More from ASH - Deininger's talk

[Guest guest]

Hi again, friends. Cheryl-Anne and Suzan left this afternoon, so I’m your

only remaining ASH denizen. It was great getting to spend time with them.

I’ve known Cheryl for a while now, both via the various listservs, but also in

New York because for a while we shared the same doc at Sloan Kettering. I’ve

known about the famous Suzan McNamara for years of course (for newbies on the

list, to her goes much credit for getting Novartis to develop Gleevec; get her

to tell you about it sometime!), but had not met her. What a delight she is.

Now I miss both my ASH buddies, but will shoulder bravely on by myself –

though tomorrow morning anyway, when it ends and we all head home.

Ok, where am I? I reported Talpaz’ Friday presentation a couple of days ago,

nothing yesterday because we were too busy absorbing, then reviewed one of

today’s talks this morning. For now, I’ll go back to the Friday symposium

and try to cover a couple more speakers. But since I’ve since filled in a few

of the gaps left by Friday’s speakers (or maybe by my poor understanding of

what they were saying), I will unabashedly cut and paste where I see fit, in

order to lend coherence to the narrative.

Deininger was the second speaker on Friday evening, and his subject was

mechanisms of IM resistance – a subject much covered in the course of ASH this

year. Not because resistance is becoming a worse problem – the reverse is

true, happily – but because quite a bit more has been learned about this

subject recently. Also because things are progressing at a walking pace only

on the treatment front, and these folks have to talk about SOMETHING, after all!

Deininger was a new name to me, btw. He’s a colleague of Druker’s at

OHSU, and quite an up-and-comer, apparently. Here’s a bit of what he said:

• We don’t yet know whether we can stop clock of CML progression with IM,

or just delay it (note from me: the pendulum of belief is clearly swinging

toward believing that we can stop it. A couple of years ago most speakers

averred that progression is just a matter of time; this year it seemed that most

believe that, as one hematologist speaker said, “we’ll die before our

patients do!†It wasn’t clear which camp Deininger is in).

• We’re getting better at predicting relapse. One way is by following the

phosphorylation of CRKL (pronounced “crackleâ€) – one of the enzymes that

bcr-abl works on downstream by putting a phosphate group onto it. When

phospo-CRKLstarts going up, you know that bcr-abl is no longer being inhibited.

I’m not sure what clinical utility this has (I don’t know of any docs

measuring phospho-CRKL on their patients), but it was interesting…

• Deininger mentioned a lot of potential mechanisms, but he did it so fast I

couldn’t type them all. They include: amplification of the bcr-abl protein,

duplication of gene, mutations in bcr-abl’s kinase domain, constitutive

activation of alternative tyrosine kinases, such as the SRC-family kinases (much

was made of these in the various talks, because dasatinib targets them along

with BCR/ABL), such as Lyn. There’s a lot still to learn about resistance,

such as how much of it is due to loss of uptake of IM into cells, or increase of

efflux out of cells. Altered plasma binding of IM may also play a role, though

this has not yet been confirmed in humans.

• There are some 30 to 50 (depending on how you count them, and who you ask)

known mutations in the bcr/abl kinase domain. They vary a lot in frequency.

Fortunately, some of the most frequently encountered mutations don’t seem to

have much clinical significance. While several of them cause some resistance to

IM, most can be overcome by either increasing the IM dose, or by switching from

IM to desatinib or AMN107. Unfortunately, one relatively common mutation,

called T315I (how annoying these names can be!), is a real baddie: it not only

confers resistance to IM, desatinib and AMN107, but it heralds advancing

disease.

• Some KD (kinase domain) mutations merely confer resistance; others also

seem to change the biology of the disease. T315I is one such.

• Novartis believes that a critical factor in IM resistance is poor adherence

by patients. According to them, some 30% of the medication prescribed is not

actually taken.

Gosh, it seems to me that Deininger said a lot more than this, but I don’t

have it in my notes. Maybe Cheryl or Suzan can fill in. If I have time, I’ll

also report on some of the “poster sessions†of which Deininger was a part.

R