Bcr-Abl sensitivity to IM at diagnosis

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Hello friends,

I'm back from a trip to France with my family, which was lovely despite

broiling hot weather and a newly expanded waistline that reflects all the

great French food I consumed! I'm just beginning to catch up on CML posts -

and probably won't get to all of them.

The following abstract from Blood is really interesting. These researchers

from Down Under studied the in vitro (in the test tube, that is, not in the

patient) sensitivity to Gleevec of Bcr-Abl taken from cells from newly

diagnosed CML patients. They found that the dose of IM required to cut the

Bcr-Abl enzyme's activity in half (IC = " inhibitory concentration; " the

IC50imatinib is the concentration of IM at which 50% of the Bcr-Abl activity

was suppressed) was strongly correlated with time to a 2 log reduction in

qPCR at 2 months, and to 3 log reduction at 12 months.

This result isn't really surprising, but it's nice to see it confirmed.

Also, once other CML drugs are approved, in vitro IC50 testing may be a

useful way of deciding who should be on what drug.

Best wishes to all,

R

______________________

In-vitro sensitivity to imatinib-induced inhibition of ABL kinase activity

is predictive of molecular response in de-novo CML patients

Deborah White*, Verity Saunders, A B Lyons, Branford, Grigg, L

B To, and

Division of Haematology, IMVS and Hanson Institute, Adelaide, Australia;

University of Adelaide, Adelaide, Australia

Division of Haematology, IMVS and Hanson Institute, Adelaide, Australia

Division of Molecular Pathology, IMVS, Adelaide, Australia

Royal Melbourne Hospital, Melbourne, Australia

* Corresponding author; email: deb.white@....

Most de-novo CML patients achieve good responses to imatinib, but the rate

and degree of molecular response is variable. We assessed the IC50imatinib

in 62 de-novo chronic phase CML patients as a predictor of molecular

response. IC50imatinib was determined in pre therapy blood samples by

measuring the in-vitro imatinib-induced reduction of the phosphorylated form

of the adaptor protein Crkl. There was marked variability between patients,

with IC50imatinib ranging from 0.375 to 1.8uM (median 0.6 uM). Patients with

low IC50imatinib (IC50 ¾0.6uM; n=36) had a 36% probability of achieving 2

log reduction in BCR-ABL by 3 months compared to 8% in high IC50imatinib

patients (n=26) (p=0.01).

The IC50imatinib was also predictive of molecular response at 12 months,

with 47% of patients in the low IC50imatinib group achieving 3 log reduction

and 23% in the high IC50imatinib group (p=0.03). The predictive power of

IC50imatinib was particularly strong in patients with low Sokal scores. This

data provides strong evidence that intrinsic sensitivity to imatinib is

variable in previously untreated CML patients, and the actual level of

BCR-ABL kinase inhibition achieved is critical to imatinib response. The

IC50imatinib potentially provides a new prognostic indicator for molecular

response in imatinib treated patients.