Richter's syndrome

It was said to be unrelated to his CLL. The appearance of an aggressive lymphoma in a patient with CLL is known as Richter's syndrome. Historically it has been said to occur in 2-3% of patients. But at ASH this year the figure of 8% was being quoted.

We always used to think that it involved the transformation of the CLL cells into a more aggressive clone, but it has become clear that at least half the lymphomas are clonally unrelated to the CLL. They arise in a cell that is part of the normal immune repertoire.

So why is it apparently getting commoner. The increase seems to be coming in patients who have been treated with drugs that suppress immunity, particularly fludarabine, Campath and total body irradiation for an autologous transplant. One theory is that the body normally operates a sort of immune surveillance against the emergence of malignant clones, and this is abolished by the treatment. Another theory is that the CLL cells themselves operate a sort of feedback control over the emergence of new clones. Clones with p53 deletions are always there, but they are kept down by the presence of all the other CLL cells. When these are almost eliminated by FCR for example, the p53 deleted cells are the only ones left and are given free rein to repopulate the marrow. Still another theory implicates Herpes viruses. We know that some of these lymphomas are caused by infections with EB viruses, but because all the T lymphocytes have been removed by fludarabine or Campath, there is nothing to hold the virally infected cells in check.

I know there has been great enthusiasm for FCR and even more intense regimes in the CLL community. But these regimes produce high response rates and in some cases prolonged remissions. They do not cure people and they have not yet been shown to make people live longer than other treatments. They still need to be evaluated in randomised controlled trials. There are bound to be downsides to such powerful treatment. We are certainly aware of severe infections with unusual bacteria, funguses and viruses. It seems that lymphomas like Bill's might be another.

I don't want to bring a distressing message at Christmas, but we have to proceed with care when new treatments come along. There is a classical pattern of over-enthusiasm, followed by deep despair with fluctuations about the mean until treatments find their proper place.

Treatment for Richter's Syndrome

There is no correct treatment for Richter's Syndrome.

Unfortunately, Richter's Syndrome is becoming more common and it is very difficult to treat. We know two things about this modern epidemic: one is the likelihood that p53 mutations or deletions have occurred and the other is that the EB virus may well be involved.

Usually Richter's Syndrome manifests as a Diffuse Large B-Cell Lymphoma, but it can appear as Hodgkin's Diseae or even a T-cell Lymphoma. There are standard treatments for these diseases such as CHOP-R for DLBCL and ABVD for Hodgkins disease, but most people's experience is that these regimens are insufficient.

Several approaches have been suggested, among them HyperCVAD-R and CHOP-R-Campath. This is where a series of Phase II trials is entirely appropriate.

30 March 2005