Molecular and Chromosomal Characterization of Resistance in CML Patients after STI-571 (Glivec) Therapy

Reviewer: Walter F. Sall, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 9, 2001

Presenter: Andreas Hochhaus
Presenter's Affiliation: Universitat Heidelberg
Type of Session: Plenary

Background
STI-571 is a promising new treatment modality for CML which functions by potent and selective inhibition of the BCR-ABL oncogene. However, STI-571 resistance has been documented in a proportion of patients undergoing STI-571 monotherapy. Mutations in the ATP binding pocket of BCR-ABL has recently been documented as a means by which STI-571 resistance occurs. In this study, other mechanisms of STI-571 resistence are described.

Materials and Methods

50 patients with STI-571 resistant CML from 6 randomized phase two trials were studied. 26 of these were initially STI-571 sensitive and developed resistance, 24 were resistant from the initial onset of STI-571 therapy.

The expression level of BCR-ABL transcripts was determined by RT-PCR.

The number of genomic BCR-ABL copies was determined by fluorescence in-situ hybridization.

BCR-ABL tyrosine kinase domain was sequenced to evaluate for point mutations.

Results

Genomic amplification of BCR-ABL was seen in 2/21 patients.

> 10 fold increase in expression of BCR-ABL was seen in 5/46 patients.

15/29 patients had novel cytogenetic aberrations resulting in clonal evolution.

11/50 patients had point mutations seen in the tyrosine kinase domain restoring kinase activity even in the presence of STI-571.

median time to development of resistance varied from 82 to 172 days.

Overall, molecular or cytogenetic mechanisms of resistance were discovered in 27/50 patients.

Author's Conclusions

Multiple mechanisms of resistance to STI-571 have evolved including gene over-expression and point mutations in the tyrosine kinase domain and/or the ATP binding domain.

These mechanisms ultimately lead to failure of STI-571 therapy in CML.

This trial provides support for the initiation of trials combining STI-571 with other drugs for the treatment of CML resistant to conventional therapies.

Clinical/Scientific Implications
Though STI-571 has proven to have remarkable efficacy in the treatment of CML, the demonstration of multiple mechanisms of resistance shows that its use as monotherapy may not be adequate. Future exploration of multidrug regimens incorporating STI-571 are needed to illuminate the ideal method by which it should be used.

Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Amgen.