Glivec resistance a concern; optimism prevails

Editor’s note: The American Society of Hematology (ASH) 42nd annual meeting and exposition was held Dec. 1-5 at San Francisco’s Moscone Center. Peter Rowbotham attended and reported significant results on Jerry Mayfield’s CML site. Although much of Peter’s reporting deals with chronic myeloid leukemia, the following excerpts may be of more general interest.

By Peter Rowbotham

As Charles Sawyers said when opening the session on STI at the ASH meeting, there is a "buzz in the air". Frederick Appelbaum (director of clinical research at Fred Hutchinson Cancter Center in Seattle, Wash) set the tone when he said "… The development of STI571 is, without question, one of the most exciting advances in clinical oncology in the last decade ..."

… In my reports over the course of more than a year, I have mentioned the interesting development of farnesyltransferase inhibitors (FTIs – after STI it should be easy to remember!). It now looks as though these are getting to a very significant stage of development, with considerable promise for chronic myeloid leukemia (CML) therapy. Schering Plough has an FTI drug, SCH66336 which has had very promising early results and should be in a Phase II trial by early summer next year. … SCH66336 is a remarkable inhibitor of leukemia in the murine (mice) model, and also of bcr-abl in human cell lines.

The graphs that I saw, looked as though they were showing results similar to those of STI571. But even if that is not so, this FTI inhibitor knocks out cell lines that are resistant to Glivec. It is a truly exciting development, and apparently this FTI is not toxic. We should enjoy this advance, while knowing at the same time that not every such advance works its way through to fruition.

It was exciting to hear that this agent seems to overcome resistance to STI. More work needs to be done, but it is an important potential addition to current CML therapies. If it works out as expected, it could perhaps be used with STI in a future trial.

On Sunday morning, Dec. 3, Dr. Brian Druker of Oregon Health Sciences University, the developer and primary investigator of Glivec, gave a very nice paper at a National Cancer Institute special session, in which he talked about some of the challenges with Glivec, including the mechanism of relapse (presumably in the context of the blast phase trial of CML in particular), and the issue of optimizing therapy for patients on an individual basis. He spoke quietly but effectively, in what I thought was a visionary way, about the broader potential of molecular pathogenetic targeting of the sort achieved by Glivec, and conveyed his hope that Glivec would be the first of many examples of molecular targeted therapy.

… The rapidly growing and very positive data on STI (Glivec) has been extensively reported in newspapers throughout the USA and the UK., and much of that information has been made available on this list. It would be redundant to repeat it, but it is worth noting that each new batch of information about STI seems to be more positive than the last.

One of the few concerns at this stage, is the potential for the development of resistance to STI. … I personally think that it would be very prudent to keep a watchful eye on what can be done if resistance does develop. The commonest form of resistance in the research work seems to be an over-expression of the bcr-abl gene, which I think means something like the bcrabl protein (nearly everything seems to be proteins in biology) has become (through an evolutionary and selective process) bigger and stronger, so that normal doses of STI don't work any more.

But, as I understand the evidence, if a patient was to go off STI for, say, four months, the over-expressed protein would disappear. STI then works again, and obviously that would have treatment (clinical) implications. It might also be possible to increase the STI dose sufficiently to overcome this stronger protein, although Sawyers it was said that, anecdotally, that he hadn't seen that happen, perhaps because the STI increase wasn't large enough.

There is a great deal more to be learnt about this whole question of resistance, but as far as I can see the present threat is relatively small, and largely manageable, and likely to be increasingly so as the research data increases. So for the moment, it is perhaps a matter of watching but not worrying.

While resistance to STI is always a possibility, the thrust of many of the comments was to the effect that this may not be an overly significant threat, and that there are ways to deal with some forms of potential resistance, and much research on other ways to overcome it.