Saturday, May 22, 2010

Your first reaction to having CLL

What do you do first when confronted with a diagnosis of CLL?

The first thing is don't panic. Three quarters of cases are diagnosed because you had a blood test for something else. When it is first diagnosed you have probably had it for years, so the day of diagnosis is not a special day in the history of your disease. It may be a special day in your life, but your disease isn't interested in that. It is plodding its weary way along a long path and it just so happens that it has been noticed for the first time.

You sometimes hear people say, "I was lucky; the doctors caught it in time." For CLL, there is absolutely no evidence that catching it early makes any difference to the outcome. Almost certainly the first type of management you will be offered is watch and wait and about a quarter of patients will never need treatment.

In the old days doctors never used to tell a patient that they had CLL so as not to frighten them and there was some merit in this. We now call many cases of what was then known as CLL by a different name. They are now called monoclonal B cell lymphocytosis (MBL) which is believed to turn into CLL at the rate of 1% a year. Since the average age of diagnosis is 70, in most patients this is never going to happen. There are still patients walking around with the diagnosis of 'leukemia' attached to them worrying about their future when they shouldn't be.

As an aside I should say that the same is probably true for certain types of cancer as well. Prostate cancer and breast cancer are examples of this - especially when the diagnosis has been made by a screening test.

We need to explore the reasoning behind watch and wait. Some twenty years ago there were a lot of trials involving more than 2000 people who were randomized to treatment at the time of diagnosis or treatment when the disease progressed. There was absolutely no difference in survival. Indeed there was a suggestion at 6 years follow up that those who had treatment did slightly worse.

I need to qualify this reasoning. At the time of the trials, treatment was not very good - nobody got cured however early they were treated. Also at that time we had no way of picking which patients would progress and which would not. So some patients who would never need treatment were treated unnecessarily.

Because of this some people think it is necessary to repeat these trials, only this time confining treatment to those who are just about guaranteed to need treatment eventually and using agents that are much more effective than they were 20 years ago. These trials are taking place in Germany, the USA and the UK, but because the outcome measure is overall survival we will not be getting an answer anytime soon.

So how does a doctor work out who needs treatment? Some patients clearly need treatment pretty soon. These are picked out by either symptoms or clinical stage. Some patients are definitely ill when they are first seen. Those with fever that isn't caused by an infection, or severe fatigue that really stops them doing anything, or weight loss - more than 10% over the past 6 months (that wasn't being aimed at by a diet and exercise program) or such severe sweats at night that they have to change nightclothes or even bedclothes. Such symptoms are usually the result of a large volume of disease - which may not be apparent on clinical examination, because it is located at the back of the tummy behind all the normal tummy organs (so called retroperitoneal disease).

It is also generally agreed that patients with Rai stage 3 or 4 or those with Binet stage C disease need treatment. Kanti Rai from Long Island and Jacque-Louis Binet from Paris are very senior CLL specialists who gave their names to staging systems that are used in America and Europe respectively. Rai stage 3 or 4 and Binet stage C are signs that the bone marrow has started to fail. Rai stage 3 means the hemoglobin (Hb) is less than 11 g/dL and Binet stage C means that the Hb is less than 10 g/dL. I have no idea why the two experts chose different levels as a trigger nor why it is the same for men and women. An Hb of 10 for a man means that he has lost 3.5 g while an Hb of 11 for a woman means she has lost only 0.5 g. Crazy isn’t it?

In my own practice I tend to take an Hb of 10 as a trigger for treatment, though I am quite willing to start if I see a consistent downward trend. Incidentally you will see that I am using Hb as an abbreviation for hemoglobin rather than Hg which many patients tend to use. The reason for this is that Hg has already been taken; it is the chemical symbol for mercury, which we use in medicine when measuring blood pressure. Aim for 120/80 mm of Hg. It is also important to be sure that the low Hb is caused by marrow failure. It would be silly and fruitless to use chemotherapy to treat simple iron deficiency. This is especially important when the anemia is cause by autoimmune hemolysis (which occurs in 15% of patients with CLL). The treatment for autoimmunity in CLL is usually steroids, and only if it can’t be controlled by steroids is it right to treat the CLL.

