Does Better Understanding of CLL Lead to Longer Life?

BartsBack in 2001 when I heard about CLL for the first time, Dr. John Gribben was at the forefront of CLL research at Dana Farber.  Couple of years later he moved back home to the UK and he is  now at the prestigeous Barts.  Dr. Gribben is one of the experts whose publications I track as a matter of course.  His most recent article in Blood does a great job of pulling together all the modern understanding of CLL and guidelines for frontline treatment of patients. Abstract of Dr. Gribben’s article is below.

Blood. 2009 Oct 22.

How I treat CLL upfront.

Gribben JG.

Institute of Cancer, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom.

Chronic lymphocytic leukemia (CLL) remains incurable, with patients having a clinical course of disease progression to requirement for treatment followed by an unremitting course of relapse of disease. Over the past decade there have been major advances in understanding of the pathophysiology of CLL and in the treatment of this disease. This has led to greatly increased response rates and durations of response, but until recently little evidence that this had led to improvement in survival. Advances in the use of prognostic factors that identify patients at high risk of progression have led us to the question that if there still a role for a “watch and wait” approach in asymptomatic high risk patients or if they should be treated earlier in their disease course. Questions remain including; what is the optimal first line treatment and its timing and is there any role of maintenance therapy or stem cell transplantation in this disease? CLL is a disease of the elderly and not all of these patients are eligible for aggressive upfront chemo-immunotherapy regimens, so what is the optimal treatment approach for more frail elderly patients? It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released and that further improvements in the outcome of this disease will result from identification of therapies that target the underlying pathophysiology of CLL.

PMID: 19850738

As Dr. Gribben point out, over the last decade we have made huge strides in better understanding of the pathology of CLL. Better drug cocktails yield higher response statistics and longer remission periods. But until very recently there has been no concrete proof that patients were living any longer because of all this new fangled stuff. Even more important, there is a lot of confusion about when to start therapy and what to use as frontline treatment. This “Best Practices” paper pulls together all the important stuff we have learnt over the last decade and how it fits into your modern treatment game plan.

Who Is Most at Risk of Getting CLL?

Dr. Gribben gives up-to-date CLL statistics that you might find interesting. Here are some highlights from his article. Remember, these are statistics based on general population. They may not reflect your specific situation.

  • Roughly 15,500 people will be diagnosed with CLL in the USA in 2009. Of these, more than half (just over 9,000) will be men.  No question, there does seem to be a slight male bias in this disease.
  • Median age at diagnosis is 72 and death due to CLL is at age 79. Almost 70% of patients are older than 65 years and patients younger than 45 is just 2%. If you are a very young CLL patient, consider yourself specially “blessed” – not that you asked for it or anything.
  • CLL is small potatoes when it comes to incidence in the general public. Just a tad over 4 people out of 100,000 get CLL each year. When statistics are examined from 1975 through 2006, there does not seem to be any increase in this rate.
  • The single biggest risk factor of getting CLL is a family history of CLL or other lymphoid cancers. CLL is a familial cancer. Remember that the next time you are reading about long term research. Your kids and grandkids may benefit from our dedication today.

Accurate Diagnoses CLL

Half the battle is making sure the initial diagnosis of CLL is correct, since there are many “kissing cousins” that sort of look like CLL and might fool the local ‘strip-mall oncologist’ that sees just one or two cases of CLL each year.

For starters, CLL is always a cancer of B-lymphocytes. What used to be called T-cell CLL has now been classified as T-prolymphocytic leukemia and a totally different beast. I need apologize no longer for not talking about this T-cell cancer. It is not in my sand box. So there.

When the disease is present mostly in the blood (as demonstrated by elevated absolute lymphocyte counts in a CBC blood test) it is called CLL. If the disease is preferentially present in enlarged lymph nodes it is called SLL. But when rubber meets the road there is no real difference between the CLL and SLL and they are treated the same way. Dr. Gribben recommends a proper biopsy of an accessible lymph node and review of the biopsy specimen by an expert pathologist for confirmation of SLL. He does not recommend the easier fine needle aspiration of lymph node for SLL diagnosis. Fine needle aspiration is a bit of a hit-or-miss affair. The needle may / or may not hit the exact location where some SLL cells are hanging out, your results may vary accordingly.  Classic CLL requires no lymph node biopsy since the disease is clearly present in the blood and can be detected by means of blood tests.

He also thinks a bone marrow biopsy (BMB) is not needed at the time of diagnosis except in special circumstances. He uses a BMB when it is time for treatment, in order to get a good sense of the lay of the land. It may also be necessary to do a BMB sooner if the patient has cytopenias (low red blood cells and low platelets), to figure out if the root of the problem is autoimmune disease (AIHA or ITP) or compromised bone marrow function.

