Correlation of Clinical Response to Dasatinib (BMS-354825) with BCR-ABL Mutation Status in Imatinib- Resistant Patients (pts) with Chronic Myeloid Leukemia (CML) Treated at MD Anderson Cancer Center (MDACC).

Resistance to imatinib in CML occurs most frequently through mutations of the BCR-ABL kinase domain. Dasatinib is an orally available, dual SRC/ABL kinase inhibitor with 300-fold greater potency than imatinib, and with preclinical activity against all but one (T315I) type imatinib-resistant Bcr-Abl mutants. Dasatinib is currently used to treat pts with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP) or with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). We analyzed the response to dasatinib among pts with Bcr-Abl kinase mutations. Prior to therapy, peripheral blood samples were analyzed for mutation by DNA sequencing. 26 pts with 13 different imatinib-resistant point mutations in the Bcr-Abl kinase domain were treated (CP n=10, AP n=11, BP n=4, ALL n=1). The most common mutations were G250E/A (n=7, 27%), T315I (n=3, 12%), F317L (n=3, 12%), and E355G/A (n=3, 12%). 20 (77%) pts responded to therapy. Responses were: major molecular remission (MMR) in one pt (4%), complete cytogenetic response (CGCR) in 3 (12%), partial cytogenetic response (CGPR) in 5 (19%), complete hematologic response (CHR) in 6 (23%), partial hematologic response (PHR) in 3 (12%), and return to CP in 2 (8%). 6 pts did not respond: 3 of them were in AP (T315I, L364I, and G250E) and 3 in CP (2 T315I and F317L). Three pts (1 CP [F317L], 2 BP [M351T and E355G]) have lost their response (CGPR, CHR, and PHR) after a median of 3 months (range, 2–4 months) without developing any detectable new mutations. The median duration of response for the other 19 pts was 5+ months (range 1+–14+); 4 pts (1 CP [F486S], 3 AP [E255V and 2 G250E]) have a sustained response (1 MMR, 1 CGCR, and 2 CHR) beyond 6 months. Among 12 pts with P-loop mutations (2 in CP, 8 in AP, 2 in BP) 11 (92%) responded to therapy and their median survival since the start of therapy is 5+ months (range, 1+-11+ months). In 2 pts (CHR) subsequent analysis revealed persistence of mutations (E355G and E255V). In one pt G250E mutation occurred while patient was on treatment, but has remained in CHR. We conclude that clinical activity of dasatinib in imatinib-resistant CML is observed in pts with a wide range of imatinib-resistant Bcr-Abl kinase domain mutations. Pts harboring the T315I mutations are resistant to BMS-354825.