Digital PCR (Dpcr) a Step Forward to Detection and Quantification of Minimal Residual Disease (MRD) in Ph+/BCR-ABL1 Chronic Myeloid Leukemia (CML)

Bernardi, Simona; Ruggieri, Giuseppina; Malagola, Michele; Cancelli, Valeria; Cattina, Federica; Polverelli, Nicola; Zanaglio, Camilla; Perucca, Simone; Re, Federica; Montanelli, Alessandro; Russo, Domenico

doi:10.4172/2155-9929.1000330

Cited by 12 publications

(40 citation statements)

References 23 publications

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“…Receiver operator curves analysis was done to recalculate the optimal dPCR cutoff value to discriminate the patients with DMR and lower probability to lose MR 3.0 after TKI discontinuation. Notably, a cutoff of 0.468 was found to be coincidental with the previous one identified discriminating the deep molecular responders by dPCR . This value divided patients with lower risk of disease molecular relapse better, with an area under the curve of 0.69 (CI 95% 0.57‐0.81), specificity of 85% and sensitivity of 54% (Figure ).…”

Section: Methodsmentioning

confidence: 54%

“…A new receiver operating characteristic (ROC) curve analysis was carried out on the present cohort of patients and confirmed the reliability of the abovementioned cutoff in identification of the DMR patients by dPCR. (Figure ) …”

Section: Methodsmentioning

confidence: 99%

“…The dPCR analysis was centralized at the Laboratory CREA (Centro di Ricerca Emato‐Oncologico AIL) of the ASST Spedali Civili of Brescia and performed as previously described …”

Section: Methodsmentioning

confidence: 99%

“…The amplification was followed by the chips imaging and the secondary analysis performed with the QuantStudio 3D AnalysisSuite Cloud Software. All samples were analyzed twice by different operators and the final results were expressed as means of the number of BCR‐ABL1 copies/µL of reaction of the replicates …”

Section: Methodsmentioning

confidence: 99%

“…Although the dPCR is not yet routinely applied for the standard analysis of molecular MRD in CML, preliminary data suggest that it is more sensitive and accurate than RT‐qPCR for monitoring the BCR‐ABL1 transcript levels and, possibly, for predicting the patients who are going to relapse after discontinuation of TKI …”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 54%

Section: Methodsmentioning

confidence: 99%

“…The dPCR analysis was centralized at the Laboratory CREA (Centro di Ricerca Emato‐Oncologico AIL) of the ASST Spedali Civili of Brescia and performed as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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Digital droplet PCR as a predictive tool for successful discontinuation outcome in chronic myeloid leukemia: Is it time to introduce it in the clinical practice?

Colafigli

Scalzulli

Prima

et al. 2021

Critical Reviews in Oncology/Hematology

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RT-qPCR versus Digital PCR: How Do They Impact Differently on Clinical Management of Chronic Myeloid Leukemia Patients?

et al. 2020

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Real-time quantitative PCR (RT-qPCR) is the gold standard to quantify the BCR-ABL1 transcript for molecular response monitoring in chronic myeloid leukemia (CML) patients, and it plays a pivotal role in clinical decision-making process, even if it presents technical limits. Increasing data suggest that digital PCR (dPCR) is more accurate and reliable than RT-qPCR in CML minimal residual disease monitoring and in patients’ selection for treatment discontinuation. But what about the identification of treatment discontinuation failures? We present the case of a CML patient enrolled both in a study aiming to comparatively assess molecular response by RT-qPCR and dPCR and in the progressive arm of the OPTkIMA trial. This is a phase III trial including CML patients randomized to receive a fixed versus a progressive intermittent tyrosine kinase inhibitor regimen. At 24 months, because of two consecutive detections of MR2.0 by RT-qPCR, the patient resumed daily treatment. Conversely, dPCR revealed a stability of molecular response and even a slight decreasing of transcript over time. An additional specimen was sampled one month after the first MR2.0 detection because of clinical decision: RT-qPCR resulted MR3.0 and dPCR confirmed the transcript’s stability. Nowadays, the resumption of therapy is RT-qPCR-driven despite its limits in detection and robustness. In this case, according to dPCR, the patient could have continued intermittent treatment and the stability of response was then confirmed by RT-qPCR. So, dPCR could be able to better identify peculiar clinical response to therapy.

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Digital PCR (Dpcr) a Step Forward to Detection and Quantification of Minimal Residual Disease (MRD) in Ph+/BCR-ABL1 Chronic Myeloid Leukemia (CML)

Cited by 12 publications

References 23 publications

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

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

Digital droplet PCR as a predictive tool for successful discontinuation outcome in chronic myeloid leukemia: Is it time to introduce it in the clinical practice?

RT-qPCR versus Digital PCR: How Do They Impact Differently on Clinical Management of Chronic Myeloid Leukemia Patients?

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