Give it to me straight Doc, I can take it..

 You have seen the scene repeated in a zillion Hollywood movies. The hero has just been told he has cancer.  Somber music plays in the background. The wise doctor looks  worried and the beautiful young nurse assisting the doctor looks like she is about to cry.  The hero looks up as the camera goes in for a close-up, his eyes bleak but no tremor in his voice.  He delivers the heart wrenching line with appropriate pathos .. “Give it to me straight Doc.  I can take it.  How long do I have?”.  Pregnant pause as the audience holds its breath and a lone violin weeps gently in the background – then the doctor gives his verdict: “A few weeks, months at most”.  There is not a dry eye in the whole theater, no matter how many times we have heard this corny dialogue before.

That is so not going to happen to CLL patients.

Frankly I do not know of any examination rooms where they play weepy violin music, the doctor and nurse rarely fill the needs of Hollywood central casting, nurses are generally not inclined to cry every time they hear a cancer diagnosis.  You would be lucky if you got your doctor’s undivided attention for the full fifteen minutes of your consultation window.  Given that CLL is supposed to be the “good” cancer, it is much more likely that instead of corny pathos and empathy you will get flip condescension and told not to worry your pretty little head about it, go home and not bother the nice doctor.

If you are like many patients, you have probably felt a twinge or two of feeling sorry for yourself since your CLL diagnosis.  Here you are, dealing with the “big C” and after the first week or so, the universe does not seem to be paying much attention.  You look about the same, you are not wasting away, hair not falling out in tufts, you are not even going to have therapy for the foreseeable future.  Friends and family wander away – sort of bemused.  And you are left alone holding the bag, as it were.  Not quite alone, because we are here for you.

What can newly diagnosed CLL patients expect?

How long do early stage CLL patients have to live?  What can they expect, by way of quality of life? How soon will they have to start therapy? Here is the abstract of a very recent paper that sifts through a very large database of patient histories to come up with some guide posts.  I will do my best to review the highlights, but really, you have to read the full text version of the paper to get all the juicy details.  Send me a personal email and I will help you locate the paper.  This is article is a keeper for your personal files.  I recommend it.

Br J Haematol. 2011 Dec 15. doi: 10.1111/j.1365-2141.2011.08974.x. [Epub ahead of print]

Defining the prognosis of early stage chronic lymphocytic leukaemia patients.

Pepper C, Majid A, Lin TT, Hewamana S, Pratt G, Walewska R, Gesk S, Siebert R, Wagner S, Kennedy B, Miall F, Davis ZA, Tracy I, Gardiner AC, Brennan P, Hills RK, Dyer MJ, Oscier D, Fegan C.

School of Medicine, Cardiff University, Cardiff Medical Research Council (MRC) Toxicology Unit, University of Leicester, Leicester Institute of Cancer Research, Belmont, Sutton, Surrey CRUK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK Institute of Human Genetics, University Hospital, Schleswig-Holstein, Campus Kiel, Kiel, Germany Royal Bournemouth Hospital, Bournemouth, UK.

Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.

PMID: 22171799

The statistics derived in this study are with reference to early stage patients – Binet Stage A is the equivalent of Rai Stages 0 and 1.  The cohort size is very large at 1,154 patients and therefore the conclusions drawn from this study are likely to be robust.  (In the editorial section I will have more to say about statistics derived from large groups of patients, and how they apply to a single patient).

As the abstract points out, the purpose of this study is to assess the value of prognostic indicators in predicting two important outcomes of crucial interest to us chickens.  First, how long will it be before “Watch & Wait” ends and therapy has to begin?  Because, much though we all like to gripe about the Chinese torture of W&W, believe me it beats the alternative by a mile.  This period, between initial diagnosis and the time when therapy must be undertaken, is called “TTFT” (Time To First Treatment). The second issue that is even of greater interest speaks to the Humphrey Bogart scenario above, how long are we going to live?  The acronym for this is “OS” (Overall Survival).

Who were these patients?

The inclusion criteria for participating in this study is that the patient has to have clinically documented CLL and be in Binet Stage A.  Here is a short list of the patient characteristics.  Notice the age range, all the way from 24 to 96 years!  24 is way too young to have this nasty disease, and I take my hat off to the brave 96 year old still game enough to participate in the study.  Not all the patients had all the prognostic tests done, and that is why the numbers don’t add up to 100% in each category.  I have highlighted the good prognostics in black, for your convenience.


Which Prognostic Indicators?

Over the last ten years a bunch of different tests and indicators have been suggested for defining prognosis.  I am glad to see the researchers stuck with the tried and true, the prognostic indicators that are rapidly becoming the standard set.

