This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLean, L. A. Articles by Dressman, M. Search for Related Content PubMed PubMed Citation Articles by McLean, L. A. Articles by Dressman, M.

Pharmacogenomic Analysis of Cytogenetic Response in Chronic Myeloid Leukemia Patients Treated with Imatinib

¹Clinical Pharmacogenetics Department, Novartis Pharmaceuticals Corporation, Gaithersburg, Maryland, and² Oncology Department, Novartis Pharma AG, Basel, Switzerland

Purpose: To better understand the molecular basis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib, we studied gene expression profiles from a total of 100 patients from a large, multinational Phase III clinical trial (International Randomized Study of IFN- versus STI571).

Experimental Design: Gene expression data for >12,000 genes were generated from whole blood samples collected at baseline (before imatinib treatment) using Affymetrix oligonucleotide microarrays. Cytogenetic response was determined based on the percentage of Ph⁺ cells from bone marrow following a median of 13 months of treatment.

Results: A genomic profile of response was developed using a subset of individuals that exhibited the greatest divergence in cytogenetic response; those with complete response (0% Ph⁺ cells; n = 53) and those with minimal or no response (>65% Ph⁺ cells; n = 13). A total of 55 genes was identified that were differentially expressed between these two groups. Using a "leave-one-out" strategy, we identified the optimum 31 genes from this list to use as our genomic profile of response. Using this genomic profile, we were able to distinguish between individuals that achieved major cytogenetic response (0–35% Ph⁺ cells) and those that did not, with a sensitivity of 93.4% (71 of 76 patients), specificity of 58.3% (14 of 24 patients), positive predictive value of 87.7%, and negative predictive value of 73.7%.

Conclusions: Interestingly, many of the genes identified appear to be strongly related to reported mechanisms of BCR-ABL transformation and warrant additional research as potential drug targets. The validity and clinical implications of these results should be explored in future studies.

This article has been cited by other articles:

				M. Raponi, J.-L. Harousseau, J. E. Lancet, B. Lowenberg, R. Stone, Y. Zhang, W. Rackoff, Y. Wang, and D. Atkins Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia Clin. Cancer Res., April 1, 2007; 13(7): 2254 - 2260. [Abstract] [Full Text] [PDF]

				M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF]

				C. R. Santos, M. Rodriguez-Pinilla, F. M. Vega, J. L. Rodriguez-Peralto, S. Blanco, A. Sevilla, A. Valbuena, T. Hernandez, A. J. van Wijnen, F. Li, et al. VRK1 Signaling Pathway in the Context of the Proliferation Phenotype in Head and Neck Squamous Cell Carcinoma Mol. Cancer Res., March 1, 2006; 4(3): 177 - 185. [Abstract] [Full Text] [PDF]

				T. Hughes ABL Kinase Inhibitor Therapy for CML: Baseline Assessments and Response Monitoring Hematology, January 1, 2006; 2006(1): 211 - 218. [Abstract] [Full Text] [PDF]

				M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF]

				M. W.N. Deininger Management of Early Stage Disease Hematology, January 1, 2005; 2005(1): 174 - 182. [Abstract] [Full Text] [PDF]

				M. A. Dressman, R. Malinowski, L. A. McLean, I. Gathmann, R. Capdeville, M. Hensley, and M. H. Polymeropoulos Correlation of Major Cytogenetic Response with a Pharmacogenetic Marker in Chronic Myeloid Leukemia Patients Treated with Imatinib (STI571) Clin. Cancer Res., April 1, 2004; 10(7): 2265 - 2271. [Abstract] [Full Text] [PDF]

				S. O'Brien, A. Tefferi, and P. Valent Chronic Myelogenous Leukemia and Myeloproliferative Disease Hematology, January 1, 2004; 2004(1): 146 - 162. [Abstract] [Full Text] [PDF]