Mug-Shot of CLL cells

Gribben CLL cellsAlongside is a picture of what CLL cells look like when they are viewed under a microscope. CLL cells are small, round B-cells (stained dark purple in this slide). Often, there are “smudge cells”; think of them as cells that have gotten squished flat. It seems CLL cells are a bit more fragile than normal B-cells and they are more likely to get bent out of shape in the process of making a microscope slide of the sample. You can see some of these smudge cells in the picture.

Accurate CLL diagnosis requires certain features. First, ALC has to be more than 5.0K, as seen in a CBC. If the ALC count is less than 5.0K it is called monoclonal B-lymphocytosis (MBL). We discussed MBL in detail in an earlier article. If you have not done so already, please read our recent articles on CBC, ALC, red blood cells and platelets to become familiar with the acronyms.

Phenotype: Devil is in the Details

The next step is to conduct a flow cytometry test. All cells have a number of special structures on their surfaces. These are given names “cluster designations” or “CD” numbers. Different cell types have different set of CD types present on their surface. Flow cytometry looks not only to see what CDs are present, but also how densely they are packed on the cell. For example, “bright” expression of a particular CD type (say, CD19) means there are many thousands of copies of CD19 present on each cell. A “dim” expression of CD20 for example means there are far smaller number of CD20 groups present per CLL cell. Some labs use “+” for dim, “++” for intermediate and “+++” for bright expression of various CD clusters.

CLL cells have their own particular profile of CDs. Think of it as a fingerprint of this particular variety of cancer cells. The fingerprint is different if we are talking of some other B-cell cancer. Flow cytometry looks for this unique fingerprint and it is very useful in confirming CLL – as well as ruling out some of the “kissing cousin” cancers. It is particularly important to rule of more dangerous varieties of B-cell cancers such as mantle cell lymphoma. The table below gives the fingerprint profiles of the various B-cell cancers.  Depending upon the sophistication of your testing lab all or only some of these CDs may be studied and reported.

Gribben CD fingerprint


There are two classic staging systems, Rai and Binet. The Rai staging system is used most often in the USA and the Binet system is used in Europe. Both systems have become a tad of date as we have learned more about CLL, but both staging systems still retain value and it is therefore important for us to learn about them.

The Rai system looks at increasing accumulation of CLL cells. It therefore focuses on ALC, presence of more and larger swollen lymph nodes over time, swollen spleen and liver, all of them choke full of CLL cells. Anemia and thrombocytopenia (reduced red blood cells and platelets, respectively) is attributed to bone marrow getting progressively packed with CLL cells and therefore preventing the bone marrow from producing new red blood cells and platelets as the old cells get worn out and die.

At the time of diagnosis about 25% of patients are Rai Stage 0. We have discussed the relevance of Rai Staging in much greater detail in an earlier article. In a less fortunate 20% of patients the disease is advanced and accompanied with anemia and thrombocytopenia. B-symptoms (weight loss, fevers, night sweats, extreme fatigue) are present at time of diagnosis in 20% of cases and may require treatment right away.

The Binet system considers three potential sites of lymph nodes (cervical, axillary, inguinal – see picture below for locations) as well as spleen and liver. Patients are staged according to the number of these five possible sites where disease is present. Anemia (hemoglobin less than 10) and thrombocytopenia (platelets less than 100K) are the other two factors taken into account in Binet staging.

Gribben lymph nodes

CLL staging is done using either one or combination of Rai and Binet staging systems along with CBC and physical examination. CT scans and BMB are not necessary or recommended for staging purposes. But Dr. Gribben cites an exception to the general rule about early use of CT scans:

“Although care has to be taken not to over-use CT scans in early stage patients, in patients identified at higher risk of progression, CT scans provide a more accurate assessment of intra-abdominal disease than clinical examination and upstaging a patient by CT scan criteria alone has prognostic significance. I therefore find it useful to perform CT scans to determine baseline adenopathy in patients who present with poor prognostic features, particularly del 11q, since this is often associated with an increased frequency of intra-abdominal lymphadenopathy.”


The biggest advances in our understanding of CLL has come in the area of modern prognostic indicators. Dr. Gribben reviews the importance of FISH, IgVH gene mutation status, ZAP70, CD38 expression in determining the risk status of patients. Below is his list of poor prognostic indicators in CLL. We have discussed some of these in an earlier article “What type of CLL do you have”? in patient-friendly language. I recommend you review it if you are not sure of your particular risk “Bucket”.