The trigger level for a low platelet count to start treatment is 100,000 per cu mm for both European and American staging systems. Again, this is a bit arbitrary. Sometimes, the platelet count will hover around 100,000 for months. It doesn’t necessarily mean that treatment starts when it touches 99,000 for a few hours. We are more concerned by the rate of fall. We might start treatment at 120,000 if the fall is very rapid. We have to worry about autoimmunity with platelets also and about a condition called hypersplenism where a large spleen acts as a reservoir for platelets so that they are rather low in the blood. Neither is an indication for treatment, but there is no easy test for either of them. Most times the doctor has to make a judgment call.

Other reasons for beginning treatment relate to the size of the spleen or enlarged lymph nodes. Here again we run into a problem because the staging systems were designed to be operated without using CT scans. You are Rai stage 2 because your spleen can be felt, not because a CT image says it is enlarged. The spleen is an organ whose job it is to get rid of dead and dying blood cells, but it also has important jobs to do in the immune system. It lives under the ribs on the left and as it enlarges it migrates towards your belly button. When you take a big breath you can feel it emerge from beneath the ribs. The pundits have decreed that treatment should begin when the spleen is enlarged 6 cm below the edge of the ribs (that’s 2 and a half inches for those not used to metric measurements). In real life that means that the spleen is about three times its normal size.

The same problem involves lymph nodes. The staging systems are about what you can feel, not what you can see on a CT scan. Doctors are expected to look in the neck, under the armpits and in the groin. Any node or group of nodes that is 10 cm (4 inches) in diameter is an indication for treatment.

What is not an indication for treatment is the height of the white count. For other types of leukemia high white counts are a worry because they can cause sludging in small blood vessels and lead to a stroke or blindness. This does not happen in CLL. Even if your white count is a million, it is not dangerous. However, rapid rises in white count may be an indication of rapid progression of your disease and rapidly progressive disease needs treating. If your white count doubles in six months then treat. If it increases by 50% in two months, then treat. There is a proviso here. It is not the rate of increase that matters but what it represents. It represents rapidly progressing disease. But if the white count goes up because of an infection or a vaccination or because you have had some steroids it doesn’t represent rapidly progressive disease and it isn’t an indication for treatment. Also, if it starts from a low base – less than 30,000 – then there is no correlation with disease progression and it should be ignored. Rapidly progressive disease can also be recognized if the spleen or lymph nodes enlarge over a short period of time, no matter what is happening to the white count.

So to summarize: 1] There is no point in treating CLL just because you have it. In most cases you can’t cure it.
2] If it is causing symptoms it ought to be treated for symptom relief.
3] If it is causing organ failure (usually the bone marrow)it ought to be treated to spare the failing organ.
4] If it is progressing rapidly it ought to be treated because it will kill you if it isn’t.

I will write again on this topic later.

50 comments:

Anonymous said...

Terry: I've had CLL for around ten years. I'm 57 now. My WBC rose into the mid 20K until about 5yrs ago and now hovers between the high teens and low twenties with a lymph % of about 75. All my other counts seem steady and fairly normal with the exception of my platlets which have come down from around 250 to 150 steadily over the ten year period. At first look does this platlet drop seem more like ITP or desease progression to you, given that the other numbers are fairly stable. Thanks if you can respond

John Liston

Terry Hamblin said...

John
This seems very typical of the mutated form of CLL. A slight and slow progression over the years, but not reaching any of the criteria for treatment.

Barry B. said...

Chemotherapy for CLL should be reserved for those about to undergo a stem cell transplant. In this case, I mean old-fashioned chemotherapy such as FCR.

I'm sure you probably know that regimes such as high-dose methlyprednisole with rituximab, EGCG, or (increasingly) revlimid plus rituximab) can give as good as, or better than over-all response rates than FCR, and about the same complete remission rates.

These treatments don't cause Richter's or myelodysplastic syndrome (MDS) as FCR does. Yet they appear to be just as effective.

Chlorambucil, a drug you mention frequently, is a mild chemo drug that I don't think is as harmful as FCR, and, as you suggest, is appropriate in an elderly person who cannot or will not take HDMP+R or R&R.

I think it increasingly the case where chemotherapy is reserved as a last-ditch thing.

Your thoughts?

Terry Hamblin said...

I shall be coming to treatment in my second and subsequent toughts.

Werner Von said...

Dr. Hamblin,

Jump from Rai stage 0 to Rai stage 4?

