Rapid clonal shifts in response to kinase inhibitor therapy in chronic myelogenous leukemia are identified by quantitation mutation assays

Yin, C. Cameron; Cortes, Jorge; Galbincea, John; Reddy, Neelima G.; Breeden, Megan; Jabbour, Elias; Luthra, Rajyalakshmi; Jones, Dan

doi:10.1111/j.1349-7006.2010.01627.x

Cited by 13 publications

(13 citation statements)

References 15 publications

(32 reference statements)

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“…The sensitivity of the assay is 5%, similar to that observed in other pyrosequencing studies 14 15. However, methods such as allele-specific PCR may be sensitive down to levels of ∼10 −4 , but very low-level mutations that may be detected with such techniques have uncertain clinical value 16.…”

Section: Discussionsupporting

confidence: 65%

“…We also illustrate that pyrosequencing results match those from Sanger sequencing with 100% concordance, but pyrosequencing provides the added value of precise relative quantification with a much lower cost to implement. Published reports of strategies to detect T315I include Sanger sequencing,12 FRET,17 AS-PCR18 19 and D-HPLC20 in addition to pyrosequencing 14 15 21. Each method is capable of detecting the T315I point mutation, but most techniques lack sensitivity, are cost-prohibitive, or require extensive reagent preparation and time to perform.…”

Section: Discussionmentioning

confidence: 99%

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A pyrosequencing-based test for detection and relative quantification of theBCR-ABL1T315I point mutation

et al. 2011

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

A pyrosequencing-based test for detection and relative quantification of theBCR-ABL1T315I point mutation

et al. 2011

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“…If the T315I mutation was detected, the amount of mutated T315I BCR-ABL transcript was quantified by a more sensitive technique, rapid pyrosequencing. 16,17 In Europe, the T315I mutation was detected by denaturing high-performance liquid chromatography. 18 If the sample was found to be positive for the T315I mutation, the amount of mutated T315I BCR-ABL transcript was quantified by qRT-PCR.…”

Section: Assessmentsmentioning

confidence: 99%

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Cortes

Lipton

Réa

et al. 2012

Blood

Self Cite

119

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Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m 2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n ‫؍‬ 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219. (Blood. 2012;120(13):2573-2580)

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“…14,15 In addition, imatinib-treated CML-CP cells and patients may continue to accumulate TKI-resistant BCR-ABL1 mutants and additional chromosomal aberrations. [16][17][18][19] Altogether, genomic instability is an early event in CML-CP, and it persists during the course of disease/treatment generating TKI-resistant clones and additional chromosomal aberrations causing disease relapse and/or malignant progression to CML-BP.…”

Section: Introductionmentioning

confidence: 99%

Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells

Bolton-Gillespie

Schemionek

Klein

et al. 2013

Blood

111

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• Imatinib does not prevent accumulation of genomic instability in CML-CP.• Imatinib-refractory leukemia stem cells may be a source of genomic instability in CML-CP.Genomic instability is a hallmark of chronic myeloid leukemia in chronic phase (CML-CP) resulting in BCR-ABL1 mutations encoding resistance to tyrosine kinase inhibitors (TKIs) and/or additional chromosomal aberrations leading to disease relapse and/or malignant progression. TKI-naive and TKI-treated leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) accumulate high levels of reactive oxygen species (ROS) and oxidative DNA damage. To determine the role of TKI-refractory LSCs in genomic instability, we used a murine model of CML-CP where ROS-induced oxidative DNA damage was elevated in LSCs, including quiescent LSCs, but not in LPCs. ROSinduced oxidative DNA damage in LSCs caused clinically relevant genomic instability in CML-CP-like mice, such as TKI-resistant BCR-ABL1 mutations (E255K, T315I, H396P), deletions in Ikzf1 and Trp53, and additions in Zfp423 and Idh1. Despite inhibition of BCR-ABL1 kinase, imatinib did not downregulate ROS and oxidative DNA damage in TKIrefractory LSCs to the levels detected in normal cells, and CML-CP-like mice treated with imatinib continued to accumulate clinically relevant genetic aberrations. Inhibition of class I p21-activated protein kinases by IPA3 downregulated ROS in TKI-naive and TKI-treated LSCs. Altogether, we postulate that genomic instability may originate in the most primitive TKI-refractory LSCs in TKI-naive and TKI-treated patients. (Blood. 2013;121(20):4175-4183)

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Rapid clonal shifts in response to kinase inhibitor therapy in chronic myelogenous leukemia are identified by quantitation mutation assays

Cited by 13 publications

References 15 publications

A pyrosequencing-based test for detection and relative quantification of theBCR-ABL1T315I point mutation

A pyrosequencing-based test for detection and relative quantification of theBCR-ABL1T315I point mutation

Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Genomic instability may originate from imatinib-refractory chronic myeloid leukemia stem cells

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