FYI: Article: Resistance

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AACR: Agent Shows Value in Gleevec-Resistant CML

By Rabiya Tuma, Ph.D., MedPage Today Staff Writer

Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of

Pennsylvania School of Medicine.

April 04, 2006

MedPage Today Action Points

Explain to patients who ask that this study suggests that dasatinib, an

investigational BCR-ABL and Src kinase inhibitor, controls chronic and

blast-phase chronic myelogenous leukemia in patients who have resistance

to Gleevec (imatinib mesylate) or are intolerant to it.

This study was published as an abstract and presented orally at a

conference. These data and conclusions should be considered to be

preliminary as they have not yet been reviewed and published in a

peer-reviewed publication.

Review

WASHINGTON, Apr. 3 - Dasatinib, a second generation tyrosine kinase

inhibitor, can control chronic myelogenous leukemia (CML) in patients

resistant to Gleevec (imatinib mesylate) therapy, according to data from

several phase II studies.

The trial results confirm phase 1 data that showed the dual kinase

inhibitor, which inhibits both BCR-ABL and Src kinases, was active when

Gleevec was not, said Sawyers, M.D., of Medical

Institute and the University of California in Los Angeles.

There are five on-going phase II trials testing dasatinib, which does

not yet have a trade name, in various CML stages. Recruitment for all of

the trials was completed last August 2005, and Dr. Sawyers presented

six-month data from each.

In the chronic phase trial, 186 patients have been treated with the

drug. Ninety have had a complete hematologic remission and 45 a major

cytologic remission (MCyR). Of 107 patients enrolled with accelerated

phase CML, 59 had a complete hematologic remission and 31 a MCyR.

Of 74 with myeloid blast disease, 32 had a complete hematologic

remission and 30 a MCyR. Seventy-eight patients with lymphoid leukemia

have been enrolled. Thirty-five had a complete hematologic responses and

54 a MCyR.

Grade 3 and 4 myelosuppression occurred in 51 to 79% of patients with

CML, and 12% to 18% of patients have had pleural effusions in the

trials.

In the phase I studies, Dr. Sawyers and colleagues found that dasatinib

inhibited most of the mutations in BCR-ABL that rendered the protein

insensitive to Gleevec. Continuing on this line of study, the team

sequenced the BCR-ABL gene in 437 of the 481 patients enrolled in the

trials. Forty-eight percent of them had mutations in the gene at 26

different amino acid positions. Four previously unknown mutations were

isolated.

In an unexpected twist, the team found that some mutations were

sensitive to dasatinib in patients with chronic stage of the disease but

the same mutation rendered patients in blast crisis insensitive to the

drug. Upon closer examination it appeared that the drug partially

suppresses the mutant form of the protein but under the conditions of

blast crisis this partial suppression was no longer adequate to control

the disease, though it was sufficient at an earlier disease stage.

That means physicians may, in the future, need to prescribe drugs based

on specific mutations, not just on protein inhibition, commented José

Baselga, M.D., of the Vall d'Hebron University Hospital in Barcelona,

Spain.

The availability of a second BCR-ABL inhibitor means that researchers

can think about using the two drugs, dasatinib and Gleevec, in

combination to try to suppress the development of mutations that lead to

drug resistance and disease progression, he said..

Already preclinical data indicate that the strategy could work, and that

the drugs have a strong additive activity. " Everyone is quite excited

about combining them upfront, " said Dr. Baselga. " It could reduces the

appearance of resistant clones, " he added, and prolong the time of drug

response.

Another investigational agent for Gleevec-resistant CML, called

nilotinib (AMN 107), is also in clinical trials

Primary source: ASCO/ASTRO Gastrointestinal Meeting

Source reference:

Sawyers, CL, et al. 2006. Development of the ABL kinase inhibitor

dasatinib (BMS-354825) in imatinib-resistant Philadelphia chromosome

positive leukemias. ASCO/ASTRO Gastrointestinal Meeting.Abstract CP-2.