Expertise & Credibility Matter!

expert consensusPeople ask me all the time, why is it so important to go to a CLL expert rather than be treated by the general run-of-the-mill local oncologist close to home.  And when I say “CLL Expert”, I am not necessarily talking about the research specialist at places like the Mayo Clinic or M. D. Anderson.  Not everyone can go far from home and be seen at these expert centers.  I will settle for a hematologist (blood specialist) who sees more than a mere couple of CLL patients in his practice, someone who bothers to keep up with the latest developments in the field, someone who is plugged in enough to be able to recommend the right clinical trial when that becomes the sensible thing to do.

This is important because CLL is such a different type of beast, there are so many ways in which it differs from solid cancers and even other blood cancers.  Knowing when to treat, how long to wait, what to treat with, how to evaluate the results of therapy so that you neither pull your punches nor go over the top, what to do with inevitable adverse effects and complications, how to counsel patients on the things they can do to help themselves – all of these are important if you want to play the hand you have been dealt to the best possible outcome.

All of us will die, sooner or later.  Most of us would prefer later, and most of us would prefer to have a reasonably good time while we wait for the final summons.  Being diagnosed with CLL makes the process a little more complicated. Getting credible advice is half the battle. Your cousin’s stockbroker is not a good source of cancer information, nor the guy spouting off on an internet chat room because he has an axe to grind.  I had one member who depended solely on the advice of her brother-in-law.  After all he was a full fledged MD.  Unfortunately, the guy was also an OBGYN, who happened to have rather strange notions about cancer.  Be smart in your choice of advisors!  It is your life riding on it.

If you were to ask me the single reason why this website is credible, it is because I cite professional references to back up my facts.  And when I write about my own opinions, I make sure you know the difference.  When new facts come to light, or previous understanding is revised, I make sure you know that too.  I try to keep my own ego out of it, as much as possible. As someone once said, we are all entitled to our own opinions but not to our own facts!

“Guidelines for the Diagnosis and Treatment of CLL”

Fortunately for us, well defined consensus documents (like the one I am going to be discussing today) makes the process easier.  An oncologist who is not thoroughly familiar with this document should not be allowed to come anywhere near a CLL patient, in my humble opinion.  The abstract is given below.  Please (pretty please!) click on this link to get the full text version of this important paper for your own files, free of charge.  And please refer to it periodically, whenever you need to refresh your memory. It is truly a treasure trove of details and a reference paper you should use frequently.

Blood. 2008 Jun 15;111(12):5446-56. Epub 2008 Jan 23.

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines.

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia.

Klinik I für Innere Medizin, Universität zu Köln, Köln, Germany.

Standardized criteria for diagnosis and response assessment are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Therefore, a National Cancer Institute-sponsored Working Group (NCI-WG) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for patients with CLL in 1988, which were updated in 1996. During the past decade, considerable progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options. This prompted the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) to provide updated recommendations for the management of CLL in clinical trials and general practice.

PMID: 18216293

Every single one of the authors on this paper is a heavy-hitter in the world of CLL.  It is the product of an international collaboration and as such represents the consensus thinking of experts from several countries.  Some of the guidelines are a bit more conservative than we are used to here in the U.S.  But that is to be expected – we tend to prefer the latest and greatest here, which has its own pros and cons.  The guidelines are broken down into different sections.  I will attempt to give brief description of each.

Diagnosis of CLL

As we have said in many earlier articles, the first step is to have a rock solid diagnosis.  There are way too many other blood cancers that can mimic CLL to an untrained eye.  It is not sufficient to be told “some sort of lympho-proliferative disease”, the diagnosis our local guy came up with after a series of MRI, CAT scan, blood test and even a painful lymph node biopsy.

SLL is now formally a subset of CLL, differing from the more common expression of the disease only in that it manifests itself more in the lymph nodes rather than blood.

CLL always involves cancerous B-cells and only B-cells.  When T-cells are the culprits, it is no longer correct to call it T-CLL.  Patients with T-cell based cancer are now a separate group, that disease is now called TPL (T-cell prolymphocytic leukemia).

The first suspicion of something wrong is usually a routine CBC (complete blood count) that shows ALC (absolute lymphocyte count) that is higher than normal.  Or, in the case of SLL, it could be a swollen lymph node that does not go away after routine prescription for antibiotics – on the assumption it is due to some infection or the other.

