FCR

The only basis for saying that fludarabine + X is better than fludarabine alone is the response rates in phase II trials. Higher response rates do not necessarily mean longer survivals. It may be that patients with CLL would survive longer with F then FC at relapse then FCR at a subsequent relapse, then FR + Campath at the next relapse than having FCR up front. It is also impossible to compare two phase II trials eve if they were conducted at the same institution, because entry criteria may have changed, there may be an unconcious bias to treating patients earlier in their disease, supportive care will have improved over time, there may have been by chance more patients with p53 mutations in one trial than another etc. The only valid comparisons are in randomized controlled trials, and although these are being conducted none has yet reached sufficient maturity to make a decision.

F + X is usually more toxic than F alone and, often, more expensive. In many cases the combination has not been licensed for use except in clinical trials.

If patients are reluctant to take part in clinical trials then we will never know which treatment is better. If we never find out the combinations will never be licensed. I understand that one pharmaceutical company ha already been summoned to appear before the FDA because of the unlicensed use of its product.

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.

It seems to have got around that I am against FCR and somehow at odds with Dr Keating. This is not true. I have some reservations about FCR (or RFC, it's the same thing) but they mainly concern who should be having it and who should not.

Dr Michael Keating is an honored pioneer of CLL research. He is a charming and amusing companion. I count him as a valued friend, and he has done more than anybody else to introduce new treatments for CLL. Almost single handed he has changed CLL from being a boring disease that nobody was interested in to one that is in the forefront of leukemia research.

He also has more experience than anybody else of FCR. And I have to say that the patients that I have treated personally with FCR as first line treatment have taken the treatment very well without major side effects and those who entered MRD negativity have not relapsed clinically yet, though my longest survivor is only 42 months out.

So we don't disagree on our experience of FCR, although his experience is vastly greater than mine. Where we disagree is in the rather arcane area of interpretation.

Dr Keating and I have already debated before an audience of International Haem/Onc specialists in Prague the question as to whether we can cure CLL with this approach. He thinks we can and I rather doubt it. The problem is nobody knows for sure because we haven't waited long enough to find out. The longest MRD negative patients after FCR are about 6 years out at the most, and there are not many of these. What I have learned about CLL tells me that you can't rely on early results. I have recently seen a trial in CLL where treatment A produced 29% complete remissions and treatment B 63% complete remissions. But at 5 years overall survival was 57% for treatment A and 45% for treatment B. Even those results were not statistically different. Such a result would be unbelievable in acute leukemia, but CLL is a different disease. We have to take the long view.

Although my personal experience of FCR is small compared to Dr Keating's I have been monitoring the results of trials of FCR taking place internationally and I do know CLL very well indeed. I know it can grow at a very slow rate and it may take many years to relapse after an effective treatment. We know, for instance that after bone marrow autograft - which involves very intensive treatment - many patients become PCR negative. But in the German study that followed patients who had achieved PCR negativity all the unmutated cases and some of the mutated cases had become PCR positive again by 4 years. Now I am willing to concede that FCR might be more effective treatment than an autograft for CLL. I hope I am wrong but I see no reason to believe that the eventual outcome will be very different. It may take more than 4 years, but it seems to me that eventual relapse is almost inevitable. Once the FCR has been given no further treatment is being used to eliminate whatever cells remain. This is unlike an allograft where an ongoing graft versus leukemia effect can be expected. I know that the argument is that when the leukemic population is reduced to a certain size then host factors kick in to eliminate the undetectable disease remaining. That is behind the strategy for acute leukemia and it probably works in that disease. However, in CLL host immunity is impaired, and after fludarabine it is even more impaired.

PCR negativity simply means that the number of leukemic cells is below the level of detection. It does not mean that there are no leukemic cells left. And it is possible that the cells that grow back will be the ones that were resistant to FCR in the first place. Notice what Dr Keating did and didn't say. He didn't say that of the 75 PCR negative cases only 2 have become PCR positive again he said that only 2 have had a clinical relapse.

This is why many CLL specialists think that something further is needed after PCR negativity is achieved - perhaps a course of Campath.

The problem with this sort of approach is the risk of collateral damage to the immune system. Both fludarabine and Campath are extremely toxic to T cells. A paper published this month in Leukemia Research from the Royal Marsden Hospital reports that of 100 patients treated there with fludarabine 12% developed Richter's syndrome; this is about 4 times the rate that we used to see before fludarabine. Perhaps this is a statistical quirk and perhaps this was a selected group of poor risk patients, but there is a general feeling that Richter's syndrome is getting commoner. It may be that the benefits we are going to see with FCR plus or minus Campath are worth the collateral damage, but I am keen to know all the facts before jumping in with this sort of treatment for everybody. I have a large cohort of patients who have lived their full natural lifespan without ever needing treatment and some who only needed a little chlorambucil now and then to control symptoms. That is why I emphasize the need for prognostic markers like VH genes, ZAP-70, CD38 and FISH to discover what sort of disease we are dealing with before embarking on treatment.

I am planning to a study of FCR followed by Campath for patients with poor risk prognostic factors treated before they develop symptoms. But this would be a very small study of carefully monitored patients, followed for a long time to check how secure the PCR negativity was.

In that debate in Prague, Dr Keating was the victor. 20% of the audience converted to his point of view and deserted mine. But that still left 60% with me.

So if you have been treated with FCR and are PCR negative, does that mean you are cured? The true answer is nobody knows. I hope so, but the information is not in yet. I am not going to assume it is so and I am still looking for better treatment, tailored to the individual.