Cancer Medicine (May 2019)

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

  • Simona Bernardi,
  • Michele Malagola,
  • Camilla Zanaglio,
  • Nicola Polverelli,
  • Elif Dereli Eke,
  • Mariella D’Adda,
  • Mirko Farina,
  • Cristina Bucelli,
  • Luigi Scaffidi,
  • Eleonora Toffoletti,
  • Clara Deambrogi,
  • Fabio Stagno,
  • Micaela Bergamaschi,
  • Luca Franceschini,
  • Elisabetta Abruzzese,
  • Maria Domenica Divona,
  • Marco Gobbi,
  • Francesco Di Raimondo,
  • Gianluca Gaidano,
  • Mario Tiribelli,
  • Massimiliano Bonifacio,
  • Chiara Cattaneo,
  • Alessandra Iurlo,
  • Domenico Russo

DOI
https://doi.org/10.1002/cam4.2087
Journal volume & issue
Vol. 8, no. 5
pp. 2041 – 2055

Abstract

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Abstract 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 MR4.0 and MR4.5 (P = 0.0104) or MR5.0 (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5‐5.0) 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 MR4.5‐5.0 (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 MR3.0 or MR4.0. 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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