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.