  • Patient’s age
  • Lymphocyte doubling time (LDT)
  • IgVH gene mutation status (IGHV)
  • CD38
  • ZAP70
  • FISH

We have discussed each of these in some detail in earlier articles but if you want a quick refresher course, I recommend an article based on one of our recent workshops: “Prognostic indicators: who, when, what and why”.  Most (but not all) of the participants in this study had these prognostic indicators tested and recorded at the time of diagnosis.

Results – Highlights

Given below are graphs showing how the time to first treatment (TTFT) and overall survival (OS) changed between patients who had mutated and unmutated IgVH.

The dark blue curve shows how many of the patients with (good) mutated IgVH stayed untreated as the years went by.  As you can see, even as far out as 25 years and more, fully half of them had not needed therapy.  For these guys, CLL is truly the “good” cancer to have.  Not so for the folks with (bad) unmutated IgVH.  Half of these guys had to have therapy by 4.6 years.  Quite a difference, you would agree.

The next graph looks at the crucial question of “How long do I have?” – namely, overall survival.  Once again the dark blue curve is for the lucky mutated IgVH guys and the red curve is for not so fortunate unmutated IgVH.  Drawing the horizontal line from the 50% mark, you can see that half of the mutated IgVH guys are still trundling along at 23.3 years, where as this milestone was reached much earlier in the unmutated IgVH folks, at only 12.6 years.

If you also take patient’s age into consideration, this difference between mutated and unmutated IgVH can make all the difference between dying with CLL versus dying because of CLL.  For a typical 65 year old CLL patient with mutated IgVH as prognostic indicator, a 50% chance of living beyond 88 years sounds pretty good!  But the scenario is not so rosy for a 40 year old patient with unmutated IgVH, looking at roughly even odds of not making it past 53 years.  Prognostics are important in how we think of overall survival, but so is the age of the patient.  Please remember that.

The authors have similar time to first treatment and overall survival graphs for the other prognostic indicators (CD38, ZAP70, FISH cytogenetics).  They also have differential projections for people whose prognostic indicators do not quite match up, where there is a discordance.  But rather than reproducing all those graphs here in my review, I strongly urge you to read the original paper for yourself.  As I said, it is one of those must keep articles.  Rather than just reproducing all the other graphs, I would like to highlight some of the interesting conclusions reached by the researchers in this valuable study.

Study Conclusions

This study is important not just because it looks at a large cohort, done at very prestigeous institutions and reports the results in great detail, but also because the authors looked at the results and came up with some interesting and important observations.  Here are some of them.

  • While the Rai and Binet staging systems have been very useful in classifying patients, they both fail to identify which of the early stage patients (roughly two thirds of them) will have progressive disease requiring therapy at some point – and which one third are going to “smolder” on for the rest of their natural lives.
  • Taken individually all of the modern prognostic indicators studied (IgVH gene mutation status, CD38, ZAP70, high risk FISH abnormalities) influenced time to first treatment.
  • LDT (lymphocyte doubling time) was the single most important prognostic indicator for TTFT. (Figures, this is sort of like the proof of the pudding is in the eating. Patients with short doubling time have demonstrated an aggressive disease, for crying out loud. This is a bit like predicting the weather by looking out the window and ‘predicting’ it is indeed raining).
  • When combined together, only this set of four prognostic indicators had the power to predict time to first treatment: LDT, IGVH, CD38 and the patient’s age.
  • The researchers wondered whether the strong showing of LDT in predicting time to first treatment has something to do with doctors treating the numbers, getting spooked by high white blood counts even if the patient did not really need therapy right away.  Interesting indeed.
  • The researchers noted a significant trend for younger patients to receive therapy sooner than otherwise – perhaps once again reflecting physicians’ bias towards treating younger patients more aggressively, while taking a more laid back approach to treating elderly patients.
  • This last point is something to think about, if you are in the younger crowd. “Given the increasingly recognized association of CLL chemotherapy with development of secondary myelodysplastic syndrome / acute myeloid leukemia (8-10% of fludarabine combinations treated patients), this observation is very important and worthy of further study”. No kidding.
  • Patients with 17p deletion (FISH abnormality) are widely accepted to have poor prognosis. But this study shows that only 53% of early stage patients with 17p deletion needed treatment over a 3 year period. Of note, patients with 17p deletion but mutated IgVH usually had stable disease.  Looks like the ‘good’ mutated IgVH takes some of the sting out of the 17p deletion.
  • Only 5-7% of newly diagnosed and untreated patients have 17p deletion, and these guys may not have such a bleak future. The situation is very different when patients acquire 17p deletion as clonal evolution during the course of their disease.
  • The researchers recommend that once disease progression happens, FISH analysis is necessary in order to develop appropriate treatment strategy. Presence of 17p deletion, for example, changes the ballgame and mandates different therapy options.
  • Bottom line, using patient’s age, LTD, CD38 and IgVH mutation status for predicting time to first treatment, and adding FISH analysis when it is time to treat, the researchers believe will be sufficient to identify the two thirds of early stage patients who will progress and need intervention.

