In the previous article I mentioned the value of becoming MRD negative. I should stress that the method used to determine MRD negativity is crucial. Not all PCR methods or 4 color flow cytometry methods are reliable. Most people use this method . which is straightforward and reliable, having been tested in many laboratories. Please beware of tests for MRD developed locally in individual labs that have not been subjected to this many-lab scrutiny.
Yesterday, at the UK CLL Forum Clinical Trials Group we took an important step in deciding to design trials around an end-point of achieving minimal residual disease negativity. One of the real problems we have with CLL trials is that they take so long. There are currently about 1000 CLL trials going on on the world and John Byrd recently identified 107 new drugs at various stages of testing. We have already accepted progression-free survival as a surrogate for overall survival in trials, but even this means that a clinical trial takes several years to complete. Now with the German CLL8 trial demonstrating that MRD negativity is a surrogate for overall survival for both FC and FCR, we are able to shorten the time it takes to reject a new drug or drug combination very considerably. With FCR we are talking about 48% of those tested achieving marrow MRD negativity with FCR. Of course, not everybody was tested so we need the greater detail of a peer-reviewed published report rather than the answer to a question at a meeting, but the German CLL8 trial will produce a standard to be bettered by other combinations.
The other combinations might include adding mitoxantrone, substituting Ofatumumab for rituximab or indeed the new fully glycosolated antibody, GA-101. There are quite a few other agents currently being considered.
The advantages of considering MRD negativity as an end-point include the fact that it can be assessed at 3 months after (starting - sorry this is an error) completing treatment and this can be used at interim assessments which will lead to abandonment of ineffective treatment at an early stage; trial results will be reportable within 12 months of completing recruitment rather than after several years; we will be able to answer induction and consolidation questions in the same trial; and trials may well be smaller and therefore less expensive.
Potential disadvantages include failure of a clear bone marrow to reflect the presence of disease elsewhere in the body. This is certainly true in follicular lymphoma, where it is possible to have residual disease in lymph nodes and elsewhere despite having a clear marrow. This is not true for CLL, even when treatment is with Campath which is notoriously unable to clear large lymph nodes despite having spectacular success in the marrow. As far as our experience allows us to say, if there is CLL in lymph nodes it will always be detectable in the peripheral blood by four-color flow.
It is also conceivable that an agent that is active against rapidly dividing cells would both lead to the rapid clearance of such cells but also rapid relapse after treatment is finished - just because the cells were rapidly dividing. At the same time slower growing cells might not be completely eliminated by such a drug yet because they are slowly growing, relapse might be delayed. The German trial suggests that this is not a problem as MRD negativity correlates with overall survival.
This is therefore an encouraging step. It looks as though we might have a chance of testing all the potential drugs an combinations for CLL.