CLL predictions

The terms" lymphocyte doubling time" and absolute lymphocyte doubling time" are essentially synonymous. One never uses the percentage lymphocyte count for much at all in people with CLL.

As to when to start treatment, that is a decision that is never based on only 1 reason. So, for some folks a doubling time of less than 1 year is associated with additional signs and symptoms and that grouping triggers the decision. For others, the single sign of a fast doubling time may just mean more close follow up since there are no other reasons to start treatment.

Here are the two major staging systems in use today

RAI STAGING SYSTEM

 0 Lymphocytosis in blood and bone marrow

 I Lymphocytosis and enlarged lymph nodes

 II Lymphocytosis with organomegaly

 III Lymphocytosis and anaemia (Hb < 11.0 g/dl)

 IV Lymphocytosis and thrombocytopenia (platelet count < 100 x 109/L)

BINET STAGING SYSTEM

 A Hb > 10.0 g/dl Platelet count > 100 x 109/L < 3 lymph node areas enlarged

 B Hb > 10.0 g/dl < 3 lymph node areas enlarged Platelet count > 100 x 109/L > 3 lymph node areas enlarged

 C Hb < 10.0 g/dl or Platelet count < 100 x 109/L

Joe, you are absolutely correct that looking at one number is a dangerous game. So too is taking the evidence from one disease and applying it to another. If you remember, last week when I wrote about beta-2-microglobulin, I was careful to refer to multiple myeloma. It has been reasonably proven that the B2M is predictive in patient with MM. It has not be proven to work the same way in CLL - which is strange since they are both B cell lymphoproliferative disorders. Apparently though there is sufficient difference between the two that little from one can be assumed about the other.
Just looking at the doubling time is also not a good idea. Some people have a slow build-up of cells but the cells themselves get "younger" and more dysfunctional. In that situation, looking at the white count would be just as misleading as a reliance on CD status or B2M levels. There is no one test that is applicable to everyone. How many times have people written about the individuality or uniqueness of their CLL when contrasted with someone else's CLL. I know that it is tedious to keep track of all the numbers and I know that you do so want to enhance the importance of the good numbers in relation to some not-so-good values but we can't
 

Do patients with IgVH mutations progress?

Being IgVH mutated is not the same as having smouldering CLL. Perhaps 60% of
patients with CLL have mutated IgVH genes. About half of these will be totally
stable throughout life, always having a total lymphocyte count less than 30
000. The other half will have a slowly rising white count. Some will develop
enlarged lymph nodes and about 10% will genuinely need some form of
treatment. The problem is that many will be treated more aggressively than is
necessary and some will be treated unnecessarily - because of a white count that hits
100 000, for instance.

Patients with mutated genes seldom get anaemia or thrombocytopenia due to
marrow suppression, although they might get the autoimmune variety. Very few
patients with the mutated version die of the disease, whereas it is the cause of
death of most of those with the unmutated version.

In our hands the survival after first treatment is roughly twice as long for
the mutated version than the unmutated version, though the numbers who
actually required treatment is small. The reason that patients who did well on
RFC or autograft are being retested for IgVH mutations is to find out whether
the good reports of those treatments are because their doctors were
over-enthusiastic in treating them. In the German autograft trial, all those who remain
in molecular remission had mutated IgVH genes whereas all those with
unmutated genes had relapsed by 4 years.

A word of caution: you have to have some CLL cells available to do a ZAP-70
test; you can't do it while you are in complete remission.

Lymphocyte doubling times

In fact Sonia's lymphocyte count has not yet quite doubled since January
2003. From 12.3 to 23.47.

Lymphocyte doubling times need to be taken in context, and it is important
not to rely on a single measurement. All sorts of things can account for an
unexpected high level: it could be a laboratory error, any infection can raise
the lymphocyte count or an immune response to a sub-

clinical virus or to a
vaccination. Finally, if you have to take prednisolone for any reason, the white
count can shoot up.

Mutated VH genes, normal karyotype, low CD38, nodular bone marrow, all point
to a good prognosis.

The new lymph nodes might go down by themselves, and be an indication of an
infection, but patients with benign CLL do enlarge their lymph nodes, and in
many cases this is not an indication for treatment.