Flow cytometry (a simple blood test) is all that is required to diagnose and distinguish CLL from its near kissing cousins – such as hairy cell leukemia, mantle cell lymphoma, marginal zone lymphoma or follicular lymphoma.  I am reproducing below a chart that I have used previously, highlighting the characteristic “CD fingerprint” of CLL and its closest mimics.  Bottom line, CLL cells express CD5, CD19, CD20 and CD23.  The clone should be predominantly alpha or kappa variety.  Expression of surface immunoglobulin (“sIg”) is generally low or “dim” (often represented by a single “+” sign instead of “++”).  CD79b and CD20 are also usually “dim” (single “+”).  If  your lab report says there is no expression of CD5 on your cancer cells, that may be good reason to consider PLL (prolymphocytic leukemia) as a possible alternative diagnosis.  Since PLL tends to be more aggressive and needs to be treated differently, it is important to check this out.

Gribben CD fingerprint

If your version of CLL does not match the fingerprint shown above, then it is really a good idea for you to see an expert and get your diagnosis confirmed.

Other Tests Performed at Diagnosis

I am delighted to see more and more experts getting on-board with the “Prognosis at diagnosis” concept.  The “Guidelines” have a lot to say about the tests that are mandatory, indicated or recommended, or not really necessary outside of  clinical trials.  If you have very healthy insurance and you tend to be a detail freak, you may decide to cajole your doctor into ordering some of the tests not deemed essential.  Here is a quick chart of the various tests and the consensus evaluation of the IWCLL (International Working Group, CLL).

IWCLL test recommendations

I have highlighted in red some of the features that I would like to discuss further.  The IWCLL now considers DAT (direct anti-globulin test) mandatory – a recognition of the frequency of autoimmune disease in CLL.  If you have AIHA (autoimmune hemolytic anemia, far more common than ITP), it is good to know that upfront.  You can die of untreated and unrecognized AIHA a lot sooner than the CLL can kill you.  It also impacts therapy decisions.  It is generally recognized that single agent fludarabine is contra-indicated in folks with AIHA.

Bone marrow examination (bone marrow biopsy) is described as “desirable” for both general practice as well as clinical trials.  I do not know about clinical trials, but I doubt most oncologists would put newly diagnosed patients through a bone marrow biopsy – sure way of frightening off a paying customer!

Why the chest X-ray? Many patients would balk at this.  I would suggest you put aside your concerns about radiation exposure on this front.  First, the level of radiation absorbed in a chest X-ray is rather small, since most of your chest is empty space (air in your lungs) and radiation passes straight through with very little absorbed.  Second, the reason for the chest X-ray is to identify any lung issues.  I am sure you are tired of me telling you that pulmonary inflammation, pneumonia in particular, is the single biggest cause of death in CLL.  Your doctor needs to know if this is going to be a problem.  You do not want to be blind-sided on this one.

I am also very pleased to see the emphasis on careful evaluation of infectious disease status.  CLL is a cancer of the immune system.  By definition, CLL patients are immune compromised, less able to defend themselves against infectious diseases.  Your doctor should know if you have had exposure to hepatitis, Epstein-Barr (mononucleosis or “glandular disease”, HIV, AIDS etc.  I continue to be amazed at the number of “strip-mall oncologists” that fail to ask these crucial questions during the initial consultations.  Notice that the IWCLL also recommends routine evaluation of blood immunoglobulin (“Ig”) levels.  Since B-cells are the source of plasma cells which in turn manufacture immunoglobulins, low Ig levels are a fact of life with advanced CLL.  Low levels of Ig can make the patient more vulnerable to infections.  IVIG therapy can correct for IgG deficiency.

FISH test is now deemed “desirable”.  Frankly, if I were writing these guidelines, I would call FISH test mandatory , even in general practice.  Notice that along with the more familiar probes for 13q, 11q and 17p deletions and 12 Trisomy, the guidelines now recommend looking for 6q deletion as well. Back when we were first pushing for more accessible FISH testing, the standard CLL FISH panel did not include 6q deletion.  Folks with this chromosomal defect were lumped into the “normal” category, along with every other abnormality that we do not know about.  6q deletion is now well documented in CLL and many of the commercial labs now include it.  As far as prognostics goes, 6q deletion falls into the middle Bucket B.

In keeping with their more conservative take on things, other prognostic tests such as IgVH, CD38, ZAP70 etc are considered “not generally indicated” for regular patients, but always necessary in the context of a clinical trial.  I am glad to see that second part.  It is a terrible waste to go to the trouble of doing a well conducted clinical trial without proper prognostic characterization of the patient cohort!

I suppose the decision not to require these tests for general practice is based as much on costs as the ability of local oncologists to interpret the test results.  If you have medical insurance that will pay for it, and you are a detail oriented guy willing to make the extra effort to understand your prognostics, by all means sweet talk your doctor into ordering them.  Even if he does not know all the details, you can find most of what you need to understand your results on this website and our original website CLL Topics.

