Saturday, December 1, 2012

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.