FYI: High-Dose Imatinib in Patients With Early Chronic-Phase CML

[Guest guest]

Hi all,

I'm posting below a discussion in the wake of the ASH meeting. This is

from a series about CML from ASH that I am privvy to. I'm not posting

them all because there are too many (62 pages in a pdf) but will post

some of them. I have also removed links and references for my

convenience.

Below is the third one.

~ G.

www.cmlsupport.com <http://www.cmlsupport.com/>

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High-Dose Imatinib in Patients With Early Chronic-Phase CML

Yang, MD, PhD:

In another interesting abstract presentation by Dr. Cortes and

colleagues,[12] 115 patients with early chronic-phase CML were given 800

mg of imatinib per day, compared with the standard dose of 400 mg per

day in a phase II study (Capsule Summary). This study was initiated

after single-center data from last year at ASH that showed higher

12-month complete molecular responses to imatinib at 800 mg per day

(Capsule Summary).[13]

Hagop Kantarjian, MD:

Both preclinical and early clinical data suggest that doubling the dose

of imatinib may result in an earlier and higher rate of complete

cytogenetic response, without increased toxicity,[14] thereby increasing

the likelihood of achieving a major molecular response. The potential

scientific implication is that attacking the disease earlier and more

intensely may prevent development of resistance and mutations, which may

ultimately improve the long-term prognosis.

As reported by Dr. Cortes, this strategy produced early and high rates

of molecular response, including a disease reduction of 4 logs or

greater. Major molecular response and complete molecular response at 1

year were 64% and 54%, respectively, which are better than response

rates reported with imatinib 400 mg daily by that time point.

Although the results do appear to be promising, the study also raises

several concerns. The first is that doubling the dose of imatinib would

double the costs of the treatment. Secondly, none of these studies has

shown a significant improvement in progression-free survival or overall

survival. A third criticism is that doubling the dose of imatinib may

not make sense, given the fact that the new kinase inhibitors are 50 to

300 times more potent. Although the concept of dose-dense imatinib was

and still is interesting, high-dose imatinib is probably going to be

relegated to second-tier treatment status as we continue to study the

new kinase inhibitors. In addition, although this study does demonstrate

that imatinib dose intensification can result in earlier and higher

rates of complete cytogenetic and major molecular responses, the rate of

major molecular response appears to plateau over time at around 70% for

both the 400-mg and 800-mg regimens. Therefore, why give 800-mg

treatment when the same results could be obtained with longer duration

of 400-mg treatment?

The rates of 4 log10 reduction or more, or PCR negativity, continue to

be promising at approximately 3 years in the MD study, although

follow-up is currently very short. However, the bottom line is that

treatment with high-dose kinase inhibitors is an interesting concept in

terms of reducing early the levels of minimal residual disease, and it

may prevent the development of mutations (eg, the BCR-ABL mutation

T315I) that lead to resistance.