Watch and Wait (AKA: Watch and Freak Out)

Nothing can make a patients head spin faster than the two juxtaposed statements, “you have cancer” and “we’re not going to treat it right now.”

Huh?

“Watch and wait” has been a mantra for patients with asymptomatic CLL and indolent lymphoma for quite a few years and sometimes no explanation is enough to comfort a patient who is understandably worried about their new diagnosis (see: when to treat CLL, choosing first treatment in CLL, and how I treat follicular lymphoma part 1).  Quite a few people have dubbed this “watch and worry” instead of watch and wait.  There is an avalanche of messaging out there about early detection and early treatment saving lives in so many cancers that watch and wait can sound more like medical quackery than good science.  For some patients, taking a nutritional supplement and avoiding chemotherapy is an easy sell – but for others, the thought of living with untreated cancer is too much.The short answer is that CLL and low grade (indolent lymphoma) are different than a lot of solid tumors – but this blog is about the long answers – so here goes.

Historically, the argument in favor of watch and wait was that our treatments did not impact overall survival – so why take chemotherapy unless you needed to get rid of some bothersome symptom.  We would argue that chemotherapy was a steep price to pay if it didn’t do you any good in the long run (see risk stratification in CLL).  Admittedly, those conclusions were based on studies from the 80’s and 90’s that used fairly ineffective treatments or drug combinations with moderate to significant side effects of their own. 

But science continuously evolves.  Several recent studies have shown that IF you are going to treat CLL, certain treatments may improve survival compared to others (FCR better than FC, Fludarabine better than chlorambucil).  While this later observation does not indicate that treatment is better than NO treatment, now that we know we can improve survival with some of our treatments those old assumptions need to be retested.

In follicular lymphoma (which is a model for many of theindolent diseases), an ongoing study already presented at ASH compared rituxan to observation.  Not surprisingly that has shown that patients who get rituxan are generally able to wait longer until their next treatment compared to the folks who were randomized to observation – not necessarily an earth shattering observation.  Whether this approach influences how long patients actually survive remains to be seen as that will take quite a few years for the study to collect data.  While the data from that study continues to evolve, others have pointed to the SAAK study in which eight doses of rituxan were given over nine months (weekly x4 then every other month x4) and note that nearly 40% of patients have not required any more treatment over the next ten years.  It is possible that early intervention may be better, but we really still do not know.  I suspect the data will look different from those old studies now that we are using drugs like rituxan that are both effective and well tolerated – but whether that means you live longer has yet to be seen.

In CLL however, single agent rituxan doesn’t pack the same punch as it does in follicular lymphoma.  There is less of the CD20 target on the surface of CLL cells than there is in follicular lymphoma.  Furthermore, CLL has some tricky ways of lulling T cells to sleep (anergic).  Interestingly revlimid may help wake those T cells up (not FDA approved for this indication and should be done very carefully as there have been reports of tumor lysis syndrome).

Along comes a new paper though that I think has profound implications on how we thing about managing ANY of our patients with ANY lymphoid cancer.  I’ve written several times on clonal evolution (here and here) because I think CLL highlights this principle better than just about any other cancer and may actually have lessons for metastatic breast cancer or other solid tumors.  I realize that I’ve probably been trying to write about watch and wait in these posts but never really put it into the right context – so here goes.

Consider the following hypothetical experiment.  You are welcome to try this at home though I would not recommend it.  Plant a lawn but make sure you have a few weed seeds included in the mixture.  Let that lawn grow but resist the temptation to pick the dandelions.  Once you have a nice back yard scattered with a few weeds here and there go down to Home Depot.  Pick up a big bottle of round-up and spray your entire back yard.  Make sure the entire lawn is covered well enough so that you will have a completely brown mess in two weeks.  Now wait……

Ok, so you have waited twelve months without doing anything to the brown mess.  Go out back again and tell me what is growing.  Is it a lush green yard with a few scattered weeds or is it a mess of ugly weeds.  Chances are, you will have a bunch of mutant dandelions that have totally taken the place over.

In SOME cases – that example MAY illustrate the effect of chemotherapy on CLL on the “clonal architecture” surviving cells.  In evolutionary biology terms, we may refer to effective chemotherapy as a “mass extinction event” – think asteroids and dinosaurs.  Any time you have a mass extinction event in a biologic system you may see “survival of the fittest” play out right in front of your eyes.  In our example above, the reason the dandelions didn’t run amok before the round-up was that there was a lot of grass competing for the soil, water, etc.  You could say that the grass was the dominant (incumbent) clone holding the dandelions back.  Once you cleared out the grass though, the weeds had plenty of room to take over (boy with weed and grass both in this post – really curious to see what sort of google searches land on this page).

