Rates of deep molecular response by digital and conventional PCR with frontline nilotinib in newly diagnosed chronic myeloid leukemia: a landmark analysis

Berdeja, Jesús G.; Heinrich, Michael C.; Dakhil, Shaker R.; Goldberg, Stuart L.; Wadleigh, Martha; Kuriakose, Philip; Cortes, Jorge; Radich, Jerald P.; Helton, Bret; Rizzieri, David A.; Paley, Carole; Dautaj, Ilva; Mauro, Michael J.

doi:10.1080/10428194.2019.1590569

Cited by 11 publications

(9 citation statements)

References 27 publications

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“…The increase in sensitivity makes dPCR also applicable for MRD monitoring and for the selection of patients with optimal chances of successful TKI treatment discontinuation, for both canonical and atypical BCR-ABL1 transcripts. 47,48,53 Only limited by the available sample size and the number of partitions, its sensitivity reaches levels of MR5.0 to MR6.0 with current protocols, which is a 1-log improvement compared to qPCR. While the depth of DMR assessed by qPCR was not predictive, several studies have shown a consistent predictive value of dPCR for successful TFR.…”

Section: Discussion: Is Digital Pcr Applicable In Clinical Practice?mentioning

confidence: 99%

Digital PCR for BCR‐ABL1 Quantification in CML: Current Applications in Clinical Practice

et al. 2020

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Molecular monitoring of the BCR-ABL1 transcript for patients with chronic phase chronic myeloid leukemia (CML) has become increasingly demanding. Real-time quantitative PCR (qPCR) is the routinely used method, but has limitations in quantification accuracy due to its inherent technical variation. Treatment recommendations rely on specific BCR-ABL1 values set at timed response milestones, making precise measurement of BCR-ABL1 a requisite. Furthermore, the sensitivity of qPCR may be insufficient to reliably quantify low levels of residual BCR-ABL1 in patients in deep molecular response (DMR) who could qualify for an attempt to discontinue Tyrosine Kinase Inhibitor (TKI) therapy. We reviewed the current use of digital PCR (dPCR) as a promising alternative for response monitoring in CML. dPCR offers an absolute BCR-ABL1 quantification at various disease levels with remarkable precision and a clinical sensitivity reaching down to at least MR5.0. Moreover, dPCR has been validated in multiple studies as prognostic marker for successful TKI treatment discontinuation, while this could not be achieved using classical qPCR. dPCR may thus prospectively be the preferred method to reliably identify patients achieving treatment milestones after initiation of TKI therapy as well as for the selection and timing for TKI discontinuation.

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Section: Discussion: Is Digital Pcr Applicable In Clinical Practice?mentioning

confidence: 99%

Digital PCR for BCR‐ABL1 Quantification in CML: Current Applications in Clinical Practice

et al. 2020

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“…The application of the Fluidigm platform was also experienced by other groups, confirming the good accuracy and sensitivity of dPCR in the setting of BCR-ABL1 transcript measurement. In the ENEST next trial, which evaluated the rate of DMR in patients treated with nilotinib as first-line therapy, dPCR detected residual BCR-ABL1 transcripts in 39.4% of samples that were estimated to be in confirmed MR 4.5 [22] by RT-qPCR, thus demonstrating the feasibility of monitoring very low BCR-ABL1 transcript levels using dPCR [24].…”

Section: Mr Monitoringmentioning

confidence: 98%

Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?

Soverini

Bernardi

Galimberti

2020

JCM

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Molecular monitoring of minimal residual disease (MRD) and BCR-ABL1 kinase domain (KD) mutation testing have a well consolidated role in the routine management of chronic myeloid leukemia (CML) patients, as they provide precious information for therapeutic decision-making. Molecular response levels are used to define whether a patient has an “optimal”, “warning”, or “failure” response to tyrosine kinase inhibitor (TKI) therapy. Mutation status may be useful to decide whether TKI therapy should be changed and which alternative TKI (or TKIs) are most likely to be effective. Real-time quantitative polymerase chain reaction (RQ-qPCR) and Sanger sequencing are currently the gold standard for molecular response monitoring and mutation testing, respectively. However, in recent years, novel technologies such as digital PCR (dPCR) and next-generation sequencing (NGS) have been evaluated. Here, we critically describe the main features of these old and novel technologies, provide an overview of the recently published studies assessing the potential clinical value of dPCR and NGS, and discuss how the state of the art might evolve in the next years.

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“…In the context of the imatinib suspension and validation (ISAV) study (NCT01578213), ddPCR was able to detect one BCR-ABL1 positive cell out of 10 7 cells, predicting relapse in CML patients after imatinib discontinuation [13]. Moreover, Fluidigm digital PCR assay has been used in the ENESTnext (NCT01227577) study, confirming that ddPCR is more sensitive than RT-qPCR in patients with confirmed MR4.5, since about 40% of analyzed samples had a detectable BCR-ABL1 [26]. Our data also corroborated results previously obtained by Della Starza et al in pediatric acute lymphoblastic leukemia, where they identify ddPCR as more accurate than RT-qPCR in the measurement of MRD, particularly in the advanced follow-up [27].…”

Section: Discussionmentioning

confidence: 84%

Droplet Digital PCR for BCR–ABL1 Monitoring in Diagnostic Routine: Ready to Start?

Bochicchio

Petiti

Berchialla

et al. 2021

Cancers

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BCR–ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDxTMBCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR–ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR–ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR.

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Rates of deep molecular response by digital and conventional PCR with frontline nilotinib in newly diagnosed chronic myeloid leukemia: a landmark analysis

Cited by 11 publications

References 27 publications

Digital PCR for BCR‐ABL1 Quantification in CML: Current Applications in Clinical Practice

Digital PCR for BCR‐ABL1 Quantification in CML: Current Applications in Clinical Practice

Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?

Droplet Digital PCR for BCR–ABL1 Monitoring in Diagnostic Routine: Ready to Start?

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