Tuesday, December 05, 2006

CLL mistakes

How much do general haematologists know about CLL? I have just been consulted about a patient who died of complications of treatment and I identified three mistakes that seem to be quite commonplace.

Mistake 1] Late diagnosis. Nowadays people are having more frequent blood tests. The usual reason is to look for anemia in someone who is 'tired all the time'. Almost always the hemaglobin comes back normal, but modern blood counters give a lot of extra information. What should a hematologist do if the lymphocyte count count comes back greater than 3.5? In our lab we look at a blood film, and unless the extra lymphocytes are large granular cells, we do some simple immunophenotyping. We pick up an extra one or two cases of early CLL every week like this.

Does it matter? Most cases of CLL are fairly indolent and immunophenotyping is relatively expensive. So what if the CLL is not diagnosed until the lymphocyte count reaches 10? In 99% of cases it doesn't matter, but in the remaining one in a hundred there is a p53 deletion and late diagnosis can seriously harm the patient's health. A lot of money to pay for one in a hundred? Sure, but it's a lot of money if you get sued.

Mistake 2] Missing hemolytic anemia. Hemolytic anemia occurs in about 15% of patients with CLL. It can be severe and even fatal. The features are a rapidly falling hemoglobin and a positive direct antiglobulin test (Coombs test). This demonstrates that an autoimmune process is going on and that pretty big doses of steroids are needed. Autoimmune hemolytic anemia in CLL differs from other types in one particular, normally one would expect to find a rush of young red cells coming into the blood to replace those that have been destroyed. These young cells are called reticulocytes. In CLL this may not happen because the bone marrow is so stuffed with leukemia cells that there is no room to make new red cells. This can be a problem because you can get a positive Coombs test in CLL without hemolysis, so if there are no reticulocytes teh diagnosis is difficult to confirm.

If the anemia is very severe, it would be unwise to assume this is not hemolytic anemia. There are other tests that will help confirm the diagnosis. Looking at the blood smear you can see red cells that are spherical instead of flat discs. A protein called haptoglobin disappears from the blood because it is used up clearing released hemoglobin from the circulation, but the test that everybody forgets - probably because it is a urine test, normally done by nurses is a dipstick test for urinary urobilinogen. This is quick and easy, and an increase tells you that red cells are being broken down more rapidly than normal.

Mistake 3] Failure to recognise when CLL is drug resistant. The commonest cause of drug resistance is an abnormality of the p53 pathway. This is most easily detected by a FISH test for chromosome 17p.

p53 is required by most drugs to kill CLL cells, including chlorambucil, fludarabine, pentostatin, cladribine, cyclophosphamide, adriamysin, vincristine, rituximab and low dose steroids. The only drigs that we know work in p53 deficient CLL cells are high dose steroids, Campath and flavaperidol.

But you don't need sophisticated tests to discover the CLL is drug resistant; just give a couple of courses ofchlorambucil or fludarabine. If the patient is not by then in a partial remission the CLL is probably drug resistant.

These are not very difficult concepts to grasp: common sense really. Even if a hematologist is more interested in acute leukemia there is no excuse for not getting this right.

10 comments:

Anonymous said...

The possibility of errors by oncologists or hematologists in diagnosing and/or treating CLL should suggest to the patient the advantages of a consultation with a CLL expert.

Even if not covered by insurance and paying out of pocket, at least one consultation prior to treatment is an excellent idea. A treatment plan may be worked out with the CLL expert, and subsequently carried out by the local doctor.

Even those from outside countries with established CLL centers can fly to a consultation if at all possible. CLL-knowledgeable docs are in the US, England, Germany, Italy and elsewhere.

Anonymous said...

I wish someone would define "CLL expert"...

Terry Hamblin said...

How about this. A doctor who has had the care of more than 500 patients with CLL.

Anonymous said...

Would you exchange private emails with a family member of a CLL/MF patient?

Terry Hamblin said...

I am quite happy to exchange e-mails with anybody.

Anonymous said...

I am a 55 yo male MD recently diagnosed with ALC of 24k. I reviewed my old labs and the only CBC I can find in 2/04 revealed an ALC of 8,800. I never really paid attention to it as I was asymptomatic. I remain asymptomatic and have no peripheral adenopathy. FISH tests reveal 11- and 13-, but no evidence of 17-. Zap-70 is negative. CT scans are to be done next week. Hgb is 14.2, plts are 208k and all other labs are WNL except for low IgG and low IgA, each about 50% of lower limit of normal. Who in the USA would you reccommend for a second opinion re therapy, etc. I am a Gastroenterologist and need to make decisions re continuing to practice, etc. I feel fine at present, but don't want to risk infection working in the hospital if imprudent and don't want to waste precious time if the 11q deletion is as worrisome as I suspect it is. I live on the eastern seabord, but would go anywhere you suggest if one oncologist or center in particular is advisable. Thank you

Anonymous said...

I have been diagnosed with CLL, at present stage 0, and also CFS. I am told that the CLL can be having no effect on me at the moment. I have been unable to work for 12 months. Is it possible that the fatigue is not a separate condition but is caused by the CLL?

I am extremely worried and would appreciate advice. Thank you.

Alison

Anonymous said...

During a stay in hospital for a chest infection I was told by the doctor I was under I had cll....shock...sometime later another Dr came along and said it was agressive...later that day a haemotologist came and took blood for slides, she told me that they could trace the cll back for 11years and that I wasn't to worry too much about it as it wouldn't kill me, my heart or lungs would go first...I was devastated..i am 47yrs old with two boys 10 & 11, the 11yr old is autistic, who is going to look after my boys I worried, cried, couldn't eat or sleep and went home a few days later after gettng a ct scan to break the news to my daughter who was getting married two weeks later...when leaving hospital I was told to come back in two weeks which was not possible so it was arranged for six weeks allowing time for wedding visitors to leave..six weeks of living hell dreading what I was going to be told when I returned. When I did return...shock again as I was told it's not there!!!!!! the haemotoligist I swa was the same one who had come to my hospital bed!!! I ask, do I have , did I have and was told it's not there now...she had no results from the c scan and none of my notes. I have since seen my GP and ask that he find out what is going on and I would like to ske you is it possible for cll to be there and then to disappear..anything at all to help put my mind at rest about this...
kind Regards

Terry Hamblin said...

Sometimes CLL only reveals itself during an infection when there is an outpouring of white cells into the blood. I suspect that you have had enough CLL cells in your bone marrow to makethe diagnosis but that these only come into teh blood when the marrow is put under stress. It is likely that you have had these for a very long time and that your disease is very indolent. Indeed at this stage it can hardly be called a disease at all and may remain in the background for the rest of your life. If it is looked for carefully it is possible to find CLL cells in the blood of about 3% of people over 40. If appropriate tests were done on your bone marrow I suspect that they could still be found.

Terry Hamblin said...

I have only just come across two of these queries so I suppose an answer is pointless, but for the record I will not recommend ant particular CLL specialist in a public way since it would be invidious, but anyone contacting me at terjoha@aol.com will receive appropriate advice for their particular proble.

As for chronic fatigue. It can be caused by CLL but it is often impossible to know whether any particular case is except by treating the CLL and seeing if it gets better. Unfortunately this will mean treating some patients unnecesarily.