Current developments in molecular monitoring in chronic myeloid leukemia

Marum, Justine E; Branford, Susan

doi:10.1177/2040620716657994

Cited by 27 publications

(18 citation statements)

References 99 publications

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“…It has previously been reported that the BCR-ABL1 transcript type may influence treatment outcomes (reviewed by Marum and Branford 17 ). Consequently, we compared molecular responses in patients having only e13a2 transcripts (n=32) or only e14a2 transcripts (n=17).…”

Section: Resultsmentioning

confidence: 99%

“…Several studies dating back at least two decades have reported inferior treatment responses among CML patients with e13a2 BCR-ABL1 transcripts. 17 , 23 Differences in molecularly-defined end points might simply reflect differing amplification efficiency in the BCR-ABL1 assay, especially in those systems that use a common forward primer in BCR e13, resulting in a 76 bp difference in amplicon length between the two transcripts. 24 In BCR-ABL1 DNA PCR, every patient-specific assay will have differing properties due to varying amplicon size and nucleotide composition.…”

Section: Discussionmentioning

confidence: 99%

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BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

et al. 2018

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Accurate quantification of minimal residual disease (MRD) during treatment of chronic myeloid leukemia (CML) guides clinical decisions. The conventional MRD method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first three months of treatment, BCR-ABL1 mRNA values declined more rapidly than DNA. By six months, the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in MRD being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first three months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond three months, falling levels of BCR-ABL1 mRNA are proportional to the depletion of leukemic cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

et al. 2018

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“…Clinical evidences unexpectedly highlight the absence of a linear correlation between the depth of the DMR, quantified following the IS, and the TFR maintenance rate. One of the causes could be related to the intrinsic limitations of real‐time quantitative PCR (RT‐qPCR), particularly concerning its lack of precision, especially in the quantification of the low levels of the target, and the variation of its sensitivity from one test to another …”

Section: Introductionmentioning

confidence: 99%

“…One of the causes could be related to the intrinsic limitations of real-time quantitative PCR (RT-qPCR), particularly concerning its lack of precision, especially in the quantification of the low levels of the target, and the variation of its sensitivity from one test to another. 14,15 For these reasons, the great majority of patients who undergo TKI discontinuation frequently have a DMR with undetectable levels of BCR-ABL1 transcript by RT-qPCR, Overall, according to the published data, 50%-60% of patients with undetectable DMR by RT-qPCR are expected to lose the DMR. [16][17][18][19] Therefore, the RT-qPCR cannot be considered as an optimal tool neither to select the best candidates for treatment discontinuation nor to design personalized treatment programs, especially in the era of the more potent second-generation TKI.…”

Section: Introductionmentioning

confidence: 99%

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

et al. 2019

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Treatment‐free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real‐time quantitative PCR (RT‐qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT‐qPCR for BCR‐ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR‐ABL1 transcripts in the RT‐qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR 4.0 and MR 4.5 ( P = 0.0104) or MR 5.0 ( P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR 4.0 vs MR 4.5‐5.0 ) were superimposable. Conversely, patients with dPCR values <0.468 BCR‐ABL1 copies/µL (as we previously described) showed a longer DMR duration ( P = 0.0220) and mainly belonged to MR 4.5‐5.0 ( P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR 3.0 or MR 4.0 . RT‐qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation ( P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR‐ABL1 values ≥0.468 and 12/86 (14%) patients with BCR‐ABL1 values <0.468 lost DMR in this cohort, respectively ( P = 0.0003). Treatment‐free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.

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“…The pathophysiology of CML is driven by the BCR-ABL fusion protein, which drives over-proliferation of myeloid precursors [85]. Historically, CML was treated with cytotoxic chemotherapy with minimal success, but the introduction of the BCR-ABL TKI Imatinib dramatically changed patient care [86,87,88].…”

Section: Tam Expression and Function In Therapeutic Resistancementioning

confidence: 99%

Targeting the TAM Receptors in Leukemia

Huey

Minson

Earp

et al. 2016

Cancers

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Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

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Current developments in molecular monitoring in chronic myeloid leukemia

Cited by 27 publications

References 99 publications

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

Targeting the TAM Receptors in Leukemia

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