Hematologic and Cytogenetic Responses in Imatinib-Resistant Accelerated and Blast Phase Chronic Myeloid Leukemia (CML) Patients Treated with the Dual SRC/ABL Kinase Inhibitor BMS-354825: Results from a Phase I Dose Escalation Study.

Abstract

BMS-354825 is a novel, orally available, dual SRC/ABL kinase inhibitor with 100-fold greater potency to inhibit BCR-ABL in vitro than imatinib and has in vitro and in vivo preclinical activity against 14 of 15 imatinib resistant BCR-ABL mutants (Shah et al, Science, 305:399, 2004). Here we report the phase I clinical results of BMS-354825 in Philadelphia chromosome positive accelerated phase (AP) and blast phase (BP) CML patients who had hematologic progression or intolerance while being treated with imatinib. As of Aug 6, 2004, 17 patients (6 with AP; 11 with BP) have been treated in 3 cohorts with doses ranging from 35 mg BID (1 patient) to 70 mg BID of BMS-354825. BMS-354825 is rapidly absorbed with peak concentrations achieved within 2 hours and a terminal phase half-life of about 5 hours. Consistent, rapid and sustained inhibition of LYN kinase, a member of the SRC family of tyrosine kinases, has been demonstrated.Of the 11 BP patients, 7 have had hematologic response: 3 complete hematologic response (CHR), 2 ‘no evidence of leukemia' (NEL), and 2 ‘return to chronic phase' (RTC). Three additional patients have had significant hematologic improvement despite being on treatment only a short period of time (10–23 days). One patient with extramedullary disease was stable. Cytogenetic data is available for 8 of the 11 BP patients. Four patients had major cytogenetic response, 2 patients had a minor cytogenetic response and 2 patients had no response. BCR-ABL mutation data is available for 2 patients: one patient did not have a mutation and one patient who had a non-sustained CHR was found to have a E355G mutation.Three of 6 AP patients have had hematologic response: 2 CHRs and 1 NEL. Two patients are too early to assess. One patient demonstrated resistance to BMS-354825 due to a T315I mutation in BCR-ABL found in 8 of 10 clones. This mutation confers resistance to BMS-354825 in preclinical studies. BCR-ABL mutation status is available for 3 additional AP patients: 2 patients had no mutations identified and 1 patient in CHR had M351T/A imatinib-resistant mutations. Of 3 patients for whom early cytogenetic data is available, 1 had a minor cytogenetic response (40% Ph+).To date BMS-354825 has been very well tolerated. Two patients in blast phase had evidence of mild tumor lysis syndrome. Dose escalation is continuing and phase II studies in chronic, accelerated and blast phase CML are currently being initiated. Further studies are required to establish LYN's potential role in imatinib-resistant CML. The clinical data demonstrate that BMS-354825 can frequently override imatinib resistance in advanced CML, and provide compelling evidence supporting the safety and efficacy of BMS-354825 in imatinib-resistant accelerated and blast phase CML.