As Charles Sawyers said today, when opening the session on STI ('Signal Transduction Inhibition') at the ASH meeting, there is a "buzz in the air". If I said that there were about the same number of people in attendance as a Notre Dame football game, I would be exaggerating greatly, but you get the idea - a large hall filled to capacity, which as Sawyers said was impressive. I had tentatively arranged to meet Betty Lou Bradshaw (a member of this list) at the meeting, and we had exchanged descriptions: of course it was two needles in a haystack situation, so we will have to try again.

There were six speakers, Sawyers, Druker, Goldman, Talpaz, Owen Witte from UCLA (Professor of Medicine), and Frederick Appelbaum (Director, Clinical Research at Fred Hutchinson in Seattle). Appelbaum set the tone when he said "It is an interesting paradox that chronic myeloid leukemia is probably the best understood human malignancy, but among the hardest to explain to patients concerning appropriate treatment options....The development of STI571 [now Glivec, as you all know] is, without question, one of the most exciting advances in clinical oncology in the last decade...". The latter statement is borne out by today's Wall Street Journal piece which was posted to the list.

It was very clear to me from all the contributions that there is still a lot to be learned about STI, and it would be good to keep that in mind. But given that very important context, my interpretation is that there is an expectation that STI will supplant IFN as the leading non-SCT therapy in the near future. Talpaz seemed resigned to that, although he spoke forcefully for the potential use of low-dose IFN in combination with STI (incidentally, I was surprised to hear him say that there is no evidence of any significant survival advantage from the IFN and Ara-C combination, even though it does reduce the Ph+ percentage).

The remaining active debate therefore revolves around STI v. SCT. SCT is already only suitable for a small proportion of CML patients, and my conclusion is that this proportion is not likely to increase. If the durability of responses to STI continues to be impressive, SCTs may be recommended less often in the future.

It looks as though STI therapy, with its molecular targeting, may become a paradigm (framework) for all cancer therapy!

There was a great deal of other useful information at this session which I hope to be able to digest and report on in coming days. It gives me pleasure to note that quiescent cells were mentioned!

Best wishes to all.

Peter

[I hope some of you saw Dr. Druker and Judy Orem on this evening's CBS national news.]

As Junia Melo (a well-known CML specialist from London, UK) said, this is a very exciting time to be involved in CML. A good measure of that excitement came in the first session. Kantarjian, as chairman of the session, was in the middle of a presentation when he was told that the fire marshall would stop the proceedings unless all the people sitting in the aisles and packed like sardines around the room perimeter left immediately. The rest of the day lived up to this stirring start.

One of the highlights came at the end of the afternoon session, when Kantarjian challenged the SCT (BMT) specialists. He asked the audience of physicians and researchers (perhaps 1,000) how many were transplant specialists. About 100 raised their hands. He then contrasted STI therapy with its minimal toxicity and efficacy with the mortality and morbidity (cataracts, sterility etc.) that could result from a BMT, and asked the 900 or so in the audience who were not transplanters, how many, if they had CML, would opt for the BMT in preference to STI. If anyone raised their hand, I did not see them! This is very revealing of Kantarjian's position and the effect his outline of the choices had on the audience. Talpaz's commented at one point in the proceedings, that he would like to say, parenthetically, "take two STI and call me in the morning". But it would not be right to leave it there, because there is another perspective. As one transplanter on the panel said, he'd like a recount!!

In my judgement, the SCT specialists have an important case to present. There position is that SCT therapies are improving, it is still the only proven way to a real cure, and STI needs a 10 year follow up before we know accurately what it can do. But as Kantarjian said, it doesn't matter what the doctor says, because patients will opt for the safer and non-toxic STI therapy. I empathise with this position, but I think that the concensus of the meeting is that there is still an important role for BMTs, although there are likely to be adjustments in the criteria for recommending them.

I have mentioned over the course of more than a year, 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 develoment, with considerable promise for 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. 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.

It has been an eleven hour day, so I cannot write more. But I can leave you with the information that 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. I left with a cautious, but very posistive, feeling about this aspect of treatment.

As you all know, I am no expert, and it is vital that my comments are understood as a well-intentioned but almost certainly flawed attempt to convey useful information. So beware!

There is much more, and I will comment further when I get a few spare minutes.

Regards to all,

Peter

[I finally found Betty Lou, and also managed to say 'Hi' to Christine.]

