The LRF CLL4 trial: long-term outcomes

Prof Daniel Catovsky - The Institute of Cancer Research, London, UK

Could you tell me a bit about your research and the findings you presented here at the conference?

Yes, the presentation here was, in a way, in the session of old drugs because this study, the difference with new drugs, is that it was a clinical trial which started in randomising patients in 1999 and it lasted five years. Now we’ve celebrated ten years since the last patient was entered, we collected long-term information to see what happened to those patients who entered into the trial and particularly those surviving ten years or more. The trial was one of the largest at the time in chronic lymphocytic leukaemia, which is the subject of this meeting. We randomised 777 patients and they were randomised into chlorambucil, which is an old drug, fludarabine was relatively newer, and the other drug was fludarabine plus cyclophosphamide. This combination of chemotherapy that we call FC formed the basis a few years later for the FCR which is now the current best standard for treatment of CLL at the moment before we acquire or we accept the new generation of drugs which are now available.

So one of the different things in this trial was that very often all the trials in many of the cancer diseases focussed on the early [?? 2:03] drug or combinations successful but then you don’t hear any more what happened because CLL is a disease where people live a relatively long time. It was interesting to see what happened, what we called the journey of the patient, because what we realised after looking in great detail about all the patients who entered, that after having what we call the first line treatment a very large number of patients, maybe 60% or 70%, at some point received, when they relapsed or when they are not responding well, received alternative treatments. Then, in fact, some of them received even three treatments. So we analysed the factors on the patients who have been alive and well ten years plus. They are about 25% of the initial lot of patients were alive and well more than ten years.

The main conclusion in this analysis is that there were two main factors which helped for these patients to live longer. One was related to the type of disease because, as we know mainly from this meeting and others, that CLL is very heterogeneous and depending on genetic abnormalities and other features some of these are favourable to make patients live longer. However, the second factor, very important, was the type of treatment they had, mostly as second line or third line. So, in fact, many patients at second line received what is now more the current standard like FCR or incorporating the new monoclonal antibodies. This group of patients who have second and third line and achieved what we call a complete remission, that is eradication or at least elimination of most of the disease from the bone marrow and from the physical signs, these patients did very well. Age was a factor in the sense that they were younger than 70 years; in fact this trial, different from some of the other trials, included patients from about 50 to over 70. So obviously we know in CLL age is an important factor. The other factor from the point of view of the biology of the disease is those patients who had what we call mutated immunoglobulin status but without having any of the bad cytogenetic abnormalities - they didn’t have a 17p deletion or mutations of the p53. The other factor which was favourable to patients is those who have slightly better status at the staging. They are what we call A, stage A progressive, as opposed to stage B and C which they didn’t in the long term do so well. Patients who achieved a complete remission at any stage of their trial, either at the first drugs or those who received subsequently those who were included, and those who lived longer than those who required many treatments but never achieved a complete remission. So one of the conclusions we draw is that having a complete remission at any stage during the treatment, if you fail the first treatment you have a chance with a second treatment. Or if you fail with a second with a third, provided at the one point it achieves what we call clinical haematological remission in CLL. So those who have combinations of treatment, as I mentioned, FCR or including some with antibodies like rituximab, did better. Also there was a small group of about 24 patients who were not doing very well but subsequently received a stem cell transplant and those patients also did extremely well. But those, the median age of those patients was younger, they were about 54 years of age. So that was a significant factor.

The other important thing about this trial is that in a way we set up a mark for the new studies to follow. So there is now a comparator of studies who have patients and we’re still collecting data, but who have at least ten years of evolution, and then compared with the new treatment see if they can match. Because we know there are new treatments and they are very successful at the moment but the question is whether they will allow the patient to live longer and with better quality of life.