Effect of ABCG2 , OCT1 , and ABCB1 ( MDR1 ) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial

Rinaldetti, Sébastien; Pfirrmann, Markus; Manz, Kirsi; Guilhot, Joëlle; Dietz, Christian; Panagiotidis, P.; Spieß, Birgit; Seifarth, Wolfgang; Fabarius, Alice; Müller, Martin C.; Pagoni, Maria; Dimou, Maria; Dengler, Jolanta; Waller, Christiane; Brümmendorf, Tim H.; Herbst, Regina; Burchert, Andreas; Janβen, Carsten; Goebeler, Marie-Elisabeth; Jost, Philipp J.; Hanzel, Stefan; Schafhausen, Philippe; Prange‐Krex, Gabriele; Illmer, Thomas; Janzen, Viktor; Klausmann, M.; Eckert, R.; Büschel, G.; Kiani, Alexander; Hofmann, Wolf‐Karsten; Mahon, François‐Xavier; Saußele, Susanne

doi:10.1016/j.clml.2018.02.004

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…Recently, Rinaldetti et al. analyzed the data of the Euro-SKY trial, in order to evaluate the expression of ABCG2, OCT1, and ABCB1, and their influence on TFR ( 25 ). Interestingly, after TKI discontinuation, ABCB1 expression was significantly downregulated in 40 patients, at the day of relapse.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, CML patients in deep molecular response showed a different expression in influx and efflux transporters after long-term imatinib treatment, compared with healthy controls. ABCB1 responded more sensitively to TKI exposure, because discontinuation of imatinib resulted in a significant downregulation or normalization of its transcription levels ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

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Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated With Nilotinib

Loscocco¹,

Visani²,

Ruzzo

et al. 2021

Front. Oncol.

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Tyrosine kinase inhibitors (TKIs) have radically changed the outcome of chronic myeloid leukemia (CML) patients in the last 20 years. Moreover, the advent of second generation TKIs, namely nilotinib and dasatinib, have largely increased the number of CML patients achieving deep and sustained molecular responses. However, the possible mechanisms capable of influencing the maintenance of the long-term molecular response are not yet fully known and understood. In this light, polymorphisms in MDR-ABC transporters may influence the efficacy and safety of TKIs. In this study, we examined seven single nucleotide polymorphisms (SNPs) in four ABC transporter genes: ABCC1 rs212090 (5463T>A), ABCC2 rs3740066 (3972C>T), ABCC2 rs4148386 G>A, ABCC2 rs1885301 (1549G>A), ABCG2 rs2231137 (34G>A), ABCG2 rs2231142 G>C, ABCB1 rs1045642 (3435C>T), to determine their effect on the achievement and/or loss of molecular response in 90 CML patients treated with nilotinib. We found that ABCC2 rs3740066 CC and CT as well as the ABCB1 rs1045642 TT genotypes correlated with a higher probability to achieve MR3 in a shorter time (p=0.02, p=0.004, and p=0.01), whereas ABCG2 rs2231137 GG was associated with lower probability of MR3 achievement (p=0.005). Moreover, ABCC2 rs3740066 CC genotype, the ABCB1 rs1045642 CC and TT genotypes were positively correlated with MR4 achievement (p=0.02, p=0.007, and p=0.003). We then generated a predictive model incorporating the information of four genotypes, to evaluate the combined effect of the SNPs. The combination of SNPs present in the model affected the probability and the time to molecular response. This model had a high prognostic significance for both MR3 and MR4 (p=0.005 and p=0.008, respectively). Finally, we found ABCG2 rs2231142 GG genotype to be associated with a decrease risk of MR3 loss. In conclusion, MDR-transporters SNPs may significantly affect the achievement and loss of molecular response in CML patients treated with nilotinib.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated With Nilotinib

Loscocco¹,

Visani²,

Ruzzo

et al. 2021

Front. Oncol.

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show abstract

“…The impact of polymorphisms of ABCG2, OCT1 and ABCB1 were also studied: no differences were observed in the expression of OCT1 and ABCB1 in relapsed and non-relapsed patients. Indeed, a weak difference was found in the expression of ABCG2 (1.1 vs 0.8%): patients with a higher value of ABCG2 normalized per GUS had a two-fold greater risk of relapse [33]. Finally, the UK group reported an increased risk of relapse for patients carrying an e13a2 type of transcript after discontinuation that needs to be confirmed in a large series of patients [34].…”

Section: Prognostic Factors Associated To Tfrmentioning

confidence: 93%

Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia

Breccia

Foà

2018

Curr Oncol Rep

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Several trials have demonstrated that with imatinib about 40% of patients discontinuing treatment in deep and stable molecular response remain disease-free. Second-generation TKIs have improved the rate of deep molecular responses and allowed to increase the percentage of patients attempting treatment discontinuation. We hereby review the current information based on the available published data and discuss the current suggestions on how to move TFR into the clinical practice.

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“…In fact, to date, there is some evidence that we cannot accurately and reproducibly monitor those patients who are able to stay out of treatment indefinitely. This is probably due to several factors, such as the limit of detection of our molecular monitoring technology, or the inherent differences in the biology of leukemia (42), and/or immune response (43) in different patients, or a combination of several still undefined factors.…”

Section: Real-time Quantitative Pcr: Its Fundamental Role In Managemementioning

confidence: 99%

Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches

et al. 2019

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More than 15 years ago, imatinib entered into the clinical practice as a “magic bullet”; from that point on, the prognosis of patients affected by chronic myeloid leukemia (CML) became comparable to that of aged-matched healthy subjects. The aims of treatment with tyrosine kinase inhibitors (TKIs) are for complete hematological response after 3 months of treatment, complete cytogenetic response after 6 months, and a reduction of the molecular disease of at least 3 logs after 12 months. Patients who do not reach their goal can switch to another TKI. Thus, the molecular monitoring of response is the main consideration of management of CML patients. Moreover, cases in deep and persistent molecular response can tempt the physician to interrupt treatment, and this “dream” is possible due to the quantitative PCR. After great international effort, today the BCR-ABL1 expression obtained in each laboratory is standardized and expressed as “international scale.” This aim has been reached after the establishment of the EUTOS program (in Europe) and the LabNet network (in Italy), the platforms where biologists meet clinicians. In the field of quantitative PCR, the digital PCR is now a new and promising, sensitive and accurate tool. Some authors reported that digital PCR is able to better classify patients in precise “molecular classes,” which could lead to a better identification of those cases that will benefit from the interruption of therapy. In addition, digital PCR can be used to identify a point mutation in the ABL1 domain, mutations that are often responsible for the TKI resistance. In the field of resistance, a prominent role is played by the NGS that enables identification of any mutation in ABL1 domain, even at sub-clonal levels. This manuscript reviews how the molecular tools can lead the management of CML patients, focusing on the more recent technical advances.

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Effect of ABCG2 , OCT1 , and ABCB1 ( MDR1 ) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial

Abstract: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation.

Cited by 19 publications

References 35 publications

Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated With Nilotinib

Clinical Relevance of ABCB1, ABCG2, and ABCC2 Gene Polymorphisms in Chronic Myeloid Leukemia Patients Treated With Nilotinib

Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia

Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches

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