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New options for patients with CML

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Entry of Imatinib (gleevec) has revolutionized the treatment of

chronic myeloid leukemia (CML). More are more patients with a

diagnosis of CML are now on imatinib (gleevec). Most of these patients

do very well on imatinib (gleevec), however some patients never

respond to imatinib (gleevec) and some other patients initially

respond to this drug but later develop resistance to this drug.

It is estimated that about 10 percent of all patients who initially

respond to imatinib (gleevec) subsequently develop resistance to this

drug. Now there are new options for those patients who progress on

imatinib (gleevec). Mutations in bcr-abl tyrosine kinase may account

for the development of resistance to gleevec. Two new drugs dasatinib

(drug from Bristol Myers, formerly known as BMS-354825) and AMN107

(drug from Novartis). These new drugs form tighter bonds with the

bcr-abl tyrosine kinase target and thus can over come the imatinib

resistance caused by bcr-abl tyrosine kinase mutation.

Dasatinib (BMS-354825)

The findings from a phase I study on dasatinib (BMS-354825) were

presented in the American Society of Hematology Meeting that was held

in December 2004. In that presentation at the plenary session of that

meeting, dasatinib was shown to be effective in patients with chronic

myeloid leukemia (CML) who have progressed on imatinib. In this study

dasatinib was given to patients who were no longer responding to

imatinib (gleevec). Eighty six percent of these patients who received

this drug achieved complete hematological response in 9 months. Twenty

eight percent of patients achieved a major cytogenetic response, more

than half of this was complete cytogenetic response. These responses

appeared to be durable during the period of study. Further data were

presented at the American Society of Clinical Oncology meeting (ASCO)

that was held at Orlando in May 2005.

Another phase I study presented at the at the American Society of

Clinical Oncology meeting (ASCO) May 2005 focused on patients with

blast crisis or accelerated phase of chronic myeloid leukemia (CML).

All these patients were either resistant to or intolerant to imatinib

(gleevec). The study found that dasatinib (BMS-354825) produced

complete hematological response of 50 percent in these patients who

had accelerated disease and 28 percent of those who were in blast

crisis. These finding are impressive considering the advanced nature

of chronic myeloid leukemia (CML) in these patients and that fact that

most of these patients were resistant to imatinib (gleevec).

At this time dasatinib (BMS-354825) looks at least as promising as

imatinib (gleevec) when it was undergoing phase I trials. Phase II

trials and phase III trials have been initiated for dasatinib

(BMS-354825) and if the data still holds good this drug may be

approved in the near future. Combination of imatinib (gleevec) with

dasatinib (BMS-354825) is another area the scientists are eager to

explore.

Dasatinib (BMS-354825) is a kinase inhibitor, and is 300 to 1000 times

more potent than imatinib (gleevec) for inhibition of bcr-abl tyrosine

kinase. Dasatinib is also an SRC inhibitor as well as an abl

inhibitor. Dasatinib is orally bio-available and can be taken as an

oral pill.

AMN 107

Positive findings from study using AMN107 was recently presented at

96th Annual meeting of American Association of Cancer Research (AACR)

that was held in Anaheim, CA. Francis Giles MD and colleagues from MD

Cancer Center in Houston presented this data at the meeting.

They evaluated 51 patients on a phase I trial. Of these 51 patients,

36 had accelerated phase chronic myeloid leukemia (CML) and rests of

the patients were in blast crisis. The design of the study allowed

escalation of dose if the response to AMN 107 is sub optimal. At the

time of reporting, responses at lower levels included complete

hematological and cytogenetic response responses. Imatinib (gleevec)

and AMN 107 have been shown to have synergistic effects and a

combination of imatinib (gleevec) and AMN 107 may be more effective

than imatinib alone. Clinical trials may be planned to evaluate the

efficiency of this combination.

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