I was diagnosed with CLL almost 4 years ago. My data since then:
WBC increased from 30,000 to 50,000. Hb is stable at 14.5. Platelet count has decreased from 140,000 to about 110,000. All else is stable and fine. If the platelet trend continues with constant slope, I will reach 100,000 in one to two years. I will then be classified as Rai stage 4.
I have not seen a discussion or read of any case in which a patient has gone from Rai stage 0 straight to stage 4.
Is this occurrence rare? Does it signify a special condition?
Your response will be appreciated.
Werner

Terry Hamblin said...

Werner,
You may have some lymph nodes or an enlarged spleen that are not apparent on clinical examination. This could be ITP. This could be hypersplenism. It just could be that your CLL is mainly in blood and marrow and when your marrow fills up your platelets reduce.

Jane said...

I've found this very reassuring- CLL was been picked up 3 months ago in blood tests I had in conjunction with treatment for Addisons disease, B12 deficiency and sudden unexplained allergic reactions.
I am 41 with small children and have been panicking a bit today after a follow up appointment with a haemotologist.
Jane

Anonymous said...

Terry, I am 35 years old and was told to have MBL 2 years ago. It was CD5-. I have been taking regular blood counts only and the total lymphocytes count have dropped since then. It used to be around 4400 and now 3200. I have observed something that intrigues me: in the early morning, lymphocytes count is 3200 but in the end of the afternoon it reaches around 5000 (I underwent a blood count at that time of the day once). I got scared and took another test in the next morning and again it was 3200.
The thing is: that has affected me psychologicaly. I have trouble even getting into new datings because I think people do not need to face someone who might have a lymphoproliferative disease later on in life.
Do you think I have a worse prognosis because I am younger?
Best wishes!

Terry Hamblin said...

CD5- MBL is probably a benign version of marginal zone lymphoma. It occurs in about 1-2% of the population and is unlikely to every cause you problems.

Anonymous said...

Terry, about this benign form of marginal zone lymphoma...do I have MBL or lymphoma itself? All CTs (head, chest, abdome) were normal. What should I do regarding follow up?

Terry Hamblin said...

No, you have MBL, but if it ever transformed it would transform to marginal zone lymphoma, not CLL. We do not recommend that it is followed up. The cahance of transformation is so small and the disease it would transform into is not an aggressive one anyway.

About 1% of the population has the same as you.

Anonymous said...

Thank you, Terry. Can you tell me of any scientific papers on that issue I could take a look?

Terry Hamblin said...

Here are some links:
http://www.ncbi.nlm.nih.gov/pubmed/20090778
http://asheducationbook.hematologylibrary.org/cgi/content/full/2009/1/430
http://www.ncbi.nlm.nih.gov/pubmed/19347733
http://www.ncbi.nlm.nih.gov/pubmed/19347732
http://bloodjournal.hematologylibrary.org/cgi/content/full/113/18/4188
http://www3.interscience.wiley.com/cgi-bin/fulltext/114106289/PDFSTART
http://www.ncbi.nlm.nih.gov/pubmed/16042682

Anonymous said...

Terry, thank you again. Last one: Do 1% of the population have CD5- MBL? Was it that you meant?
Kind of scary but you have cleared things up a lot.

Terry Hamblin said...

Yes, that is the estimate. The percentage increases with age, but in the vast majority it never amounts to anything.

Burke said...

Dr. Hamblin,

When I was first diagnosed, my cll population was 36% of the cells tested on the BMBx, and there was a second, unidentified B cell population making up an additional 7%. My doc's put me on W & W.

I assume from your comments, you would have recommended treatment immediately.

(I had a very successful FCR treatment 19 mos later.)

Terry Hamblin said...

Burke
I don't follow you. Why would I not have recommended w&w?

Burke said...

I got that impression from this comment of yours:

"3] If it is causing organ failure (usually the bone marrow)it ought to be treated to spare the failing organ."

Terry Hamblin said...

That means if your Hb is less than 10 or your platelet count less than 100,000.

Fritz said...

Terry, I also found this reassuring, great article. Diagnosed 5/2008 with wbc of 40K, Hb of 14, Plt 225. 5/2010 was 116K, HB of 13 Plt 160. So not quite doubling every year. Mutated, 13qdel.
No health issues presently. Seems like I am not one of these to jump up to a level and flatten out (thus far). Am I looking at treatment in 1,2 or 5 years?

