Contributions
Abstract: PB1901
Type: Publication Only
Background
The selective targeting of ATP binding pocket in ABL gene by 1st generation tyrosin kinase inhibitor (TKI) imatinib led a huge success in the nearly complete control of chronic myeloid leukemia (CML). However, the inevitable development of resistant mutation bypassing the inhibitory effect of imatinib in CML cells initiated the development of 2nd generation TKI (2G-TKI) of nilotinib and dasatinib. With the introduction of 2G-TKI, the standard frontline treatment of CML is now changed into 2G-TKI.
Aims
We investigated the molecular predictor for the treatment response in patients with newly diagnosed CML and treated with 2nd generation TKI, nilotinib.
Methods
We performed mRNA sequencing (>30M reads) in peripheral blood samples from 12 patients who achieved MR3.0 at 6 months (n=3) or not (n=3) and achieved MR2.0 at 3 months (n=3) or not (n=3) for candidate gene discovery, and then conducted real-time quantitative PCR (RQ-PCR) for validation in 72 patients who were treated with nilotinib as frontline treatment. Gene expression from follow-up samples at 3 months was also measured.
Results
According to the criteria of│fold change│ >2.0 and q-value <0.01, a total of three genes of AOC1 (Amine oxidase, copper containing 1), BEX1 (The Brain-Expressed X-linked (BEX) 1 gene), and PRSS57(Protease, Serin, 57) were extracted from mRNA-sequencing data as candidate genes for the molecular predictor for the response to nilotinib (Figure 1). The results of RQ-PCR for validation of these 3 genes demonstrated that baseline expression level of AOC1 and PRSS57 were not associated with MR2.0 at 3 months (p = 0.95 and 0.81, respectively). However, low baseline BEX1 gene expression (2-ΔCt X 100 <12.09) at baseline was significantly associated with good early molecular response at 3 months. Baseline high BEX1 expression was significantly associated with the reduced cumulative incidence of deep molecular response of MR5.0 (HR=0.41, p = 0.022), and showed a trend toward the decreased incidence of MR4.5 (HR=0.53, p = 0.052). BEX1 gene expression was decreased in most cases (84.3%, 59/70 patients), while it was increased in 11 patients. The median change of BEX1 expression (2-ΔCt X 100) was -11.9 (range, -286.2 ~ 27.5). However, MR2.0 at 3 months since the nilotinib treatment was not associated with the direction of change of BEX1 expression (χ2=0.54, p = 0.46)
Conclusion
Our study showed that lower BEX1 gene expression can predict early (3 months) molecular response and deep molecular response of MR5.0 in newly diagnosed CML treated with nilotinib. Further larger scale confirmatory study is warranted.
Session topic: 7. Chronic myeloid leukemia – Biology & Translational Research
Keyword(s): Prediction, Chronic myeloid leukemia, Molecular response
Abstract: PB1901
Type: Publication Only
Background
The selective targeting of ATP binding pocket in ABL gene by 1st generation tyrosin kinase inhibitor (TKI) imatinib led a huge success in the nearly complete control of chronic myeloid leukemia (CML). However, the inevitable development of resistant mutation bypassing the inhibitory effect of imatinib in CML cells initiated the development of 2nd generation TKI (2G-TKI) of nilotinib and dasatinib. With the introduction of 2G-TKI, the standard frontline treatment of CML is now changed into 2G-TKI.
Aims
We investigated the molecular predictor for the treatment response in patients with newly diagnosed CML and treated with 2nd generation TKI, nilotinib.
Methods
We performed mRNA sequencing (>30M reads) in peripheral blood samples from 12 patients who achieved MR3.0 at 6 months (n=3) or not (n=3) and achieved MR2.0 at 3 months (n=3) or not (n=3) for candidate gene discovery, and then conducted real-time quantitative PCR (RQ-PCR) for validation in 72 patients who were treated with nilotinib as frontline treatment. Gene expression from follow-up samples at 3 months was also measured.
Results
According to the criteria of│fold change│ >2.0 and q-value <0.01, a total of three genes of AOC1 (Amine oxidase, copper containing 1), BEX1 (The Brain-Expressed X-linked (BEX) 1 gene), and PRSS57(Protease, Serin, 57) were extracted from mRNA-sequencing data as candidate genes for the molecular predictor for the response to nilotinib (Figure 1). The results of RQ-PCR for validation of these 3 genes demonstrated that baseline expression level of AOC1 and PRSS57 were not associated with MR2.0 at 3 months (p = 0.95 and 0.81, respectively). However, low baseline BEX1 gene expression (2-ΔCt X 100 <12.09) at baseline was significantly associated with good early molecular response at 3 months. Baseline high BEX1 expression was significantly associated with the reduced cumulative incidence of deep molecular response of MR5.0 (HR=0.41, p = 0.022), and showed a trend toward the decreased incidence of MR4.5 (HR=0.53, p = 0.052). BEX1 gene expression was decreased in most cases (84.3%, 59/70 patients), while it was increased in 11 patients. The median change of BEX1 expression (2-ΔCt X 100) was -11.9 (range, -286.2 ~ 27.5). However, MR2.0 at 3 months since the nilotinib treatment was not associated with the direction of change of BEX1 expression (χ2=0.54, p = 0.46)
Conclusion
Our study showed that lower BEX1 gene expression can predict early (3 months) molecular response and deep molecular response of MR5.0 in newly diagnosed CML treated with nilotinib. Further larger scale confirmatory study is warranted.
Session topic: 7. Chronic myeloid leukemia – Biology & Translational Research
Keyword(s): Prediction, Chronic myeloid leukemia, Molecular response