MBL – Beast of a Different Color

A recent paper authored by Dr. Landgren et al in the New England Journal of Medicine has caused some controversy in the CLL patient community.  Controversy is fine, but I worry when the Internet chat rooms hype things out of proportion or just plain get the details wrong. I have received dozens of emails from worried members asking for clarification. This review went to the top of my to-do list when I also received a request from one of the authors of the paper, concerned about misrepresentation of the implications of their research in the patient community.

What is MBL?

Healthy people have B-cells with a wide repertoire of receptors targeted to battle an equally wide selection of pathogens out there.  At any given time there may be only a few B-cells targeting any given pathogen, the idea here is to have diversity and not group think. This is one of the most important parts of our immune system, a surveillance system that is constantly on the look out for a bewilderingly large and diverse array of ‘enemies’ out there in the hostile world attempting to get a toe hold in our bodies.

But once in a while there may be a slightly larger-than-usual collection of B-cells that are all fixated on the same pathogen. This is called a clonal population where each member of the clone has the same exact receptor, targeting the same pathogen. When the size of the clone is bigger than normal – and large enough to be detected by our most sensitive methods (please read a recent Updates article on flow cytometry), the person who is harboring this clone is said to have monoclonal B-cell lymphocytosis, or MBL for short.

Yes, the article on MBL is really cool science and I enjoyed reading and discussing it with the authors.  But there is less than meets the eye here, as far as patients worried about familial CLL are concerned. The abstract of the article is below.  Write to me if you are a geek like me and want to read the full text of the article as well as the accompanying Editorial.

N Engl J Med. 2009 Feb 12;360(7):659-67.

B-cell clones as early markers for chronic lymphocytic leukemia.

Landgren O, Albitar M, Ma W, Abbasi F, Hayes RB, Ghia P, Marti GE, Caporaso NE.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. landgreo@mail.nih.gov

BACKGROUND: Otherwise healthy persons with a small number of B-cell clones circulating in the peripheralbloodhave been designated as having monoclonal B-cell lymphocytosis (MBL). Hospital-based series indicate an excess risk of progression from MBL to chronic lymphocytic leukemia (CLL). In this prospective cohort study, we tested the hypothesis that CLL is always preceded by MBL. METHODS: Among 77,469 healthy adults who were enrolled in the nationwide, population-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 45 subjects in whom CLL was subsequently diagnosed (up to 6.4 years later) through the collection of a peripheral-blood sample. Using six-color flow cytometry (with antibodies CD45, CD19, CD5, CD10, kappa, and lambda) and immunoglobulin heavy-chain gene rearrangement by reverse-transcriptase-polymerase-chain-reaction assay, we determined the association between MBL and subsequent CLL and characterized the immunoglobulin gene repertoire of the prediagnostic B-cell clones. RESULTS: On the basis of either flow-cytometricormolecular analysis, 44 of 45 patients with CLL (98%; 95% confidence interval [CI], 88 to 100) had a prediagnostic B-cell clone; in 41 patients (91%; 95% CI, 79 to 98), the presence of the B-cell clone was confirmed by both methods. The presence of immunoglobulin heavy-chain variable (IGHV) genes was determined in 35 of 45 prediagnostic clones (78%). Of these clones, 16 (46%) were IGHV3 subgroup genes (including 6 [17%] IGHV3-23 genes) and 9 (26%) were IGHV4 subgroup genes (including 4 [11%] IGHV4-34 genes). Furthermore, 27 of 35 of the IGHV sequences (77%) had mutations, with similar distributions after stratification either below or above the median time between the collection of the prediagnosticbloodsample and the subsequent CLL diagnosis. CONCLUSIONS: In peripheral blood obtained up to 77 months before a CLL diagnosis, prediagnostic B-cell clones were present in 44 of 45 patients with CLL. 2009 Massachusetts Medical Society

PMID: 19213679

Translating Cool Science into Plain English

  • Roughly 77,000 healthy people between the ages of 55 and 74 years had participated in cancer-screening tests earlier on (1992-2001), your tax dollars at work.
  • 129 of this group were later diagnosed with CLL, but prior blood samples were available for only 45 of these people. Therefore these 45 folks were the basis of this study.
  • Using the blood samples obtained years earlier, researchers were able to demonstrate that tell-tale MBL clones could be seen in 44 out of the 45 CLL patients.
  • The tiny MBL clones identified in each case had the same phenotype and molecular characteristics as the CLL clone that finally reared its ugly head years later in that individual.
  • It is safe to say that in these 44 patients, the MBL clone detected in samples collected several years earlier from these individuals had grown up to be full fledged, clinically diagnosed CLL.

OK, we get it.  MBL can gradually grow over time from a tiny cluster of clonal B-cells to full fledged CLL with fangs and all.  But here is the most important thing to remember: MBL does not guarantee full blown CLL down the road, far from it. Perfectly healthy people can have MBL and be none the worse for it, never even know they have MBL in the first place, never get diagnosed with CLL in their lives.