Terry Hamblin said...

Fritz, you probably will need treating within the next 5 years, but you should respond well and have a long remission.

Anonymous said...

Terry: I was diagnosed last year with CLL and my total WBC was around 32, it is now 50.7 with 43.74 Lymphocytes, 5.2 neutrophils, 14.6 Hb and 164 platlets. My bloods had been done six weeks ago and the total WBC was 41.7, 4.7 neutrophils, 13.7 Hb and 155 platlets. I feel fine and the small lymph nodes in my neck have actually reduced. Is the upward trend in my Hb, platelets and neutrophils good or potentially bad? Could the rise in my Lymphocytes be down to stress- we had a school inspections at the end of April and the five weeks prior were very demanding?

Bill

Anonymous said...

Correction, my Hb was 14.5 six weeks ago! Sorry!

Bill

Terry Hamblin said...

Bill
These changes are trivial and could be induced by stress of the time of the day or whether you are incubating an infection or some other medicine you were taking or a hundred and one other unknown things. Don't worry

Eileen said...

Hello,
What is your experience re: improvement of anemia and hypoglobulinemia with treatment?
Thanks
Len

Terry Hamblin said...

Hypogammaglobulinemia rarely improves. Anemia usually does, but sometimes does not.

chanakya said...

Hi Terry,
my dad have cll and pletlets count is approx 30000. the wbc count is also very high. will any form of treatment will benifit him ?

Terry Hamblin said...

Almost certainly, though it all depends what is causing the low platelet count.

chanakya said...

after the bone marrow biopsy the doctor has told that bone marrow is involved in CLL. He has told that we can either go for oral medicines or cimo... which one would be better as he doesnot have any other problem.his ct scan shows the lymp nodes of approx 1 to 3 cm but all other organs are not affected. and how long he can live without any problem...and what other option we have. his age is 55.

Thanks a lot for ur advice

Terry Hamblin said...

A platelet count of 30,000 is a reason for treatment. Ideally he should have FISH to ensure that he does not have del 17p. But this is only useful to exclude the 5% who are resistant to standard chemotherapy. IF rituximab is available to you, then FCR is the favored treatment since it causes an increase in overall survival compared to other treatments. In any case it is wise to begin with a course of prednisolone to try and raise the platelet count, since all types of treatment will lower it before it gets better. If rituximab is not available then there is no evidence that it matters what type of treatment he has first.

chanakya said...

sir,
thanks a lot for ur suggessions... it has given us a lot of hope.it will a great help for us if u can help us to detrmine his stage of CLL as we are getting diffrent answers form diffrent doc.Below is the details of the investigations....
Haemoglobin 12.8
RBC 3.36
HAEMATOCARIT 37.3
PLATELETS 30.00
WBC 70.70
NEUTROPHIL% 15.1
LYMPHOCYTE% 73.3
His Bone Marrow ASPIRATION report is as follow
Myeloid Series % is as follow
Promyelocytes 01
MYELOCYTES 11
Metamyelocytes 01
Polymorphs 29
Basophils 00
EOSINOPHILS 03
Monocytes 00
PROMONOCYTES 00
Erthroid Series as follow
Cellularity Adequate
Maturation Mild megaloblastic
Megakaryocytic Serice as follow
Cellularity Adequate
Abnormal Cell / blast Nill
Descriptive Morphology Non Erythroid : ratio 4:1
CD 38 neg
CD10 NEG
CD19 63%
FMC7 NEG
CD22 neg
cd23 42%
KAPPA 39%
CD79B NEG
CD20 36%
cd3 Neg
cd4 neg
cd5 47%
cd8 Neg

Terry Hamblin said...

This is stage 4 because of the low platelet count unless the platelets are low from ITP or a big spleen.

chanakya said...

Hi Sir,
Thanks a lot for your valuble time and suggesions... Is there any way using which we can determine it ITP and not the cll 'coz his slpeen is normal and the lymp nodes are size of only 1 to 3 cm max. His HB is about 13(12.8).

Terry Hamblin said...

ITP is difficult to diagnose in CLL. The anti-platelet antibody tests are unreliable. Bone marrow should so increased megakaryocytes that are not budding platelets, but that is quite difficult to assess when teh marrow is filled with CLL cells. Sometimes the onlyway to be sure is a therapeutic trial of prednisolone 1 mg/kg.

chanakya said...

