Notes from ASH

[Guest guest]

Hi Folks,

Cheryl Ann, Suzan and I are here at ASH, working away to find out the latest

in CML research and pass along whatever we can to y'all. Cheryl has created

a new website just for the purpose, www.cmlsociety.org, just for the

purpose, but since not all the bugs have yet been worked out of it (it does

something odd to the formatting), I'm going to post my first report here as

well as there.

My first post is from one of the Friday Corporate Symposium meetings: ³CML:

A Paradigm for translating Sciences to the Bedside² ­ which was sponsored by

Bristol Myers Squib. Five experts spoke at this one: Moshe Talpaz,

Deinninger, Goldman, Neil Shah and s Hochaus. I'll fill you in on

Talpaz' talk first. When we next get back to our laptops, we'll decide who

will report on the others.

A lot of what Talpaz and others told us was not new. This is partly because

there¹s not all that much that¹s new in the CML world (at least compared to

when a number of us came aboard this train a few years ago), and quite a few

people want to tell us about it, so the new stuff gets parsed pretty thinly

among them. Still, there were a few nuggets worth passing along:

€ Talpaz believes that any given patient¹s risk for becoming resistant to IM

will decline over time, rather than remain constant or increase as some

investigators have suggested. The average incidence of resistance in the

first several years for all patients in chronic phase is 4%/year, though

it¹s higher than this for patients in late CP or who do not achieve major

molecular response (MMR ­ a 3 log reduction in their qPCR, that is), and

much lower for patients who show a rapid and highgrade response. Whatever

your risk of resistance/relapse though, it¹s good news that it¹s likely to

decrease over time. Talpaz is a well-known optimist, but it¹s nice to hear

him say this stuff just the same.

€ Since IM was approved in 2001, the rate of CML-related death has been only

3%/year. Interestingly, the annual death rate for CML from all causes is 9%.

This includes deaths from stem cell transplantation. Unfortunately Dr. T

didn¹t specify what those other causes were, nor what percentage is

attributable directly to transplant. He did say that if this were the

1970¹s (before interferon, SCT and IM, that is), more than 50% pts diagnosed

over the same five years period would be dead by now. Here I pause for yet

another moment of gratitude!

€ Dr. T mentioned in passing that PCR is a better indicator of risk at all

levels of remission than is conventional cytogenetics. For example,

patients who reach CCR have quite varying levels of qPCR; those with the

lower values are at much lower risk of progression than those with higher

values. He didn¹t say this, but extrapolating from his talk, I¹d say that

achieving a 3-log reduction in qPCR is a more important milestone than

reaching CCR.

€ Since this was Dr. Talpaz (³Mr. high-dose IM,² right?), he naturally had

to mention the stats on high dose IM. In particular, patients on higher

doses achieve all milestones sooner than do patients on the standard 400mg

dose, and higher percentages of patients reach these milestones. For example

90% of patients on 800mg reach CCR by 18 months, compared to 74% of patients

on 400mg. What he did not mention (but has been pointed out elsewhere at

the conference) is that no one has yet showed any difference in progression

or survival between patients on low and high dose IM. Dr. T suggested that

adverse side effects were a little higher on higher dosesŠ.

€ I liked Dr. T¹s description of resistance to IM, as ³a persistent but not

a huge problem.² 16% of patients in CP (chronic phase) develop resistance.

He mentioned that desatinib is better, but that we¹ll have to wait until

Monday to get the new stats on this. He did say that the new drugs

(desatinib and the AMN drug) don¹t do any better than IM in treating

advanced disease, and that there¹s still much work to be done on this.

€ Can IM cure CML? Probably not in most patients, and maybe in none, because

(for reasons yet to be determined), quiescent CML stem cells are insensitive

to IM. No big news here. However, I found it of great interest that Talpaz

believes that most disease progression results from mutations in committed

cells, not in stem cells. If this is so, then we¹ve greatly improved our

chances of living a long time by killing off all those committed cells, and

that our little residual pool of quiescent cells is no big deal (still, it

would be nice to get rid of them).

€ He talked a little about the use of immunotherapies, especially

interferon, along with IM therapy. He mentioned the experience of patients

who stopped IFN after several years good response, many of whom have not

relapsed, even though they¹re not on any therapy and their qPCR¹s are still

positive for BCR-ABL. This has something to do with IFN activating CTLs

(cytotoxic T-lympocytes) and PR1, though I didn¹t follow all this. The

question is whether IM and IFN can be combined in such a way as to achieve

similar results (an ³operative cure,² he called it) in some patients.

Perhaps by using the two drugs sequentially? He thinks it will only require

low doses of IFN, not high doses like in the bad old days.

€ Dr. T raised but did not resolve the question whether CML begins in normal

cells or in marrow cells that are already deranged in some way, such as in

cells whose chromosomes which are already unstable. That would help explain

why chromosomal abnormalities are found in such a surprising percentage of

Ph- cells (7%) once the phillies are killed off. Could it be that people who

get CML had a DNA repair enzyme defect to begin with?

€ Finally, Talpaz speculates that in the future, CML therapy will be based

on individual molecular profiles. Therapy will range from improved single

agents to various combinations. He predicts that treatment for most

patients will move from maintenance (where we are now) to cure. This may

not change survival much until we get better at treating AP an BP disease,

but it will have a huge economic impact. Plus patients will be happier

because we don¹t want to stay on any drug forever!