In this prior post, I highlighted a paper that followed a single individual at several time points and showed how there were three separate subclones at the time of diagnosis.  Before FCR chemotherapy there was a small subclone (1% of total cells) with a bad mutation.  After chemotherapy, that clone which was the “fittest” took off and became the dominant clone and ended up being the one that caused the patient to pass away.  This example has been replicated in a few other papers too so I think it has some validity to it.

Now – it is really important to stress the things we DO NOT KNOW.  If we go back to our analogy of the backyard, would we expect the dandelions to take over if we used napalm instead of round-up?  What if we just turned on the hose and let it flood the backyard for a month – would that select for the dandelions?  Or is it possible that may cause the crabgrass to run wild.  Perhaps we could just put a bunch of biblically hungry locusts in the back yard.  After they ate everything in sight – maybe it would be the grass that came back instead of the dandelions or the crabgrass.  In other words – does the nature of mass extinction event select for different types of “fittest” to come back?  Maybe the extinction has no bearing on what comes back in some cases.  Put into chemotherapy terms – does bendamustine have different outcomes for clonal selection than fludarabine?  Is rituxan different than chemotherapy?  Do the new drugs like ibrutinib and idelalisib have any effect on clonal selection?  We DON’T KNOW the answer to that question BUT we do know that treatment DOES exert a selection pressure on cancer cells and gives me an argument to consider “watch and wait” that I believe is more sophisticated than just saying, “our treatments don’t keep you alive longer.”

I often tell patients, “bad” may be a good enemy of “worse.”  Yes, having indolent lymphoma or CLL may be a bummer, but it may be better than having a super mutant, chemotherapy resistant, transformed beast come back at you.  I have often been puzzled by studies that show a dramatic improvement in “progression free survival” that have zero impact on “overall survival.”  In other words, treatment “x” does a better job keeping your disease away than treatment “y” but ultimately you both pass away at the same time – huh?  Maybe the better treatment is beating the disease back further – but also selecting for a more resistant set of cells to come back when it does come back.

In the paper I referenced above that shows how “clonal architecture” can change over time, one of the most interesting findings to me was that the presence of a “subclonal driver mutation” generally predicted for a shorter remission duration and the emergence of resistance.  “Subclonal driver mutations” are a lot of the bad markers we’ve been describing in other posts such as BIRC3, NOTCH, SF3B1,P53 etc. but that these mutations are in a very small population of the cells.  In other words, you may only have 3% of your cells that are really smart (ie P53 mutated) and 97% of your cells that are generally dumb (del 13q), but that 3% of cells are the dandelions.  Your chemo may make your numbers look a whole lot better and even make you feel better, but now you’ve traded the devil you know for the devil you don’t know – and that second devil might be really nasty.

Newer sequencing technologies are about to enter the clinic and help us find these “subclonal driver mutations” with vastly better skill (though there will still be limitations on how well we can look).  I HYPOTHESIZE (though this is absolutely conjecture and should not be taken as settled science) that in 5-10 years knowing the full clonal architecture will influence our recommendations surrounding watch and wait.

With all this in mind, I think it is easy to take the "watch and wait" strategy too far.  Some folks will do anything possible to avoid treatment and get themselves into a deeper hole than they need to.  Sometimes with a slow disease, it can feel like you can just wait it out a "little bit longer."  For low grade lymphoma there are criteria for treatment.  In CLL, I've written about "when to treat" which is my summary of the IWCLL guidelines.  The caution here is that you can get yourself a lot sicker than you need too if you hold things off for too long.  I would wager that it is even quite possible to feel a lot sicker from the disease than from some of the treatments available.  I've seen quite a few patients literally feel A WHOLE LOT BETTER after starting treatment that they had delayed longer than they should have.

So a few key take home points

1)      Watch and wait was historically based on ineffectiveness of therapy

2)      Newer treatments have led scientists to revisit #1 but the answers are not in yet

3)      One risk of treatment is the emergence of resistance but not all patients experience this

4)      We may be able to begin measuring a patients risk for resistance based upon “subclonal driver mutations” soon

5)      To date, we do not have much insight into what sorts of therapies influence emergence of resistance

6)      Watch and wait is not crazy in appropriate patients – there may have been benefit to it for a long time that we are only just now starting to figure out.

7)    Patients should not wait too long otherwise they just feel lousy when they could have been feeling better with treatment.

Thanks for reading

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.