors of this paper are to be thanked profusely for their remarkable effort to create a single predictive model of this magnitude.  I would imagine that there were thousands of hours put into creating and analyzing the data.  This paper will serve as a landmark for quite a few years and will help guide countless numbers of patients.

How did I get lymphoma / How did I get CLL?

I am sure there is a profound philosophical lesson to be learned about why this question comes up so frequently in clinic.  Being on the receiving end of bad luck doesn’t make sense to a lot of people.  Maybe others are thinking of missed prevention opportunities, prior bad behavior, or risks to loved ones.  Understanding “why me?” is important and I wish we had a better answer.  I suspect most patients instinctively know that despite our white coats and walls of framed diplomas, we really don’t know – medical science does not have a good answer. 

Despite the absence of a universal answer for all patients, we do know enough about lymphocyte biology to make some educated inferences.  More often than not, I feel compelled to ask the question, “why not me?”   

I am constantly in awe of the unbelievable sophistication of the human body.  Our genome contains six billion base pairs encompassing over thirty thousand genes across forty six chromosomes – in every cell.  If you were to line them up end to end, they would stretch several feet long yet they get packaged into a tiny nucleus.  Somehow those six billion base pairs need to be faithfully copied with no errors every time a cell divides.  For a B cell this may be thousands of replications. 

I saw one paper that estimated that human bone marrow stem cells acquire about ten mutations per decade of life.  That is an such an amazingly low error rate that it should affirm your faith in evolution or God depending on your leaning.  The fact that life can persist at all is more remarkable to me than the observation that it can break down from time to time.

B lymphocytes however have a number of molecular behaviors that increase the risk of genomic malfunction.  B lymphocytes make antibodies (aka B cell receptor / BCR).  You make antibodies to fight of bacteria, viruses, and all manner of germs.  The mechanism that gives us unlimited antibody diversity involves very deliberate damage to DNA – sometimes with cancerous consequences. 

Despite having six billion base pairs, that is not nearly enough to “hardwire” every antibody we may ever need into our genome.  Instead, our antibodies are built in a more modular way.  We have five types of heavy chains, two types of light chains and every antibody pick one of each.  Furthermore, each heavy or light chain has a number of choices for the “variable” region that gets attached to the “D” and “J” regions to create the “VDJ” re-arrangement.  At this point, I’ve already lost track of how many possible combinations there are.  When it comes to antibody creation, it is like a huge game of Mr. Potato Head.

Each time your B cell takes one “v” region and attaches it to a “d” and then a “j” region, it has to deliberately break the DNA and have it come back together in a different place.  That is biologically like trying to jump out of an airplane and land in your swimming pool.  Unfortunately that process is sloppy at times – perhaps more amazing is that it ever works at all.  Many lymphomas are recognized for having pieces of chromosomes come together wrong called translocations (such as t 4:14, t11:14, or t14:18).  If you notice that chromosome 14 seems to keep showing up, that is because it is the chromosome where most parts of the b cell receptor heavy chain are encoded.  Sometimes that break and re-attach process comes down in the wrong place near important proteins like Myc, Cyclin D-1, and BCL-2 that cause these cells to take on cancerous behavior (Burikitt’s, Mantle Cell, Follicular respectively).

Even though that process should give us hundreds of antibodies, we need other processes to create antibody diversity enough for life on planet earth.  Not surprisingly, there is another diversity mechanism that can run amuck known as “somatichypermutation.”  This process takes a perfectly well constructed antibody and starts adding in random mutations.  This is key to helping us generate the virtually unlimited number of antibodies necessary.  Unfortunately we can find evidence that these deliberate mutations are not always confined to the “variable” regions of antibodies.  In fact we can find them sprinkled throughout the genome and sometimes they turn on key proteins like BCL-6, CD79, A20, etc.  In CLL we even look for evidence of this process to classify our patients as “mutated” or “unmutated” as it confers a different prognosis between the two.

If you took those two processes alone I think it would probably be enough to explain a lot of cases of lymphoma – but wait there is more.

