Analyses of Treatment Outcome According to Age in Patients With Chronic Myeloid Leukemia Receiving Front-line Imatinib Therapy

2017 ◽  
Vol 17 (10) ◽  
pp. 696-702
Author(s):  
Irena Ćojbašić ◽  
Lana Mačukanović-Golubović ◽  
Miodrag Vučić ◽  
Ivan Tijanić
Keyword(s):  
Treatment Outcome ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Imatinib Therapy ◽  
Front Line

Impact of Drug Transporters ABCB1 and ABCG2 and Regulators of Xenobiotic Transport and Metabolism Pxr and CAR Gene Polymorphisms on Clinical Efficacy of Imatinib in Chronic Myeloid Leukemia (CML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5222-5222
Author(s):  
Anna Stepien ◽  
Alessandro Martino ◽  
Federico Canzian ◽  
Daniele Campa ◽  
Angelika Stein ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Transporters ◽  
Pregnane X Receptor ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Primary Resistance ◽  
Allelic Variants

Abstract Background: Inherited background in mechanisms regulating cellular uptake, elimination and metabolism of imatinib and other BCR-ABL tyrosine kinase inhibitors may influence treatment outcome in chronic myeloid leukemia (CML). Despite good efficacy of imatinib in CML therapy, a proportion of patients show suboptimal responses or even primary resistance. Imatinib is a well-established substrate of ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). However, the results of published studies regarding impact of ABCB1 and ABCG2 single nucleotide polymorphisms (SNPs) on imatinib treatment outcome have shown discrepant results. Moreover, little is known on the potential role of polymorphisms of regulators of xenobiotic transport and metabolism, pregnane X receptor (PXR, NR1|2) and constitutive androstane receptor (CAR, NR1|3) in imatinib efficacy. Aim: In this study we verified whether 61 tagging SNPs in drug transporters genes (ABCB1 and ABCG2) and regulators of xenobiotic transport and metabolism gene (PXR and CAR) genes affect imatinib therapy outcomes in CML. Methods: Genotyping was performed in 256 patients of Polish Caucasian origin (141 men and 117 women) treated with imatinib as first line treatment (229; 89.5%) or after second-line after interferon therapy (27; 10.5%). Tagging SNP approach was used to select the genetic variants and resulted in a selection of 61 tagging SNPs including 26 SNPs for ABCB1, 17 SNPs for ABCG2, 11 SNPs for PXR and 7 SNPs for CAR gene. Complete clinical data on imatinib treatment outcome were assessable for analyses of associations with tested SNPs. The influence of SNPs on imatinib outcomes including achievement of complete cytogenetic response (CCyR) at 12 months, achievement of major molecular response (MMR) at 18 months, progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. Three inheritance models (co-dominant, dominant and recessive) were tested for all allelic variants. Results: In this study we found that carriers of minor allele of CAR rs4073054A>C SNP significantly associated with shorter TTF on imatinib therapy (OR=2.42, 95%CI 1.41 - 4.17; p=0.0014; Bonferroni corrected p=0.048). In contrast, no impact of other tested allelic variants in ABCB1, ABCG2, PXR and CAR genes on proportion of patients who achieved CCyR at 12 months, MMR at 18 months as well as on probability of PFS, TTF and OS was observed. Conclusion: Our data suggest that inherited variants in the regulator of xenobiotic transport and metabolism CAR gene may modify results of imatinib therapy in CML patients. In contrast, the results of this relatively large study indicate that polymorphic variants in ABCB1, ABCG2 and PXR genes do not seem to play major role as determinants of response to imatinib in CML. Disclosures Robak: MorphoSys AG: Research Funding.