You want a silly analogy to make this point clear?  Every single unlucky person who has ever died in a plane crash had flown in airplanes at one time or another. (Duh. How can you die in a plane crash if you have never flown in a plane?). But the converse of the statement is not true, that anyone who has ever flown in a plane is going to die in a plane crash.  You get it?

What are the implications of this research for CLL patients?

If we were to waste a lot of money and conduct mass screening of the general public, we will find a certain percentage of people with tiny clusters of clonal B-cells (MBL), microscopic clones with a mere million or so members that require our best efforts to even detect them.

Best guesses put folks with MBL in the general public somewhere between 4-8%.  The percentage will be higher in older groups of people, certain ethnic groups (AshkenaziJewish groups, for example?) perhaps higher percentage in men than in women.  Perhaps we may even find a link between mononucleosis or frequent episodes of pneumonia and likelihood of MBL diagnosis down the road.  Whatever.  I will leave discovering those epidemiological connections to researchers.

Here is the picture you need to see clearly.  If one were to follow for several yearsthe fate of all these people in the general public in whom MBL has been detected, I expect the group would divide into three sub-groups, thusly:

  • A very tiny percentage of the MBL folks will indeed develop full fledged CLL down the road, the clone detected at the MBL stage having grown into clinically diagnosed CLL. The NEJM article estimates the rate of conversion of MBL to CLL at roughly 1% per year, give or take a little (remember, the sample size of this study was not all that large).
  • We might find the percentage of conversion from MBL to CLL to be higher in people who have first degree blood relatives with CLL, reflecting the familial nature of this disease.  You are more likely to have clinically diagnosed CLL if you had first degree blood relatives that also had CLL.
  • But the vast majority of people who have MBL detected in them will probably never “graduate” to clinically relevant CLL. They may trundle along with the same MBL signature for the rest of their lives, the darn thing never getting any worse and not quite disappearing either.  Their ALC (absolute lymphocyte count) may ‘oscillate’ over time, increasing gradually over time and subsiding again.
  • Here is the good news, a large percentage of the MBL folks will actually revert back to a state where even the MBL will disappear and is no longer detectable in subsequent testing, a case of effective immune system functioning.

Microscopic clusters of skin cancer cells are present in most of our bodies and tiny clusters lung cancer cells are often present in the lungs of heavy smokers.  This does not mean all these people will soon be battling full fledged skin cancer or lung cancer.  These tiny clusters of malignant cells are killed off by a vigilant immune system as soon as they are detected, majority of these malignant colonies never graduate to become clinically relevant cancers.  Same thing is true of tiny clonal clusters of B-cells (MBL clusters); in a majority of cases these small clusters are killed off and the MBL disappears over time.

Editorial

Exactly five years ago, also on Valentine’s Day, I wrote an article titled “Not the worst day of your life“. For all of us with children or grandchildren, the familial nature of CLL is a stark reminder of how much worse things can get.

In that earlier article I discussed the pros and cons of getting our kids and grand kids tested for tell tale signs of CLL.  With the improved understanding of MBL and the knowledge that future CLL can be detected years earlier as MBL, should we get our kids tested? I am still convinced the answer is “No”.  Should the general public at large be screened?  A resounding NO, in my opinion.

Down the road it may be possible to kill the tiny MBL clone right at the beginning, as soon as it raises its ugly head, at a time when it is still tiny and vulnerable.  Perhaps that is the route to curing CLL, by not letting the MBL to gain a toe-hold in the first place. If and when we can do that, there may be reason to proactively screen high risk people (familial clusters?) for MBL.  But we are not there, yet.  We may be able to detect MBL today, but we do not know what do about it.

What should we do, as parents and grandparents, today? Here are my thoughts on the subject.

  • Don’t panic.  Learn to enjoy each day with your kids and your families as if it were your last.
  • Teach your children habits of healthy living – eating a wide variety of fresh vegetables and fruits, avoiding junk foods as much as possible, regular and vigorous exercise habits, avoiding the cardinal sins of obesity and smoking that account for the majority of illnesses in the developed world.
  • I would go a few steps further, even though these have not been suggested formally by any researcher.  I would keep an eye out for chronic inflammatory and autoimmune diseases.  I would not take lightly “walking pneumonia” or bronchitis that seems to linger too long. I would make sure my kids understood the difference between getting some fresh air and exercise versus over-the-top sun exposure.  Frequent teenage sun burns can come back to haunt us when we are much older.
  • Last but not least, I would do all I can to support research such as that reported in the NEJM article we are discussing here.  Today we can detect MBL years ahead of when it may bloom into full blown CLL.  Maybe tomorrow (or the day after that!) we can find ways in which to control or totally eradicate the MBL clone in people who are at high risk of this clone developing into full fledged CLL.

How are we going to get from our bleak today where CLL is an incurable cancer to a brighter tomorrow where we may be able to prevent it from right from the get go, if we do not support research that will bridge the gap?  The horse has fled the barn for our generation, as far as controlling MBL goes, as a way of curing CLL.  But which of us would not work hard to make that a reality for the next generation, our children and grandchildren?

Happy Valentine’s day, from my family to yours.