Abnormal b-cell receptor (BCR) activation appears to be an enormously important event that plays out across many b cell malignancies and possibly explains the fantastic clinical activity of drugs like ibrutinib, CAL-101 (GS-1101) and the like.  Different lymphoid cancers get there by different ways.  Diffuse large B cell lymphoma occasionally has a mutation in CD79 that locks the BCR into an active state.  Other DLBCL’s have mutations in CARD-11 which is farther downstream in the signaling pathway, but activates a key inflammatory complex called Nf-kB.  Some cases of CLL may have abnormalities in their “variable” region that trick the cell intothinking it has identified the germ it is supposed to destroy and thereforesends off growth signals to the cell.  In follicular lymphoma antibodies may recognize abnormal sugar molecules on each other and get turned on etc.  Marginal zone lymphoma sometimes regresses when you treat the stomach or viral infection it is trying to fight off.  In Hodgkin’s lymphoma, a viral protein encoded by Epstein-Barr virus (LMP-2) can actually mimic the BCR.  That observation was whatled me to hypothesize that inhibiting BCR might be a good idea – way back in2006 before many others had ever thought of the idea.

The theme is that something turns on the BCR in many of these diseases and that gives off growth signals that can lead to cancer.  It also explains why some of our most exciting research drugs are ones that turn off that signal.

None of this explains though why some of these things run in families.  Occasionally you will find a single family with five cases of CLL.  The odds of that happening by chance are a lot worse than your chance of winning the powerball jackpot with one ticket. 

One of my favorite researchers / colleagues Dr. JenniferBrown at Dana Farber in Boston is studying this with some of the most powerful technology available.  She has identified several families where a shared genetic abnormality explains the occurrence of lymphoid cancer in each of the family members.  One interesting example is the loss of a gene called DLEU7 (deleted in leukemia #7).  I find this fascinating because that is buried in the middle of chromosome 13q – the most common geneticabnormality in spontaneous CLL.  It really points to an area of significant biology for future therapeutic intervention.  If you introduce the 13q abnormality into lab mice you will find that they get a variety of lymphomas and CLL.

Finally, there are environmental considerations such as being a meat packer, exposure to pesticides, exposure to certain viruses, etc.  This is where science gets a little hard to pin down as it is subject to a lot of forms of bias.

So doc – why did I get my cancer?  If “all of the above” was a test choice – that would be my answer.  Genomic instability of lymphocytes, a rogue B cell receptor, bad genes, something you were exposed to…

As genomic sequencing gets cheap enough to become a routine clinical test, we may be able to profile an individual cancer for the various hallmarks above and give a more precise answer – but for now, I still have to shrug my shoulders and admit that, “I don’t know.”

When to treat CLL

The "watch and wait" mantra in CLL can be a test of wills unlike most other cancer experiences.

Let's face it, sitting there and doing, "nothing" is hard enough when we are conditioned to believe "early detection saves lives" or "catching it early is your best chance to beat it."  Those things are true in common cancers like breast, prostate, colon, lung, etc. but at least for now those do not necessarily hold true in CLL (I hope that will change).

Furthermore, the trip to the doctors office takes on new levels of anxiety when the WBC count keeps slowly ticking up - 20 - 30 - 50 - 80.  I think a lot of patients see those numbers and experience a lot of angst.  How high do you let it go? Shouldn't I do something about it?  Watch and wait is hard enough, but getting run over by a steamroller in slow motion seems like a medical version of water boarding.

The first thing I tell patients is that there is no single number that tells me it is time to treat a patient.  I think many docs start to get uncomfortable when things hit 100 or higher, but for the CLL specialists out there, 100 is often just another number and you will see things periodically go quite a bit higher.  I suspect a number of CLL docs take a deep breath when things get much higher than 200 but for a stable patient without other problems - 200 isn't necessarily any worse than 50.  I suppose we may need to take extra precautions when you treat someone with a sky high WBC to make sure they don't experience tumor lysis (when too many cells die all at once, it can cause the "gunk" to back up in the kidneys or cause your heart some electrical problems).  The highest I've heard of in a stable patient was 500 on one of the ibrutinib studies - I am glad that wasn't my patient - I would have been pretty anxious.

In some of the "acute leukemias" which are very different conditions - such numbers would be terrifying.  The biology is very different though - 100 CLL cells is very different than 100 AML cells.

So if we don't look at a single number - then what should we look at.  In clinical trials we use the term, "clinically active disease" as a reason to start treatment.  In my mind, "clinically active disease" is largely about trends.  Here is where you need some judgement though.

It is one thing for a white blood count to go from 20 -30 - 50 - 80 over a two year period.  It is another thing all together if that happens over four months.  All too often, I hear people get anxious when the wbc goes from 30 to 50 without other changes.  When that happens to my patients, I normally look for any signs or symptoms of infection or other abnormalities.  I will often repeat it a few weeks later to make sure it is really a trend instead of a "blip."  These things can jump around from time to time and I've seen plenty of cases where that 50 went back to 30 and I never knew why.   When the WBC doubles over a several month period and that trend looks real / sustained - that is active disease.  Often such a patient can still sit tight if other things are holding steady, but chances are that patient is headed for treatment in the next 2-6 months.  It is another thing too if it doubles from 30 to 60 (often lots of room to spare) versus 100 to 200 (more likely your marrow might get compromised).