Characteristics of BCR/ABL1 kinase domain mutations in the patients with chronic myeloid leukemia who are primary resistant to the imatinib therapy

2019 ◽  
Vol 11 (1) ◽  
pp. 27-33
Author(s):  
I Dmytrenko ◽  
J Minchenko ◽  
I Dyagil
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
High Efficiency ◽  
Kinase Domain ◽  
Imatinib Therapy ◽  
Missense Mutations ◽  
Primary Resistance ◽  
Kinase Domain Mutations

The chronic myeloid leukemia (CML) development is associated with the formation of the BCR/ABL1 fusion gene and the BCR/ABL1 protein with increased tyrosine kinase activity. Despite the high efficiency of targeted therapy, up to 30% of patients do not respond on such therapy i.e. are primary resistant. The presence of BCR/ABL1 kinase domain mutations is considered to be one of the reasons of tyrosin kinase inhibitors resistance. To evaluate the frequency of BCR/ABL1 kinase domain mutations in Ukrainian cohort of CML patients with primary resistance to imatinib therapy, we retrospectively studied BCR/ABL1 kinase domain mutations in peripheral blood of 107 CML patients. The nucleotide sequence was determined by direct sequencing by Sanger. Mutations were reported in 45 of 107 (41.7%) CML patients. Two mutations at a time were revealed in 8 patients. So a total of 53 mutations were found out. Among them 49 were missense-mutations and 4 - deletions of different regions of the BCR/ABL1 kinase domain gene. The missense-mutations F359I/V (12 patients), T315I (8 patients) and G250E (6 patients) were most common. By localization, the mutations majority (23 of 53) was in the P-loop, 10 mutations - in the contact site, 13 mutations - in the catalytic domain and 6 – in the A-loop. Of the detected mutations, 26 (49%) resulted in a disruption of the hydrogen bond between BCR/ABL1-tyrosine kinase and imatinib. Significant reduction in overall survival was found in patients with BCR/ABL1 kinase domain mutations compared with patients with wild-type of BCR/ABL1 gene (p=0.018). The estimated 3-year overall survival was 83.4% (95% CI: 77.0%-89.8%) and 94.3% (95% CI: 91.0%-97.3%), respectively. Therefore, mutations of the BCR/ABL1 kinase domain are one of the mechanisms of primary resistance in CML patients on imatinib therapy. The occurrence of BCR/ABL1 gene mutations impairs the prognosis of imatinib therapy response.

scholarly journals Treatment outcome in a population-based, ‘real-world’ cohort of patients with chronic myeloid leukemia

Haematologica ◽  
2017 ◽  
Vol 102 (11) ◽  
pp. 1842-1849 ◽  
Author(s):  
Inge G.P. Geelen ◽  
Noortje Thielen ◽  
Jeroen J.W.M. Janssen ◽  
Mels Hoogendoorn ◽  
Tanja J.A. Roosma ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Chronic Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
Population Based

scholarly journals A case of severe digital vasculopathy during imatinib therapy in a hemodialysis patient with chronic myeloid leukemia

2016 ◽  
Vol 49 (8) ◽  
pp. 553-558
Author(s):  
Kotoko Yamatani ◽  
Hayato Mikami ◽  
Tetsuya Yoshikura ◽  
Sachiyo Osawa ◽  
Yoshihiro Takami ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hemodialysis Patient ◽  
Imatinib Therapy

Twin pregnancy in a patient of chronic myeloid leukemia on imatinib therapy

2008 ◽  
Vol 32 (10) ◽  
pp. 1620-1622 ◽  
Author(s):  
V. Meera ◽  
Farah Jijina ◽  
Mitu Shrikande ◽  
Manisha Madkaikar ◽  
K. Ghosh
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Twin Pregnancy ◽  
Imatinib Therapy

scholarly journals European Treatment and Outcome Study (Eutos) Score Predicts Early Molecular Response to Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Patients (Cp-Cml)

2014 ◽  
Vol 25 ◽  
pp. iv337
Author(s):  
K. Sudheer Reddy ◽  
M. Manickavasagam ◽  
V. Venkata Sampath ◽  
D. Barghavi ◽  
A. Vindhyavasini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Outcome Study ◽  
Eutos Score

The effect of homoharringtonine in patients with chronic myeloid leukemia who have failed or responded suboptimally to imatinib therapy

2009 ◽  
Vol 50 (11) ◽  
pp. 1889-1891 ◽  
Author(s):  
Yu-Feng Li ◽  
Xiaolin Liu ◽  
Ding-Shen Liu ◽  
Ban-He Din ◽  
Jian-Bin Zhu
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Imatinib Therapy
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