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

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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.

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Data availability

All data generated or analyzed during this study are included in this published article.

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

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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.

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Authors and Affiliations

  1. Laboratory of Hematology, Bordeaux University Hospital, Avenue de Magellan, 33604, Pessac Cedex, France

    Stephanie Dulucq, Emilie Klein, Claudine Chollet & Fanny Robbesyn

  2. INSERM U1218, University of Bordeaux, 146 rue Léo Saignat CS 61292, 33076, Bordeaux Cedex, France

    Stephanie Dulucq, Beatrice Turcq & François-Xavier Mahon

  3. French Group of CML (Fi-LMC), Bergonié Cancer Institute, 229 Cours de l’Argonne, CS61283, 33076, Bordeaux Cedex, France

    Stephanie Dulucq, Gabriel Etienne, Sandrine Hayette, Franck E. Nicolini & François-Xavier Mahon

  4. Bergonié Cancer Institute, 229 Cours de l’Argonne, CS61283, 33076, Bordeaux Cedex, France

    Gabriel Etienne & François-Xavier Mahon

  5. Lieu–dit La Caillatte, 01150, Chazey sur Ain, France

    Stephane Morisset

  6. Léon Bérard Cancer Institute and INSERM U1052, 28, rue Laennec, 69373, Lyon Cedex 08, France

    Stephane Morisset & Franck E. Nicolini

  7. Laboratory of Hematology, Centre Hospitalier Lyon Sud, 165 chemin du Grand Revoyet, 69495, Pierre Bénite Cedex, France

    Isabelle Tigaud & Sandrine Hayette

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  1. Stephanie Dulucq
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  2. Gabriel Etienne
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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.

Corresponding author

Correspondence to Stephanie Dulucq.

Ethics declarations

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.

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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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Dulucq, S., Etienne, G., Morisset, S. et al. Impact of second decline rate of BCR-ABL1 transcript on clinical outcome of chronic phase chronic myeloid leukemia patients on imatinib first-line. Ann Hematol 98, 1159–1168 (2019). https://doi.org/10.1007/s00277-019-03633-x

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