Imatinib mesylate resistance in CML and Ph+ ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to inhibit BCR-ABL. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor, which targets BCR-ABL and SRC kinases. Dasatinib is 325-fold more potent versus imatinib in cells transduced with wild-type BCR-ABL, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants (

O’Hare, et al. Cancer Res 65(11):4500–5, 2005
;
Shah et al, Science, 305:399–401, 2004
). Here we present an update of a Phase I dose-escalating study, initiated in November 2003, of dasatinib in imatinib-resistant/intolerant patients with CML in late chronic phase (CP) or advanced disease (accelerated phase [AP], myeloid blast crisis [MBC] or lymphoid blast crisis [LBC]) or with Ph+ ALL. Data are available for 84 patients (40 CP, 10 AP, 23 MBC, 11 LBC/Ph+ ALL). As of this writing, 40 CP patients, with 8 years’ median duration of CML (range: 1–17 yrs), have been treated with dasatinib (15–180 mg/day, once-daily [QD] or twice daily [BID]) for a median of 13 months. The rate of complete hematologic response (CHR) in CP is 88% (35/40). Major cytogenetic responses (MCyR) were observed in 40% (16/40), with complete CyR (CCyR) in 33% (13/40). In advanced disease, 44 patients have been treated with dasatinib (70–240 mg/day, BID) for a median of 3–7 months, depending on the cohort (see Table); 2 patients (1 MBC and 1 LBC) are not evaluable for response, but are included in the analysis of time to progression. The rate of major hematologic response (MHR) (bone marrow blasts <5%) is 80% (8/10) in AP, 77% (17/22) in MBC and 60% (6/10) in LBC/Ph+ ALL. The CHR rate (<5% bone marrow blasts, with recovery of peripheral blood counts) is 50% (5/10) in AP, 18% (4/22) in MBC and 50% (5/10) in LBC/Ph+ ALL. The overall rates of MCyR and CCyR in advanced disease were 36% (15/42) and 21% (9/42), respectively. Cytogenetic responses were seen in patients with a wide spectrum of BCR-ABL mutations, as well as in patients with minimal or no prior CyR with imatinib. Treatment was well tolerated. Reversible grade 3–4 myelosuppression was observed in all cohorts [CP (38%); AP (70%); MBC and LBC/Ph+ ALL (91%)]. 8 patients developed unexplained pleural effusions (2 CP; 6 BC), which were easily managed without treatment discontinuation. No patients have gone off study for toxicity. Responses are durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL cohorts, often due to dasatinib-resistant BCR-ABL mutations. These data support the therapeutic potential of dasatinib in patients with imatinib-resistant or -intolerant CML/Ph+ ALL. Phase II studies (the ‘START’ [SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib] program) are currently ongoing in imatinib-resistant/intolerant patients with all phases of CML and Ph+ ALL.

Phase of CML/ALLPatients remaining in response at July 31, 2005Follow-up, median (range) days
CP (N=40) 36 (90%) 392 (95–588) 
AP (N=10) 8 (80%) 200 (39–365) 
MBC (N=23) 9 (39%) 144 (2–364) 
LBC/Ph+ ALL (N=11) 1 (9%) 77 (8–233) 
Phase of CML/ALLPatients remaining in response at July 31, 2005Follow-up, median (range) days
CP (N=40) 36 (90%) 392 (95–588) 
AP (N=10) 8 (80%) 200 (39–365) 
MBC (N=23) 9 (39%) 144 (2–364) 
LBC/Ph+ ALL (N=11) 1 (9%) 77 (8–233) 
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Topics:
acute lymphocytic leukemia, dasatinib, imatinib mesylate, leukemia, myelocytic, chronic, philadelphia chromosome, bcr-abl tyrosine kinase, blast phase, accelerated phase, cancer, did not receive therapy or drug

Author notes

Corresponding author

2005, The American Society of Hematology
2005
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