Yo-Yo Ma, performing at an ASH charity concert at the Davies Symphony Hall in San Fransisco, told the community of hematologists present (with at least one exception!) that he never felt safer. He said that the audience would have appropriate remedies if anyone delivered an anaemic performance. Introducing the accompanying violinist Lynn Chang, and the pianist Richard Kogan, he told us that Chang had doctors in his family, and that Kogan, who is a psychiatrist, could take care of both he and Chang. The page turner for Kogan was also a physician. Kogan told us that he had taken a hematology course, and it was that which led him to be a psychiatrist.

It was perhaps the fact that these three had been friends at Harvard which led to an unusually moving concert. There were pieces by Brahms, Beethoven, and Shostakovitch. The latter a deeply moving work which began with a trompe l'orielle (an aural illusion), with Yo-Yo Ma playing a pitch considerably higher than the accompanying violin. The piece was written by Shostakovich in 1944 as a tribute to his great friend Sollertinsky who died in a concentration camp. Logan put it nicely when he said, that just as hematologists are advocates for patients, musicians are advocates for composers, such as Shostakovich, who are no longer with us.

The intense beauty of this occasion, and the exciting work that is being done in CML, made this for me a very satisfying ASH meeting. We are seeing, I think, a paradigm change (a new way of looking at things, a new model) in CML therapy. The huge advance from the molecular targeting by Glivec (STI) is leading to a deep reassessment of current CML therapy ("a raging debate", as Druker put it) and a rethinking of the appropriate research direction. We are seeing the usual thing with paradigm shifts, with some older specialists holding to the existing paradigm, and the younger researchers moving to the new one. Kantarjian and Druker are good examples of the shift, as are many of the papers by younger researchers on aspects of Glivec treatment, such as the problem of resistance. When this sort of shift occurs (e.g. from the Newtonian paradigm to the one of Einstein's relativity), it seems to be accompanied by a burst of new research work and dramatic advances in understanding. I am no clairvoyant, but that is what I see in CML.

I mentioned in a previous ASH post, the growing importance of FTIs (farnesyltransferase inhibitors). Today there was a paper on this topic. It is potentially a brilliant development for CML patients. The drug 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 Glivec. 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. As I reported earlier, it should be in Phase II trials next year, and we should collectively find out all we can about this ongoing and very promising development.

On Sunday morning Dr. Druker gave a very nice paper at an NCI 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 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.

On a personal level, I am greatly intrigued by a paper this morning by a Johns Hopkins team, that reported on the value of adding a cell growth factor (GM-CSF) to IFN therapy. I did not hear quiescent cells mentioned, but I am wondering how relevant they might be in this context, and will try and find out more about the connection. But irrespective of whether I am on the right or wrong track, this combination produced extraordinary results. So good that I would like to see further studies confirming this. Response was rapid, at a high rate, and the regimen was well-tolerated (see abstract #2339 at the ASH website). The data are very exciting, and I am beginning to understand the possible mechanism based on the discussion of the paper. The research has only been going for a short time, so we need more supportive data, but be encouraged! There was no mention of whether a similar approach would work with STI (Glivec), but that is something that I want to find out as soon as possible. At the moment, this non-expert can't see why such a combination wouldn't also be effective.

There is much more, and I will try to put together a few more comments after I return to Vancouver and catch up on some sleep.

Goodnight from San Fransisco.

Peter

The expression "drowning in data" was used in one presentation at ASH. That is good news; it means that there is a lot of productive research work, and the potential for even more rapid advances in cancer therapy. (Although it also makes it that much harder for the spectator to make sense of it all!)

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. Laboratory work has shown that cell lines can be produced that are resistant. Talpaz said that such lab events may or may not have clinical relevance. He suggested that patients in the chronic phase are likely to have very durable remissions, and that "hints are solid that resistance does not develop over time." This is of course an assumption, as he admitted. He said that the tiny level of resistance was a surprising finding (it is about 2-3% of patients in the chronic phase). Nevertheless, although there is considerable optimism among some experts on this score, 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 bcr-abl 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 said that, anecdotally, he hadn't seen that happen, perhaps because the STI increase wasn't large enough.

For more advanced stages of CML, inhibiting bcr-abl may not be sufficient, and there may be other cell communication pathways that will need to be targeted. One of these is RAS, which is an oncogene, and a bad guy implicated in many cancers. The very exciting FTI (farnesyltransferase inhibitor), SCH66363, that I have referred to before, targets RAS. It is able to inhibit bcr-abl, and also destroy some of the resistant cell lines. If the early results hold up, it will be very good news indeed. The Phase II trial that should start in the summer of next year will use an oral drug and is designed for CML blast crisis patients. Presumably, if the trial is successful, we may see it being used in conjunction with STI, although that is speculation on my part.

