15th International Workshop on Chronic Lymphocytic Leukaemia (iwCLL 2013)

Clinical highlights in CLL

Prof Clemens Wendtner - Klinikum Schwabing, Munich, Germany

What latest developments have been showcased at iwCLL 2013?

At this conference we have seen long-term updates of clinical trials using also classic cytotoxic drugs in combination with antibodies. We have seen data from the MD Anderson Cancer Center, from our study group, the German CLL study group, using a triple combination based on fludarabine, cyclophosphamide and rituximab being used in quite fit CLL patients. So this long-term update documented very appealing survival curves. We would almost dare to define this as a cure .This is true for a specific subgroup of patients, patients with a so-called mutated IgVH status, so accounting roughly for 50% of all CLL patients. We can say that this kind of patients are doing very fine with this classic chemo-immunotherapy and I think this is one of the main messages of this meeting. So although we have now a bunch of very interesting new drugs, sexy new drugs on the market, we should not discount gold standards too early. This will be the task for the future.

What are the most interesting recent developments in the area of CLL?

So far we have identified, I would say, two or three very interesting targets. So one is the B-cell receptor; you can interfere with the B-cell receptor signalling by using a drug, so we do have two targets, one is the BTK, the Bruton’s tyrosine kinase, and the other target is the PI3 kinase delta especially, a sub-unit that you can hit. For both targets we do have not only one but several drugs; different companies are developing them. Within clinical trials we have seen at least very high response rates also in these very miserable subgroups like the 17p cases. Survival curves are still very young, I would call it, so not more than two years follow-up. So it’s early signs.

The other major target is the apoptotic pathway. There are new drugs being developed trying to activate pro-apoptotic molecules and we call them BH3 mimetics. One of the most prominent representatives of this group is the ABT-199, so it’s a different mechanism compared to the B-cell receptor inhibitors. John Seymour from Australia has shown fantastic data also using this kind of drug but, again, early data.  We also have seen some slight warning signals already so these drugs are so far a miracle but we already see some resistance. Therefore we have to be cautious not to discard too early our standards.

What are future trials in your group looking to focus on?

As you know, we are very traditional so we try to build up on trial results. Right now we built up the third generation of our trials using results from the second generation. The second point that I would like to make, that we tried to dissect our patient groups based on fitness. So all of us know that CLL is a disease of the elderly ones so we really tried to include also elderly patients in our trials. So our second generation trial portfolio has defined that chlorambucil is still a good backbone, a chemo backbone, but nowadays you should use it together with an anti-CD20, so either rituximab or maybe after approval with GA101, the new anti-CD20.

So going from this standard in the elderly ones we will try now in the third generation of our trial portfolio to omit the chemo component, so just using an anti-CD20 plus one of these new drugs I mentioned, either the BTK inhibitor or a BH3 mimetic. This is for the elderly ones, for the fitter ones we call them go-go. Again, we have a second generation trial comparing FCR, the triple combination fludara-cyclo-rituximab, versus benda-rituximab. We do not know the winner so far, this we will know at the end of the year. The winner will be taken in the next generation, the third generation, trial portfolio. This will then be combined with a BTK inhibitor in a randomised fashion against placebo.

What advice would you give to practicing clinicians managing patients with CLL based on current knowledge?

First they should stick to the standard. So go-go patients should receive FCR until the new data really mature and elderly patients should receive chlorambucil plus anti-CD20. The new drugs will be available, at least the BTK inhibitor we assume will be licensed next year. This then is a good option, this is my personal point of view, for the elderly patient, maybe not sending too much chemotherapy, tolerating too much chemotherapy. For the fitter go-go patients I think we have to wait more than one or two years until the new trials will come. So the take home message would be please include your patients as much as possible into clinical trials so that we can build up on future standards in a very evidence based way.