The statistics I was quoting relate to my own series of over 600 patients
seen in Bournemouth over the last 30 years. Of course nobody knows the true
incidence of CLL because (in my experience) 75% are discovered only because
someone has asked for a blood test on a patient for a completely unrelated
reason. Therefore, if you don't have an incidental blood test you don't get
diagnosed.

There is a lot more artifice in the system. Someone has decided that CLL can
only be diagnosed if the lymphocyte count is greater than 5000. However, we
know from Andy Rawston's work that there are a lot more people who have a
population of cells in their blood, that in every respect resemble CLL cells,
but there are fewer than 5000 of them. The incidence of this is 3.5% in the over
40s, based on a series of random blood tests done in Leeds, England. This has
been confirmed by a similar series in Milan, Italy.

So in almost every case we diagnose we don't know how long the patient had
the disease, and therefore the age at which it was diagnosable. We can be
pretty sure that as more younger people have regular blood tests, we will discover
that the age of diagnosis will go down. On the other hand, if we are
prepared to do blood tests on very elderly patients (those over 90, for example) who
would be left alone by a previous generation of doctors, we might find the
average age of diagnosis increasing.

In my series the age range of Bournemouth residents is skewed, since it is a
popular retirement area. 30% of the population is over-60. The modal age
(that is the age at which there are most people) for males is 19 and for females
is 74. That sounds strange, but what it means is that there is a bimodal
distribution of the population, with the peak at 74 for women being higher than
the peak at 19 (the time when school-leavers leave the town to go to
University), whereas, since fewer men live so long, the peak at 19 is higher than
the peak at 74.

Apart from my own study we have the statistics from large multi-centre
trials. The average age in these tends to be rather lower because very old people
tend not to be entered into clinical trials. Then we have groups derived from
the internet. These tend to be younger still, because very old people tend
not to be as internet savvy as rather younger people.

When I was collecting my series, I saw every blood count that came through
the laboratory, and made a point of investigating every blood count with a
lymphocyte count greater than 5000. Many haematologists don't do that.

As far as the gender ratio is concerned, my latest data comes from 310
patients on whom I have done the V gene test. For those with unmutated VH genes
the gender ratio is between 2-3 to 1 in favour of males, for those with mutated
VH genes the ratio is close to one to one.

Everybody's series contains some bias. We can only tell it as we see it. As
I see it my series is as representative as I can get it of a town in England
whose children tend to leave at 19, but which attracts more than average
numbers of the over 60s at retirement.
 

Doubling times again

Although lymphocyte doubling times of less than 12 months are one of the
accepted indications for treatment I find them to be unreliable because there
are so many exceptions.

1 Do not rely on single measurements. There are any number or reasons for a
single high reading - a rogue result from the laboratory; a recent infection;
use of steroids for some other reason such as asthma, arthritis, rash,
transfusion reaction etc.; vaccination; violent exercise such as running a
marathon.

2 Beware of interlab variation. Machines differ in their ability to read
high white counts. Susan would have more to say on this. With very high white
counts the blood has to be diluted to get an accurate result. Dilution adds
another variable.

3 For some reason white counts increase in spurts and stops. You need to
follow a trend over a period of three months or so if this is the only reason
for treatment.

A doubling lymphocyte count is not the only indication for treatment and
not the most reliable. Better would be a fall in Hb or platelets or the
development of severe symptoms. Generally mild symptoms are difficult to construe.
They could equally well be an intermittent illness or the sort of functional
symptoms that we all get. The patient may or may not be a good judge.

The only indication for a new BMB would be a change in morphology of the
lymphocytes or rapid increase in a group of lymph nodes. However more
information might be obtained by repeating FISH or CD38.

Dr Khalifa has good prognostic factors and all I would add is VH gene
mutations or ZAP-70.
 

1. One of the more maddening aspects of CLL is the erratic
nature of the cell activity. Alterations in white cell counts could
be due to viral infections, low grade inflammation, stress, drug
reactions and literally hundreds more. While individual instruments
may be more or less sensitive, these values are within the standard
ranges for the vast majority of instruments.

2. Doubling time is an important aspect of treatment decisions.
It is reflection of how aggressive the cell activity is. But as you
now the rule is to treat the whole patient not the numbers.

3. Repeated immunophenotyping is not necessary unless the cell
morphology is significantly altered. Repeat bone marrow examinations
should be done on a somewhat regular basis to assess progression. You
would need to discuss the timing with your physician.
 