B2M (beta 2 microglobulin) level is included in the blood serum tests.  Frankly, I would even suggest periodic monitoring of the patient’s B2M level – something that would be seconded by all the folks as M. D. Anderson. Also included in the blood serum tests are levels of CD23  and thiamidane kinase.  These are less well characterized than B2M, and therefore harder to interpret the results.

I am dismayed that we still do not have sufficient attention paid to the risks of secondary cancers – especially skin cancer.  Surely, an important consensus document such as this can help us get the word out to less expert physicians!  Our guys are much more prone to skin cancer.  And fighting a two front war with CLL and skin cancer is not something I would recommend, even to my own worst enemy.

Disease Staging

Two staging systems have been used previously, the Rai staging system in the U. S. and the Binet staging system in Europe. Now the IWCLL has made modifications so that the two systems become just one, a system that can be used by physicians everywhere.  All that is required for this new staging protocol is careful physical examination and standard laboratory blood tests.  There is no need for CT scans or MRI scans to stage the patient. There are only 3 major stages, describing early, moderate and advanced stages of the disease.

  • Early stage disease: Elevated levels of lymphocytes (“Lymphcytosis“) in blood or bone marrow aspirate.
  • Intermediate stage disease:  Lymphcytosis along with swollen lymph node(s) anywhere in the body, as well as swollen spleen or liver.
  • Advanced stage disease: All of the above, as well as disease related anemia (defined as hemoglobin (Hg) less than 11.0) or thrombocytopenia (defined as platelet count less than 100).

Note the emphasis on disease related anemia or thrombocytopenia in determining advanced stage disease.  This is in order to rule out those patients whose low hemoglobin or platelet counts are due to other reasons, such as autoimmune disease, dietary issues etc.  We discussed this in greater detail in an earlier article.

Guidelines for start of therapy

IWCLL guidelines for start of therapy can be summarized into a neat little table.  Here it is.

IWCLL start of therapy guidance

Some explanation and discussion of this chart is necessary, I think.  In general practice, no oncologist in his right mind should start therapy for a patient in early stage disease.  Remember your staging criteria.  Even with very high ALC, patient is still in early stage disease unless other indications are also present.

Is it appropriate to treat early stage patients in the context of a clinical trial? Not until recently.  We did not have any drug where the risk versus potential benefit of the treatment was in our favor.  Most of you know that old classic clinical trial:  treating patients earlier with chlorambucil did them no favors.  But now things seem to be changing.  We have biologic drugs such as the new family of kinase inhibitors (CAL-101, PCI-32765) and immune modulators (lenalidomide, also known as Revlimid) which may be able to roll back the disease without exerting too high a price in terms of toxicity.  Are we there yet? Do we know for a fact that initiating therapy sooner with these new drugs, during early stages, will actually benefit patients in terms of longer life and/or better quality of life?  I am afraid not.  These are still early days.  We do not know all the hidden dangers, yet.  That is the reason why treating patients in early stage disease is still a research question.  Let us hope we get solid results soon, and the results are positive.

How about intermediate stage disease? What if there is high ALC, reasonable level of swollen nodes, spleen/liver etc, but the hemoglobin and platelet counts are still holding in normal levels?  IWCLL makes this a judgment call, it is possible (but not mandatory) to treat such patients both in general practice as well as in clinical trials.  Other medical factors may drive the decision.  For example, if there is frequent infections, if the nodes are pressing against other organs or nerve bundles and causing pain etc.

How about late stage disease (i.e., high ALC, plenty of swollen nodes and spleen/liver, hemoglobin and/or platelet counts a tad below healthy levels), should that always be treated, even if the patient is stable? IWCLL suggests treatment is not necessary if the patient is stable, if the disease is not actively progressing.  Prudence is the better part of valor in this situation.  But as always, these guys are fair game as cohorts in a clinical trial.

IWCLL guidelines go further, detailing criteria to look for prior to start of therapy.  Here they are, bullet point style:

  • Evidence of bone marrow failure, as shown by worsening anemia, platelet counts
  • Massive splenomegaly (swollen spleen, at least 6 cm below left rib cage)
  • Massive (larger than 10 cm in longest diameter) lymph nodes, or where they are obviously growing rapidly, or causing other symptoms (such as pain and discomfort).
  • Increase in ALC that is more than 50% over a two month period.  Warning:  change in ALC from 6.0K ti 9.0K does not count.  This difference is too small, it falls within the range of random or instrument error. Another way of looking at rapid change in ALC is to look at lymphocyte doubling time of less than 6 months.  Once again, this parameter is only applicable if the starting ALC is more than 30K.  In other words, going from 30K to 60K in six months counts.  But not if the change is from 10K to 20K in 6 months.
  • Autoimmune disease (AIHA, ITP) that is poorly controlled by steroid or other standard therapy. If that is the case, it may be that treating the underlying CLL will help relieve the autoimmune disease as well.
  • One or more of the classic “B-symptoms”: unintentional weight loss of more than 10% in the last  months; significant fatigue, enough to make work and QOL difficult; fever that is higher thana 100.5 for 2 or more weeks; night sweats for more than 1 month – without evidence of any infection.
  • Low immunoglobulin levels by themselves do not necessitate start of CLL therapy.  However, the IWCLL guidelines suggest keeping an eye on these levels, especially if there is evidence of frequent infections.
  • Pretty much the same guidelines are applicable for initiating the second and subsequent lines of therapy.  Short time to progression the first time around, or those with 17p deletions, are not likely to get good response to presently available standard therapies.  Such patients should be encouraaged to try new clinical trials or a mini-allo transplant where applicable.

Definition of Response

A lot of jargon filled details in this section of the guidelines.  Here is the quick and dirty, looking only at “CR”, “PR” and “PD”

IWCLL response definition

It looks complicated, but actually it is pretty straight forward if you take the time to read it carefully.

But notice one little point that matters most to us chickens.  Getting a “CR” does not say anything about how long the remission will last, or how long you will live after end of therapy.  It is reasonable to assume that someone who gets a CR response will do better on these important criteria (duration of remission and overall life) than someone who got a PR, or worse still, had progressive disease (“PD”) at completion of therapy.  But that does not mean you are guaranteed long life, long remission, just because you got a “CR” response.  All the same, I will take a CR response any day of the week, if the other choices are PR or PD.


If there is just one CLL paper that you plan to print out and keep for future reference, this IWCLL guidelines paper is a good candidate.  Heck, it is so important, it is available free of charge.  Make an extra copy for your local guy, if you think he has not seen it yet.

I have tried to hit the highlights  in my review.  But there are a lot more details in the original article than the ones I have covered.  Nothing like going to the source to get detailed information.  My review may help you deal with the jargon intimidation factor, make it a bit easier to wade through the original article.

One of the most frequent “rookie” mistakes made by inexperienced oncologists is to start therapy too soon.  Our local guy wanted my husband to make an appointment for start of chemotherapy (single agent fludarabine, no less!) on our way out the door after our very first  initial consultation with him.  Forget about prognostics, he did not even have a firm diagnosis in hand! He called it “some sort of a lymphoproliferative disease”.  Suffice to say, we voted with our feet and lucky to have done so.  I doubt PC would have lived 7 more years with the quality of life he had, if we had done what this guy had suggested.

I hear from dozens of patients whose oncologists want to start therapy when their ALC (absolute lymphocyte count) reaches some pre-determined “magic” number.  How do I advise these folks?  If their guy cannot be reasoned with, made to change his approach based on best practices guidance provided by experts, then the patients should vote with their feet and find themselves a new physician. That simple.  Life is too short as it is, you do not want a doctor that treats the numbers, because it is too much of an effort for him to come up the learning curve, do his best to treat the needs of the patient in front of him.

I would not be doing you justice if I did not also highlight patients who are so terrified of the word “chemo” that they would procrastinate until the train has left the station for good.  No one in his right mind would want to poison his body with chemo drugs, I fully grant you that.  But in case you have forgotten,  there is this pesky little thing called CLL that has made its home in your body.  When the alternative is dying sooner than necessary, I think chemo looks pretty good.  Yes, there are quality of life issues.  But more often than not, proper treatment (yes, possibly with chemo drugs) at the right time actually improves quality of life.  I can imagine the frustration of doctors when faced with patients who clearly need chemotherapy and refuse it for less than logical reasons.

I cannot honestly say I have looked into it in any great detail, but perhaps you should try and find out more details of Steve Job’s preference for unproven “alternative” therapies.  More conventional treatment may have allowed him to live longer.  Someone with early stage CLL, also blessed with good prognostic indicators that will keep them there indefinitely, these are the lucky folks.  I wish them well, congratulate them on their good fortune.  But that does not mean everyone else is as lucky as they are.  I sure as heck wish the lucky ones do not jump to the conclusion that they are doing as well as they are because of some particular potion  or diet they have decided to follow.  Or more to the fact, even if they believed it, I wish they would not preach it to the rest of us.  Bad advice hurts, as surely as bad medicine.  “Buyer Beware” is a good thing to remember in life, especially when it comes to ‘buying’ medical advice from strangers.  Credibility counts!  And it goes without saying, you should be just as careful in evaluating my bona fides.

Fake experts