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Editor's Note: Peter Rowbotham attended the 2001 meeting of the American Society of Hematology, held from Dec. 7-11 in Orlando, Florida, U.S.A. Rowbotham, whose wife has CML, has long dedicated himself to researching new treatment advances and passing that information along to others. Here, his series is presented verbatim.
By Peter Rowbotham
[Note from Peter: This report, and any following reports, are based on written notes which may be inaccurate or incomplete. Patients should check with medical professionals as necessary.]
Orlando Part 1 was an optimistic report, energised by Kantarjian's assessment of Gleevec's future. But after this acceleration, Orlando (IV) gently applied some much-needed braking with a reminder about the potential problem of resistance. In this report, it is time for some more, cautious, acceleration.
The Tuesday morning session was on "Clinical Results with STI571." There were 8 papers. Kantarjian started with an update of the Phase II study of chronic phase (CP) patients who had failed IFN (abstract #3508 - see www.hematology.org). This was a study involving 40 institutions in 40 countries and there were 532 patients. After 15 months, 41% of patients had CCRs (complete cytogenetic responses), and a further 19% had MCRs (major responses), for a total of 60%. The response rates continue to improve, although more slowly. He anticipates that the results will be even better with newly diagnosed patients. These figures are quite extraordinary considering the difficult situation that many of these patients were in, some 16% of whom had additional chromosomal abnormalities!
At 18 months the survival of these IFN refractory patients was 95%. Kantarjian anticipated it would have been 15-25% if the patients had remained on IFN. It appears that STI571 is better than IFN on most, if not all, measures. The only oustanding issues that come to mind are the durability of these STI571 responses and the possibility of long-term side-effects. But there is nothing that I heard that suggests that both of these won't be as good or better than they are with IFN therapy. It will take time and more data, of course, to be certain.
Age is not a prognostic factor as it is with SCTs. Early therapy improves results, and the use of combinations such as IFN may also help.
Talpaz, who like Kantarjian is from MDACC, is usually a dominant figure at CML sessions, but I hadn't seen him until this last session, so it was a pleasure to find him giving a presentation on a Phase II update (#3509) of the accelerated phase patients (roughly 15-30% blasts, with many really close to blast crisis). A 600mg dose produced a significantly better outcome for accelerated patients, and this should be noted. The 12-month survival rate was 75%, and an additional 12-month follow-up shows sustained remissions. Complete responses, according to Talpaz, were highly durable. Considering the advanced nature of the disease in these patients, the results are very encouraging indeed.
It is clear that the more advanced the CML at the time that STI571 therapy is started, the less good the results are, so one would expect the Phase II Blast Crisis responses to be less pleasing. Sawyers (UCLA) updated the myeloid blast crisis (basically 30% or more blasts) Phase II multi-centre trial results (#3501). The initial responses are good, but they are not sustained. Again, for the best responses, the higher dose of 600mg is clearly needed. Overall survival time is better than it has been historically, but single agent therapy is simply not the answer. The median survival time (i.e. half the patients more, and half less) was 8 months on the 600mg (?). The side-effect profile was similar to that in CP and AC. About 20% of these patients were surviving at 18 months. Unfortunately, cytogenetic responses in this group of patients doesn't seem to have a strong advantage. Sawyers was asked what he would combine the STI571 with, and his response was that he had "no idea." This is really a very significant gap in the treatment of CML, and mirrors the difficulty that many patients with advanced disease have in deciding, with their doctors, what the best treatment is. There is lots of important work being done on this problem, and I see no reason not to look optimistically to the future.
Druker updated the Phase I study of STI and Ara-C, and concluded that it was worth looking further at this combination. But my own poor assessment was that the results were disappointing, and there is no improvement over STI571 alone. In vitro (literally 'in glass' i.e. test tube) results of the combination promised a synergy between these agents, so one has some reason to doubt the applicability of some in vitro results to in vivo (i.e. in patient) studies. I see no obvious reason to opt for this combination at the moment.
Steve O'Brien from Newcastle reported on the multi-centre Phase I and II PISCES trial of PEG Intron (pegylated IFN) and STI. This combination does seem promising. The best dosing of the two drugs hasn't been sorted out, but these agents seem to be effective together, and I think that there will be a Phase III study. Talpaz raised a very important issue, the trade-off with this combination versus a higher dose of STI. In other words, STI can't be given at the valuable higher dose with PEG Intron because of myelosuppression. Kantarjian, who I listen too carefully, thought that O'Brien was on the right track. The answer may be to give STI at a dose of 400mg and a tiny dose of IFN. This seems to make good sense.
O'Dwyer, from OHSU, gave a related paper on STI plus low dose IFN for CP patients. One rationale for the combination is the worry about resistance to a single agent. There is also evidence that IFN provides a survival advantage. The results were encouraging, but the number of patients was too small to determine efficacy. But of all the combinations, the STI + IFN one is shaping up as a real possibility for increasing the number of patients with major responses in the CP (chronic phase).
Such a lot of material came out of this meeting that I can not report on it all, but I hope that some of the lessons will enable me to post more helpfully in the future.
I have written far too much already, but I do want to comment in one final report about the presidential session, and particularly Wang's talk which referred to Leptomycin B.
Peter
[I have tried to be accurate in the reports, but it is not unlikely that there are errors and misinterpretations, so caution is advisable.]
Source: Peter Rowbotham, reprinted with permission
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