Other trends that are VERY important to me are the hemoglobin and platelets.  When WBC keeps going up, those will often start to fall.  The marrow can only do so much.  If it is too crowded with CLL cells, there isn't enough room to make RBC and platelets.  Here again, there is no single number that tells me to get started but when there is a sustained trend in the platelets and it gets under 100 or the hemoglobin falls to less than 11 under similar conditions it suggests treatment is coming soon.  It is important to make sure it is an "overcrowding" phenomena and not an "autoimmune" situation.  Sometimes CLL cells can go on a rampage and make antibodies that destroy RBC and PLT's.  This can happen quite suddenly.  When a hemoglobin goes from 11 to 7 in several weeks, chances are that is autoimmune.

There are other reasons to treat that are not based on trends.  Sometimes a patient has overwhelming fatigue, other times lymph nodes can become really troublesome.  Sometimes CLL really compromises somebodies immune system and they keep getting significant infections (see video link to Brian Koffman video we did together: Feeling run down from CLL.)  Those are fair reasons though somewhat "softer" indications to start on treatment.

So why do we wait so long?  In the past, our treatments were chlorambucil and fludarabine.  There was an old study in follicular lymphoma (close cousin to CLL) where watch and wait was compared to chlorambucil.  If anything the chlorambucil patients did a little worse in the long term.  The idea took hold that nothing we did ultimately impacted how long a person survived so don't jump too soon.  If taking "chemotherapy" didn't do anything more than make you feel better (not a typo), let's make sure you were feeling pretty bad before we got started.  I've written in other posts about clonal evolution - another concern for jumping in too soon.  One important thing to note however is that it can be very difficult to show that ANYTHING improves survival in CLL.  For a condition that can often last over a decade, it takes a long time to prove your point.  Even with the most exciting new research drugs, we may not see that they improve overall survival for average CLL patients for another 10 years!

Things have started to change though.  Two studies in the past few years have shown we can improve overall survival in CLL (both started quite some time ago).  Frontline fludarabine keeps patients alive longer than frontline chlorambucil in patients needing treatment and the Germans have shown us that FCR keeps patients alive longer than FC.

Those are milestone studies, yet I think the real change will happen when we get to a place where we have effective biologically informed treatments that are not chemotherapy based.  We are spoiled to have a substantial number of these working through clinical trials now (ibrutinib, GS-1101, GA-101, ABT-199, and others).  My personal conviction is that once we can start combining some of these treatments we will really be off to the races with the "new era in CLL."

In follicular lymphoma, things are changing for the better.  Rituxan is "biologic therapy" that is a pretty effective treatment that does not necessarily need to involve chemotherapy.  70% of patients will respond to rituxan and disease control can be quite durable for some patients.  Unfortunately, as a single agent, it is not nearly as effective CLL.

There are always exceptions to the definition of "active disease" I outlined above.  I watch my patients with 17p a little more closely and may jump in a little earlier.  I don't know that I am right for doing this, but I think a lot of docs do the same.  Since these cells can be so resistant to treatment it might not be a good idea to collect so many of them before getting started.  The same is true for 11q minus patients but perhaps not to the same degree.  Another thing to consider is that patients with "unmutated" cells might on average go up faster than someone with "mutated" cells.

Things also change in patients with relapsed disease.  It is not uncommon to see faster kinetics with relapsed disease (see clonal evolution post).  Also, over time, lymph nodes become more problematic.  Keep in mind that CLL cells in bone marrow and lymph nodes are considered more difficult to eradicate than the ones in the circulation.  I think docs tend to jump on relapsed disease a little earlier than they do in untreated patients - even though the indications really do not change.

We spend a lot of effort as docs and probably freak out a lot of patients by looking at all sorts of expensive prognostic markers (BCR mutation status, b2 microglobulin, CD38, ZAP-70, etc.)  Ultimately, we try to use these to tell us what the trends are going to look like in the future.  Better yet, get an old blood test from the last time you had blood drawn.  It is very common for me to meet a patient, dig up a three year old blood test and point out that their CLL was present way back when, just not enough to trigger the alarm bells.  I think a lot of patients are relieved to know things haven't really changed a whole lot over a several year period.

Anyhow, hope that helps explain how I think a lot of docs think through this sort of question.