A study led by researchers from the Howard Hughes Medical Institute has found that dasatinib provides significant benefit in chronic myeloid leukemia (CML) patients resistant to Gleevec® (imatinib), according to a study presented today during the 97th Annual Meeting of the American Association for Cancer Research.

In an update of a phase I study initiated in November 2003, researchers looked at the use of dasatinib in imatinib resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC/Ph+ ALL). Data are available for 84 patients (40 CP, 11 AP, 23 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.

Imatinib - which blocks the irregular protein that allows the overproduction of abnormal white blood cells - has become a standard therapy for CML patients not undergoing stem cell transplantation. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.

The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and complete cytogenetic response (CCyR) in 35 percent.

In advanced disease, 44 patients have been treated with dasatinib (50 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 80 percent in LBC/Ph+ ALL. The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL groups, often due to dasatinib-resistant BCR-ABL mutations.

CML is usually diagnosed by finding what is called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of a genetic abnormality among portions of chromosomes 9 and 22. In this, part of the BCR (breakpoint cluster region) gene from chromosome 22 is merged with part of the ABL (abelson leukemia virus) gene on chromosome 9. The irregularity takes place in a single bone marrow cell and - through the process of cell division and expansion - results in leukemia, including some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Imatinib resistance in CML and Ph chromosome positive ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to stop BCR-ABL overproduction. Dasatinib (BMS-354825), which targets BCR-ABL, is 325-fold stronger than imatinib in cells with normal BCR-ABL genes and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.

*Abstract No. CP-2: Development of the ABL Kinase Inhibitor, Dasatinib (BMS-354825), in Imatinib-Resistant Philadelphia Chromosome Positive Leukemias



The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 60 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 16,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

Warren Froelich
froelichaacr
American Association for Cancer Research

View drug information on Gleevec.