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Annals of Hematology

, Volume 98, Issue 5, pp 1159–1168 | Cite as

Impact of second decline rate of BCR-ABL1 transcript on clinical outcome of chronic phase chronic myeloid leukemia patients on imatinib first-line

  • Stephanie DulucqEmail author
  • Gabriel Etienne
  • Stephane Morisset
  • Emilie Klein
  • Claudine Chollet
  • Fanny Robbesyn
  • Beatrice Turcq
  • Isabelle Tigaud
  • Sandrine Hayette
  • Franck E. Nicolini
  • François-Xavier Mahon
Original Article
  • 108 Downloads

Abstract

Early molecular response has been associated with clinical outcome in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The BCR-ABL1 transcript rate decline from baseline to 3 months has been demonstrated to be more predictive than a single BCR-ABL1 level at 3 months (M3). However, it cannot be used routinely because ABL1, as an internal gene control, is not reliable for BCR-ABL1 quantification above 10%. This study aimed to compare clinical outcome and molecular response of chronic phase CML patients, depending on the percentage of BCR-ABL1 transcript decrease from month 3 to month 6 using ABL1 as an internal control gene. Two hundred sixteen chronic phase CML patients treated with imatinib 400 mg for whom M3 and month 6 molecular data were available were included in the study. Associations with event-free (EFS), failure-free (FFS), progression-free (PFS), and overall survivals (OS) molecular response 4 log and 4.5 log were assessed. The percentage of BCR-ABL1 decline from month 3 to month 6 was significantly linked to the EFS and the FFS (p < 0.001). A common cut-off of 67% of decline predicted the better risk of event. Patients with a decrease below 67% have worse EFS and FFS as compared to those having a higher decrease (p < 0.001). The impact was confirmed by multivariate analysis. Since the slope between diagnosis and 3 months cannot be reliable using ABL1 as an internal gene control, the second decline rate of BCR-ABL1 transcript between month 3 and month 6 could efficiently identify patients at higher risk of event.

Keywords

Early molecular response (EMR) Imatinib Event-free survival (EFS) Second slope Failure-free survival (FFS) 

Abbreviations

ABL1

Abelson

AUC

area under the time-dependent ROC curve

BCR

breakpoint cluster region

cDNA

complementary deoxyribonucleic acid

CP

chronic phase

CML

chronic myeloid leukemia

DMR

deep molecular response

EAC

European Against Cancer

EFS

event-free survival

ELN

European Leukemia Net

EMR

early molecular response

FFS

failure-free survival

GUSB

β-glucuronidase

HR

hazard ratio

IM

imatinib

IPCW

inverse probability of censoring weighting

IS

international scale

M3

BCR-ABL1 level at 3 months

M6

BCR-ABL1 level at 6 months

MR

molecular response

MMR

major molecular response

OS

overall survival

PFS

progression-free survival

RNA

ribonucleic acid

RT-qPCR

reverse transcription–quantitative real-time polymerase chain reaction

TKI

tyrosine kinase inhibitors

Notes

Acknowledgements

The authors gratefully acknowledge Mathieu Lewis for proofreading the manuscript and English corrections. We thank also the CRB-K Bordeaux and CRB-K Lyon for storage of samples.

Authors’ contributions

FXM conceived and designed the study; SD coordinated the study and wrote the manuscript; GE, FXM, and FN provided patients; FR monitored the local data; CC, SD, and SH performed the molecular analysis; IT and EK provided the cytogenetic data; SM performed statistical analysis; SD, FN, GE, BT, and FXM analyzed the data. All the authors reviewed the manuscript.

Compliance with ethical standards

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Clinical and laboratory data are recorded CCTIRS N°: 14.251 and CNIL N°: 915088.

Consent for publication

Not applicable.

Competing interest

FXM, FN, and GE declare partnerships with Bristol-Myers Squibb, Incyte, Novartis, and Pfizer in support of educational, clinical, or scientific activities.

SD declares partnerships with Bristol-Myers Squibb, Incyte, and Novartis in support of educational or scientific activities.

SH, IT, EK, FR, CC, and BT declare no competing interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Stephanie Dulucq
    • 1
    • 2
    • 3
    Email author
  • Gabriel Etienne
    • 3
    • 4
  • Stephane Morisset
    • 5
    • 6
  • Emilie Klein
    • 1
  • Claudine Chollet
    • 1
  • Fanny Robbesyn
    • 1
  • Beatrice Turcq
    • 2
  • Isabelle Tigaud
    • 7
  • Sandrine Hayette
    • 3
    • 7
  • Franck E. Nicolini
    • 3
    • 6
  • François-Xavier Mahon
    • 2
    • 3
    • 4
  1. 1.Laboratory of HematologyBordeaux University HospitalPessac CedexFrance
  2. 2.INSERM U1218University of BordeauxBordeaux CedexFrance
  3. 3.French Group of CML (Fi-LMC)Bergonié Cancer InstituteBordeaux CedexFrance
  4. 4.Bergonié Cancer InstituteBordeaux CedexFrance
  5. 5.Lieu–dit La CaillatteChazey sur AinFrance
  6. 6.Léon Bérard Cancer Institute and INSERM U1052Lyon Cedex 08France
  7. 7.Laboratory of HematologyCentre Hospitalier Lyon SudPierre Bénite CedexFrance

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