Copy number variation analysis in cytochromes and glutathione S-transferases may predict efficacy of tyrosine kinase inhibitors in chronic myeloid leukemia

<div><p>Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of <i>BCR/ABL</i> fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations. CNV detection was performed using SALSA MLPA P128-C1 Cytochrome P450 probe mix. Patients with optimal response and with failure of TKI therapy showed different frequencies of wild type and mutated CYPs and GST (p<0.0013). Validation in the group of 15 patients proved high prognostic value (p = 0.02): positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Wild type genotypes of CYP and GST associate with a worse response to TKI treatment in CML patients. This test can be recommended for further clinical trials.</p></div

Diagnostic value of CNV in <i>CYP1A2</i>, <i>CYP2A6</i>, <i>CYP2C19</i>, <i>CYP2C9</i>, <i>CYP2D6</i>, <i>CYP2E1</i>, <i>CYP3A4</i>, <i>CYP3A5</i>, <i>GSTM1</i>, <i>GSTP1 and GSTT1</i> for prediction of optimal response and failure of TKI therapy in CML patients (<i>P</i> = 0.0001).

<p>Diagnostic value of CNV in <i>CYP1A2</i>, <i>CYP2A6</i>, <i>CYP2C19</i>, <i>CYP2C9</i>, <i>CYP2D6</i>, <i>CYP2E1</i>, <i>CYP3A4</i>, <i>CYP3A5</i>, <i>GSTM1</i>, <i>GSTP1 and GSTT1</i> for prediction of optimal response and failure of TKI therapy in CML patients (<i>P</i> = 0.0001).</p

Difference in CNV status of CYP and GST genes (<i>P</i>< 0.0013) in optimal response, TKI failure and control groups of CML patients.

<p>Difference in CNV status of CYP and GST genes (<i>P</i>< 0.0013) in optimal response, TKI failure and control groups of CML patients.</p

Outcomes of TKIs treatment in validation group of CML patients.

<p>CML = chronic myeloid leukemia; CNV = copy number variation; TKI = tyrosine kinase inhibitor; CyR = cytogenetic response; CCyR = complete cytogenetic response.</p

Analyzed genes.

<p>Analyzed genes.</p

Patient profiles.

<p>Patient profiles.</p

Diagnostic value of CNV in <i>CYP1A2</i>, <i>CYP2A6</i>, <i>CYP2C19</i>, <i>CYP2C9</i>, <i>CYP2D6</i>, <i>CYP2E1</i>, <i>CYP3A4</i>, <i>CYP3A5</i>, <i>GSTP1</i> and <i>GSTT1</i> for prediction of optimal response and failure of standard TKI therapy in CML patients (<i>P</i> = 6.2*10⁻⁷).

<p>Diagnostic value of CNV in <i>CYP1A2</i>, <i>CYP2A6</i>, <i>CYP2C19</i>, <i>CYP2C9</i>, <i>CYP2D6</i>, <i>CYP2E1</i>, <i>CYP3A4</i>, <i>CYP3A5</i>, <i>GSTP1</i> and <i>GSTT1</i> for prediction of optimal response and failure of standard TKI therapy in CML patients (<i>P</i> = 6.2*10⁻⁷).</p