The success of imatinib for the treatment of chronic myeloid leukemia (CML) has created a need for a sensitive and accurate method of monitoring disease response and burden. Quantitative PCR (Q-PCR) has been previously shown to correlate well with cytogenetic response in patients treated with imatinib, whereby a one-log reduction in BCR-ABL transcript level corresponded well with attainment of a major cytogenetic response (MCyR) and a two-log reduction correlated with a complete cytogenetic response (CCyR) (Branford et al,

Leukemia 17:2401, 2003
). BMS-354825 is a novel orally bioavailable SRC/ABL kinase inhibitor with impressive activity against imatinib-resistant BCR-ABL mutant isoforms in vitro (
Shah et al, Science 305:399, 2004
). The compound is presently undergoing evaluation in phase I clinical trials (see Sawyers et al, Talpaz et al, abstracts submitted for this meeting). We sought to address whether cytogenetic responses in patients treated with BMS-354825 correlated with reduction in BCR-ABL transcript levels as determined by Q-PCR. Of 13 evaluable imatinib-resistant/intolerant patients with chronic phase CML treated at UCLA, four have attained a MCyR. Achievement of MCyR corresponded with a one to two-log reduction in BCR-ABL transcript as assessed by Q-PCR. In the majority of cases, a substantial reduction in BCR-ABL transcript was detected four weeks after initiation of BMS-354825. Overall, the median reduction in BCR-ABL transcript level after four weeks of therapy was 32%. Three of these patients had developed resistance to imatinib, and two harbored the common imatinib-resistant M351T mutation. Of the nine patients who have failed to achieve a MCyR, none have achieved a one log reduction in BCR-ABL transcript level. We conclude that similar to imatinib, BMS-354825-associated MCyR in chronic phase CML is highly associated with a one to two-log reduction in BCR-ABL transcript level. Furthermore, Q-PCR offers a rapid and reliable method to assess for disease response in this setting, which promises to be of significant clinical value. Although the maximal tolerated dose of BMS-354825 has yet to be determined, the compound is clearly capable of substantially reducing disease burden in patients with imatinib-resistant CML. Updated Q-PCR data from all chronic, accelerated, and blast crisis-phase patients on study at UCLA will be presented.

Topics:
bcr-abl tyrosine kinase, cytogenetics, leukemia, myelocytic, chronic, imatinib mesylate, polymerase chain reaction, leukemia, myeloid, chronic-phase, kinase inhibitors, leukemia, protein isoforms, maximum tolerated dose

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2005, The American Society of Hematology
2004
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