Unmutated VH genes are predictive of progressive disease, though there is often a period of indolence before the progression occurs. 30% CD38 is right on the borderline of positivity (this may change over time). It sounds as though your lymphocyte doubling time was fast enough to justify treatment. The FISH test shows no evidence of p53 abnormalities so you don't fall into the most malignant group that has a prognosis of 2-3 years.

Physicians should still be using NCI guidelines to tell them when to treat. The new molecular markers (VH genes, ZAP-70 and FISH) are still under evaluation in clinical trials, and they do form a guide to help interpret NCI guidelines, but there is nor evidence yet that using these markers to treat early confers any benefit on the patient. That's why we need to do clinical trials.

FISH can change during the course of the disease, so it may need to be repeated. I am not a great fan of BMBs or CAT scans, except in special circumstance in CLL.

Good prognostic indicators don't mean that CLL will necessarily smoulder. About a half will, but the general rule is for slow progression. Eventually about a quarter of good prognosis cases will need some treatment, but this will often be for non-life threatening reasons, such as unsightly lymph nodes, splenic enlargement, hemolyric anemia, mild thrombocytopenia, mild fatigue etc. Patients very seldom die of CLL if they have your prognoostic features.

What we can say is that the dangers of immunodeficiency caused by chemotherapy - especially drugs like fludarabine and Campath - are greater than the dangers of the disease.

This is why we still suggest W & W for mutated cases even though we don't need to watch so closely as we do for the unmutated cases.

Trisomy 12

The Bournemouth unit has been studying trisomy 12 as long as anybody. There is no doubt that it was originally thought of as indicating a poor prognosis, and some of our early papers suggested this. However, we have gone beyond that now. Compared to del 13q14, it is certainly worse, but patients with del 13q14 do better than average. The most quoted paper is the 2000 NEJM paper by Dohner and his colleagues. In their hands trisomy 12 was neutral. In our 2002 paper in Blood (first author David Oscier) we find exactly the same, and in the same issue of Blood Dohner and his colleagues extend their series and confirm the finding.

Our up to date results suggest that how well you do with trisomy 12 depends entirely on whether your VH genes are mutated or unmutated.

Conflicting results with prognostic markers.

One of the predictable problems with all the prognostic markers available is that some patients will have results which fall in between. Unmuted VH, ZAP-70 neg. CD38 pos, ZAP-70 neg. Del 13q14 and unmutated. How should we regard them?

To a degree, the outcome for patients with mixed markers is an intermediate one. In the study I reported in 2002, patients who had unmutated VH genes and were CD38 negative, and those with mutated VH genes and were CD38 positive had similar outcomes and these were intermediate between those with concordant results. So their average survival was 15 years (opposed to 7 years for those with unmutated VH genes and positive CD38, and 25 years for those with mutat ed VH genes and negative CD38).

Similarly, in the Rassenti et al paper in the NEJM, those who were ZAP-70 negative, unmutated VH genes or ZAP-70 positive, mutated VH genes had treatment free intervals midway between those groups with concordant results. But as we accumulate more results we are beginning to recognise patterns.

So when I saw the following results posted by Linwood:

Normal Hemo, RBC, Hematocrits, Platelets, etc. B2M 2.0, Negative ZAP-70, Negative Cyclin D1, Mutated lgVH, Negative t(11;14), Asymptomatic, Lymph Absolute Count - 38 Bone Marrow - Nodular and Interstitial Patterns - 76% Involvement, Atypical CLL/SLL, FMC-7 Expression, CD38 on 94% of CD19+ cells

I immediately thought that this would be trisomy 12 disease,

The rest of the results were CD5 - 98%, CD19 - 92%, CD23 - 92%, CD20 90% and 3+, FMC7 - 87%, CD52 - 99%, CD79b - 41%, CD11c - 73%, CD22 - 49%, CD19+/CD5+ 92%

and these are fairly characteristic of trisomy 12, although the surface If is not mentioned I would expect it to be rather denser than is usually seen in CLL.

The Chromosomes were Trisomy 12 - 60%, Trisomy 18 and 19, 17p13.1 deletion 14.5%, 13q14.3 deletion 11.5%.

This needs a bit of explaining. Triple trisomies of 12, 18 and 19 are seen in CLL and we have an interesting small collection of cases. So far we have no evidence to suggest that they behave any differently from trisomy 12 cases, but they are a group that needs studying.

