The reason that chlorambucil is more popular in Europe is the cost is so much less. Fludarabine is 16 times more expensive.

What is the evidence that fludarabine is better than chlorambucil?

In all the trials bar one where it has been compared head-to-head with chlorambucil it has produced higher response rates and higher complete response rates. Length of remission has been greater, but overall survival has been not been longer. The problem is that those who have failed chlorambucil have been allowed to have fludarabine after, so the trials have really compared fludarabine with chlorambucil first, then fludarabine. The one trial where chlorambucil was as good as fludarabine came from Croatia. In this study, chlorambucil was given in much higher doses. It may be true that the differences in response with fludarabine compared with chlorambucil is simply a matter of dose. Newer trials involving chlorambucil have used a higher dose than the old ones.

Dr Sue Richards, who is a statistician from Oxford, has added together the results of all the published trials comparing fludarabine and chlorambucil and finds a survival advantage for fludarabine, but there are still 3 trials that haven't been published yet and these contain so large a group of patients that they could even swing the results the other way.

As far as side effects are concerned, chlorambucil is more likely to cause marrow suppression, but fludarabine suppresses the T lymphocytes more. This is likely to mean that there is a greater risk of viral and fungal infections with fludarabine than with chlorambucil.

In Europe Fludarabine is available as a capsule which makes it less trouble to take and cheaper since it doesn't involve any hospital time. I understand that it is unlikely to become available in the USA in this form.

Other side effects of fludarabine include triggering hemolytic anemia, but chlorambucil can do that too. Some people think it does so just as frequently.

The combination of fluda/cyclo is more potent than fluda alone, but also more toxic. There is a greater risk of neutropenia and more hair loss. It is only two thirds the price of fluda alone. FCR produces even more CRs but it is much more expensive. Although CLL cells have much less CD20 on their cell surfaces than other lymphoma cells, and the response rate to Rituxan alone is only 16%, this does not stop the FCR combination being the most potent one that we have.

As far as Marjeta's husband is concerned, having a 13q deletion is usually associated with a good prognosis, as is having nodular and interstitial bone marrow pattern. A high white count alone is not an indication for treatment, but a big spleen and lymph nodes may be. If someone were ZAP-70 negative and CD38 negative, I would think twice about aggressive treatment. It might be worse than the disease. This is a difficult and as yet unsubstantiated question, but one of the things that is troubling CLL doctors is what to do with patients belonging to the mutated subset who have a rising white cell count and big spleens and lymph nodes. This may be the group that has most to gain from an autograft, but there is also a case for avoiding treatment unless the disease becomes intolerable, and then trying to control it with small doses of chlorambucil that cause no side effects.

Sorry, Marjeta, if this is all a little vague, but there are still things we need to do to find out about CLL. On the list I can only speak in generalities because individuals need individual attention that includes taking a full history, examining the patient and doing all the appropriate blood tests.