There was a very interesting paper (ASH #2024) by a young researcher, Mercedes Gorre, and others at UCLA, which dealt with the problem of potential resistance. If this paper is correct, it looks as though the main culprit is not likely to be something to do with the biology of the patient, or other genetic mutations, but rather the over-expression of the bcr-abl protein that I referred to above. That would be good news. 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.

Peter

[Keep in mind that I am reaching when I talk about these complex topics, so be sceptical. Anything that is important to the reader should be checked with a hematologist. I may try to comment on growth factors, angiogenesis, and mini-transplants in the next ASH post.]

There were 5,000+ papers presented at ASH and perhaps 16,000+ participants, making this annual meeting of hematologists the largest in the world. One of the topics frequently referred to was that of growth factors (GF), and some of these play very significant roles in CML. In discussing these, I want to reiterate my amateur status and ask that the assertions put forward here be treated with great caution. If I become aware of any errors (and these are likely), I will inform the list.

Growth Factors are "a complex family of...hormones or biological factors that are produced by the body to control growth, division and maturation of blood cells by the bone marrow. They regulate the division and proliferation of cells and influence the growth rate of some cancers." They are produced naturally in the body, and also artificially as drugs. Erythropoetin is a natural hormone (or growth factor) that regulates red cell production, and the drug Procrit (or Epogen) is a synthesised erythropoetin product that stimulates the production of red cells, and may be used in CML therapy if a patient has very low red blood cell counts. Neupogen is a drug which increases the production of the white cells, and may be used in the collection of stem cells for an SCT.

What growth factors do in sending signals to cells is very complex. It seems that in malignancies such as CML, they can have both positive and negative effects. Two growth factors were the focus of several CML papers at ASH. One of these was VEGF (Vascular Endothelial GF) which is a gene responsible for the growth of blood vessels, and the other was GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) which stimulates the production of white cells from the BM (like Neupogen).

There were four papers on VEGF, three of them by MDACC researchers (including Kantarjian), and one jointly by teams from Canada (U. of Alberta) and the US (U. of Penn) [ASH abstracts #1510, 1519, 3196, 3197]. VEGF in CML patients is a positive regulator of angiogenesis (i.e. it creates small blood vessels which nourish the liquid tumour of CML). One of the hot topics in cancer research is the value of antiangiogenesis drugs, which appear to weaken tumours by cutting of this new blood supply. The research indicates that not only is angiogenesis at a high level in CML patients (i.e.there is a lot of VEGF bringing this about), but this high level can impact very negatively on survival. So it looks as though antiangiogenesis therapy for CML patients might have significant benefits. I think that this is something that we can reasonably expect to see in the near future (MDACC is already trialing an antiangiogenesis drug for AML).

There were several papers on GM-CSF and CML, of which the most exciting was #2339 by the Johns Hopkins team. GM-CSF appears to have a role in the generation of a circulating angiogenesis inhibitor, and the activation of dendritic cells which play an important role in fighting tumours (and more complex effects which I don't yet fully understand). GM-CSF + IFN in this CML trial, rapidly produced a high rate of major cytogenetic responses (MCR), and the paper concluded that it "may ultimately improve the long term outcome for patients with CML" [the paper is properly cautious, but the following discussion was more enthusiastic]. I am anxious to find out what if any role this GF would might have in Glivec (STI) therapy.

So it may be that the inhibition of VEGF, and the promotion of GM-CSF, will have very significant benefits in some CML treatments. We can expect to hear more on these two topics in coming months.

Another hot topic at the meeting was Nonmyeloablative Allogeneic Stem Cell Transplantation (NMSCT), which goes under various names, and has different treatment regimens depending on the hospital. While this approach of a less toxic SCT therapy holds considerable promise, it is still experimental and the follow-up data have been short, and additional time and more patients are needed to determine the efficacies and difficulties with this immunotherapy. In particular, "graft-versus-host disease remains a major clinical concern and treatment challenge." My reading is that it is going to be a very useful treatment, but at the moment it is no panacea, and there is still a lot of work to be done.

There is much more information about these and other topics that I am tempted to expand on, but I know how weary you all will be! May the force be with you. And thank you for your patience.

Peter

[There is good evidence that escalating DLIs produce markedly better results than big batch doses in SCT treatments (Hammersmith, London). This might be worth checking with your hematologist, if applicable.]

Source: Peter Rowbotham

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