How should we look at deletions at the level of 11.5% and 14.5%?

First, they may be artefact. The way that the preparations are made sometimes means that instead of getting two signals with FISH you only find one, even though both chromosomes are really intact. Most laboratories have a quality control system that allows for this and have a threshold for the sensitivity of the test. However, this is usually less than 10%, but labs do vary.

Second, a paper by Danny Catovsky at last year's ASH suggested that del 17p results only indicated a poor prognosis if the level was greater than 20%

So, as with most answers we need more information. Than you all for your willingness to share details about your cases. I have learned so much by reading your postings.

What to do about bad prognostic indicators.?

At present there is no evidence that early treatment of CLL produces a better outcome than delaying treatment until the disease is symptomatic. There is clear evidence from both the French study and a meta-analysis of several studies worldwide that after 10 years follow up, as many people are alive in the delayed treatment group as there are in the early treatment group.

But the treatment for these groups was chlorambucil, and we now have treatments that produce higher response rates, higher complete response rates, higher PCR negative rates, and longer progression free survivals than chlorambucil. However no one has yet shown that these treatment produce higher overall survivals than chlorambucil.

Also the studies that compared early treatment with delayed treatment treated all CLL patients the same without respect to what the prognostic markers said - because there were none of these prognostic markers to consult when the trials were performed.

So the question is, "Would patients with bad prognostic markers do better if treated with one of the newer drug combinations early rather than delaying treatment until symptoms begin?"

And the answer is, "We don't know."

And when we don't know, that is the time to begin trials.

You might think intuitively that it must be better to treat early when there isn't so much disease about. But there are several reasons to hedge that bet. First, the treatment is not in itself harmless. Drugs like Campath and fludarabine cause profound T cell deficiencies, opening the way to serious virus infections such as CMV, EBV (which can lead to Richter's syndrome), adenovirus, human papilloma virus, Herpes Zoster, parvovirus, HHV6 and HHV8. Second, early treatment might select out resistant cells such as those with p53 deletions or mutations, so that when the disease does return it is almost untreatable. Third, there is some evidence that fludarabine is capable of causing myelodysplastic syndrome and acute leukemia, and certainly cyclophosphamide can do this.

Now it might be possible to find a harmless early treatment based on rituximab plus something to make it more effective, but at the moment we are not clear that any such regimens are very effective.

So I am an advocate of randomized controlled trials in this area. There is a current French and German trial for early stage patients with poor prognostic markers who are randomized between early and delayed RFC, but that will not report for some years. I am currently designing a British trial that will look at early RFC followed by Campath.

There is no agreement yet on what constitutes poor prognostic markers. I favour unmutated VH genes with CD38 positivity. Del 11q is difficult because some patients do very well despite this and in our hands and the current MRC trial del 11q patients are much the sam as trisomy 12 patients. Also ZAP-70 by flow is not yet accepted as a satisfactory test except in the hands of a few University labs.

So my final answer is, "There is no correct answer; we need more trials."

Men and Women

There is a clear difference between men and women in CLL. Women have a much better deal. In all published studies women survive longer than men. Partly this is because women are more likely to have the mutated form of the disease. In the unmutated subset here are rougly 2 men for every woman, though some series put the ratio as high as 6:1. In the mutated subset the numbers are rougly equal.

But it doesn't end there. In my series in the unmutated subset women survive on average longer than men. This is not because there is a longer period before they need treatment, but because they survive for longer after their first treatment. In the mutated subset women are more likely than men never to need treatment.

Why there is this difference is unclear. I suspect it is because testosterone may be a growth factor for CD5+ CD19+ B cells, although it inhibits the growth of normal B cells.

28 March 2005

6q deletions are usually secondary abnormalities. Although there may be nothing wrong with 11, 12, 13 or 17, there is usually something wrong with another chromosome (but it isn't looked for with the usual FISH test. 11% of 6q deletions doesn't signify anything in terms of prognosis though.

2 April 2005

CD38 was originally describes as a T cell antigen (T10) and it is present  on activated T cells. So when looking at your CD38 result you must be careful to
 look only at the percentage of CD19 cells that are CD38 positive. As long as they are less than 30% you are in the good prognosis group. Note however
that  the results with CD38 are not so exact as those with VH genes or ZAP-70.