Editorial

Allow me to give you a simple example of how statistics works, and something called a normal distribution.  I promise I will make it clear why and how this applies to cancer patients like you.

You are out shopping for light bulbs. Obviously, you want a brand that has a reputation for lasting a long time without burning out. The manufacturer provides the following information about his light bulbs. He says his light bulbs have a mean life of 1000 hours and a standard deviation of 100 hours. Does this mean all the light bulbs made by the company will last exactly 1000 hours? No, it does not. It means that exactly half the light bulbs will last more than 1000 hours and the other half will last less than 1000 hours. That is precisely what a “mean value” implies. The majority of their light bulbs (68.2% of them) will last somewhere between 900 hours and 1100 hours.

Now, what are the chances that you get lucky and the particular light bulb you pick up lasts more than 1,200 hours? If you do the math using the standard deviation of 100 hours he quoted, it turns out you have a 1 in 45 chance (2.3%) of getting such a super bulb. But remember, there is an equally slim chance (1 in 45) that the bulb you got is a dud and lasts less than 800 hours before giving up the ghost.

So. The point to remember is this. While the vast bulk of light bulbs will last somewhere close to the 1,000 hour mark (the mean of this data set), there are always going to outliers. A few bulbs will last a lot longer than 1,000 hours, and an equally small number of bulbs will die a lot sooner than 1,000 hours.  The further you get away from the mean value of 1000 hours, the smaller the chances that you will get such a light bulb, either that extremely good or extremely bad.

Now, lets talk about what all this has to do with CLL patients.

Let us say you fall into a particularly bad prognostic group and the mean overall survival for this group of unlucky folks is quoted to be 5 years.  That means in a sufficiently large group of such patients, half of the group would be gone by 5 years, half would survive past 5 years.  And here you are, 4 years into this 5 year mean overall survival mark.  That sucks!!  What to make of it?

If you are not familiar with statistics, you might take that to mean you have one year left to live.  You may decide to quit your job, sell your house, say goodbye to heartless family and friends and head out to see the Taj Mahal or the pyramids, buy that red sports car you always wanted  - whatever happens to be on the short form of your “Bucket list”.  But beware.  You may well find that you live past the one year deadline, run out of money and have to slink back home – sans job, money, family or friends.  Of course, it is equally likely that you are an outlier on the other (ugly) side of the mean value, and you kick the bucket sooner than the one year you thought you had.

Same sort of logic holds for patients with the best of all prognostic indicators, where the group’s mean overall survival is, say, 25 years.  You would not be too far off the mark to look at that statistic and thank your lucky stars.  With reasonable safety you can continue to procrastinate getting your affairs in order, writing out your will and last testament or mailing off the checks to your favorite causes (ahem).  However, it is important to remember that this good statistic of overall survival does not guarantee that you as an individual will indeed live for another 25 years.  Anything can happen.  You could get hit by a bus crossing the street. You could develop a second cancer, a nothing squamous cell carcinoma on your balding scalp that decided to get aggressive.  Lots of things can go bump in the night.

Which of these scenarios is the right answer?  Should you expect to do better than the mean value quoted for your risk group, or worry that you may not do as well as the mean?  That depends on your personality, your individual circumstances.  Are you an optimist, a glass half full type of guy who expects to win the lottery every time you buy a ticket?  Or are you the kind that worries lightning may strike you as you head out into a light spring time drizzle?

There are also more concrete circumstances having nothing to do with optimism or pessimism.  Do you have good medical insurance?  Do you have a good support system to help take care of you, give you something to live for?  Are you otherwise in good health? Do you come from a long line of family that lived well into their eighties?  Do you take care of yourself or do you believe in burning the candle both ends?

You see what I mean?  Statistical averages based on large groups of patients just give you the odds – what are the most likely outcomes, if everything else is exactly the same.  But nothing is ever exactly the same; so while it is important to know the odds stacked in your favor or against you,  it is also important to remember your own mileage may vary.  That is perhaps the single most important take away lesson from statistics.  You are an individual, and group statistics cannot exactly predict what will happen to you.  You can influence the odds, either in your favor or against yourself, by the decisions you take.  Not always, since Lady Luck is notoriously fickle.  But enough of the time that it is worth the effort.  You agree?