Hi Sir,
After showing all the reply from you local doc here has started d med which u told @ .5 mg/kg. i have one more question. if it is a ITP how long it will take to improve the plt.

Thanks.

Terry Hamblin said...

I doubt that that is a big enough dose, but if it is you should see a change within a week.

chanakya said...

Hi Sir,
After taking prednisolone for 4 days when we checked the plt count it has gone up from 30 to 136.
Does it mean his CLL is not in 4th Stage ?
Thanks

Terry Hamblin said...

Yes. This is ITP and depending on whether you have lymph nodes or a spleen you could have stage 0, 1 or 2.

Anonymous said...

What does FMC7+(48%) mean in a recent flow cytometry test?
Other indictors were CD5, CD38-, CD23+

Terry Hamblin said...

It usually means that you have trisomy 12.

Larry said...

Thank you for your prompt response.
I am from Canada and the specialist has advised that FISH testing ( I presume that Trisomy 12 is determined via this test) is not available unless treating CLL.

I have no other symptoms other than mild night sweats.
My WBC is 14.4 and ALC 7.7 and B2M 1.72 with all other readings in normal range.Ultra sound showed no abnormalties in the spleen and do not have any enlarged nodes at this point.

Is this Trisomy 12 something that should be dealt with soon?

What are your thoughts?

Terry Hamblin said...

No. Even we would not do it except for a research interest. Be content to watch and wait.

Larry said...

Terry

I took your advice from a previous blog and got an IGHV mutation test done from the Mayo Clinc
The results were as follows
39% of nucleated blood cells have 11q22- and IGHV mutation analysis shows use of the VH4-34 gene segmentation which is unmutated (0%)
total Bcell Count 3.6x10(9)/L
negative for expression CD38
ZAP-70 (0%) and CD49d (16%)
Bilateral inguinal adenopathy 1x1 cm
Bilateral axillary adenopathy 1x1 cm on right hand and 2x1 on the left
Bilateral cervical adenopathy all nodes less than 1
WBC 13.6 ALC 7.4
liver & spleen normal
all other blood counts within normal range

Would you be kind enough to recommend how you would proceed given the statistics. I have a problem in Canada as they do not recognize CLL until ALC counts exceed 10

Terry Hamblin said...

I take it that your cell markers are CD5+, CD19+ and CD23+. Although some might diagnose you as MBL, on the basis of the 2 x 1 enlarged lymph node this would be diagnosed as CLL/SLL and to be the SLL form. Although it is Ann Arbor stage 4 it does not require treatment at present, though in your case I would advocate a CT abdomen and pelvis, since del 11q is associated with enlarged abdominal glands. If these were enlarged then there might be a case for treatment.

larry said...

Thank you

Yes I do have those CD markers

I have had 2 doctors think it is MBL and another doctor at the Mayo has diagnosed it as CLL/SLL

I am scheduled for an ultra sound of the abdomen in a few days would this take the place of a CT scan?

What would be the normal treatment and if there are enlarged abdomal glands is it wise to get treatment sooner rather than later. Next appointment with hematoligist is in Feb

Terry Hamblin said...

It depends on the size of the glands. US would be fine for this, but if you have nodal masses larger than 10cm then treatment is indicated.

Larry said...

Dr Hamblin

I received the results of the ultra sound which showed a normal abdominal utrasonography including normal spleen and no lymphadenopathy.
Given this what would your recommended course of action be and also considering that Canada does not recognize the low WBC of 13.6 and needs a lymphocyte count above 10 ( currently at 6.3) before they will proceed with any further testing or treatment.
Thank you for your consideration.

Terry Hamblin said...

Do you still have the 2x1 axillary gland? This is the critical difference between SLL and MBL. In any case the management would be watch and wait to see what develops.

Larry said...

Thank you again for allowing us to run questions by you, I know you have your own issues to deal with.

The technician performing the ultrasound did not check any lymph nodes outside of the abdominal area.

Since it is watch & wait ( I have a follow up with the hematoligist in late Feb ) it probably does not matter

One last question, is it possbile to have MBL and also be 11q del and have the unmutated gene?

Terry Hamblin said...

Yes, though we do not yet have a prognosis for this group. Just before I retired I diagnosed someone as MBL with exactly those features and I notice that she is now an ACOR subscriber and having treatment.