Gribben prognostic indicators

As Dr. Gribben points out, “a current challenge is to understand how we should use this new information in clinical practice”. Here are some interesting quotes from the paper:

“However useful the biomarkers may be in predicting how cohorts of patients will behave, they are less precise in predicting outcome in Individuals.

“It is often the patient who demands the results of the prognostic tests. Certainly, if I were to be diagnosed with CLL I would want to have as much prognostic information as possible for planning purposes.

“My own experience is that patients usually request these tests hoping that they will have good prognostic markers and the finding of poor risk factors can often lead to increased anxiety, while not changing management, and this requires considerable time in the clinic explaining the potential significance of the findings.

Editorial Comments

OK Doc. We get it. If you got CLL, you would want to know all the prognostic information for “planning purposes”. But a generic Joe Patient walks in, unprepared and uninformed, he may not be able to deal with the bad news and it takes up too much of professional time walking him through all this complicated stuff, not to mention holding his hands as it were.

But how about the patients’  “planning purposes”?  We too have lives, families, finances and stuff that can benefit from having a rough idea of what is coming at us round the curve in the road. But I accept we live in the real world, we understand limited time is available to each patient during expert consultations.

So, how about this Doc, how about truly informed and involved patients? Patients who learn about all this difficult stuff on their own time, patients who come to you for the facts, just the facts, and all the hand holding and emotional and educational support is done elsewhere? Would that not be a good solution for all parties concerned? How do you feel about patient-friendly educational websites that present credible information such as this excellent article of yours, reviews that are CME (continuing medical education) suitable to layperson patient audience?

Patient follow-up

Dr. Gribben follows patients every three months for physical examination, history and blood counts. If the track record shows an indolent disease, it may be OK to see the patient less frequently. He pays special attention to any changes in symptoms (such as development of B-symptoms, increasing adenopathy at one site, elevated LDH – lactate dehydrogenase) since this may suggest transformation to more aggressive Richter’s disease. He does not use routine CT scans, only in specific circumstances as we discussed earlier.

Frontline therapy: When, What Why

One of the most interesting and useful aspects of this paper are the excellent flowcharts Dr. Gribben has included for therapy decision making. Here is his approach to frontline therapy:

Gribben frontline therapy

  • This chart is very easy to follow. The present day standard of care is to initiate treatment only when the patient is symptomatic, until then the safest course seems to be good old Watch & Wait. There are always special circumstances and we discussed some of these in an earlier article “To wait or not to wait”.
  • Dr. Gribben has a full section on treatment of elderly patients who are not in the pink of health even without CLL. For them, chlorambucil may be the best bet. Recent comparisons between fludarabine versus chlorambucil as single agent therapies in such patients have shown little advantage for fludarabine. Chlorambucil is easier to tolerate, cheaper, easier to dispense and has fewer adverse effects.
  • But if the patient is younger and in better physical shape, the choice of therapy depends on whether or not he has the dreaded p53 deletion (FISH test). Alemtuzumab (Campath) is one of the few drugs that is known to work well with p53 deleted patients. Dr. Gribben does not mention a couple of others, Revlimid, flavopiridol etc, that are also thought to work in these patients. But that is perhaps because these drugs are not quite there in terms of full fledged clinical trials certifying their usefulness in p53 deleted patients.
  • In keeping with recent emerging expert consensus, Dr. Gribben recommends eventual mini-allo transplants for patients in this high risk group.
  • In the absence of p53 deletion or mutation, Dr. Gribben recommends FCR, the triple combo showcased at M. D. Anderson. FCR is potent chemoimmunotherapy and it gives excellent response rates and deep responses to many patients. While 6 cycles of FCR is no walk in the park, the remissions are longer lasting than most other therapy regimens. Life after FCR remission ends can be problematic, as we discussed in an earlier article.

While this flowchart may look simplistic, notice there is “or clinical trial” at two different points in the chart. This covers all the other drugs and their various combinations, both recent and a few years older. Dr. Gribben gives a good review of the results obtained in many of the clinical trials that have been pivotal in defining the advantages and disadvantages of these other options.

As I said, this is an excellent and expert overview of the CLL scene. Long as this review has been, I have done it scant justice since there is a lot more detail than I have addressed. Thank you Doc, for your thoughtful and well considered comments.  Muchas gracias, on behalf of several thousand of our determined members. Our guys are going to be that much better informed the next time they see their local oncologists.  Heck, they might even give a printout of your article to their local healthcare provider at their next meeting, bring this valuable “Best Practices” guidance to his/her attention.  I am all for access to important information, it does not matter much to me whether it is trickle down through traditinal channels or bottom up on patient advocacy / education forums such as this one.