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No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib

  • Markus PfirrmannEmail author
  • Dobromira Evtimova
  • Susanne Saussele
  • Fausto Castagnetti
  • Francisco Cervantes
  • Jeroen Janssen
  • Verena S. Hoffmann
  • Gabriele Gugliotta
  • Rüdiger Hehlmann
  • Andreas Hochhaus
  • Joerg Hasford
  • Michele Baccarani
Original Article – Clinical Oncology

Abstract

Purpose

The genomic break on the major breakpoint cluster region of chromosome 22 results in two BCR-ABL1 transcripts of different sizes, e14a2 and e13a2. Favorable survival probabilities of patients with chronic myeloid leukemia (CML) in combination with too small patient samples may yet have obstructed the observation of differences in overall survival of patients according to transcript type. To overcome potential power problems, overall survival (OS) probabilities and probabilities of CML-related death were analyzed in 1494 patients randomized to first-line imatinib treatment.

Methods

OS probabilities and probabilities of dying of CML were compared using the log-rank or Gray test whichever was appropriate. Both tests were stratified for the EUTOS long-term survival score.

Results

Between the groups with a single transcript, neither OS probabilities (stratified log-rank test: p = 0.106) nor probabilities of CML-related death were significantly different (stratified Gray test: p = 0.256). Regarding OS, the Cox hazard ratio (HR) of transcript type e13a2 (n = 565) to type e14a2 (n = 738) was 1.332 (95% CI 0.940–1.887). Considering probabilities of leukemia-related death, the corresponding subdistribution HR resulted in 1.284 (95% CI 0.758–2.176). Outcome did not change if patients with both transcripts (n = 191) were added to the 738 with type e14a2 only.

Conclusions

The prognostic association of transcript type and long-term survival outcome was weak and without clinical relevance. However, earlier reported differences in the rate and the depth of molecular response could be relevant for the chance of successfully discontinuing TKI treatment. The effect of transcript type on molecular relapse after discontinuation is unknown, yet.

Keywords

Chronic myeloid leukemia Overall survival Probabilities of CML-related death BCR-ABL1 transcript type Prognosis 

Notes

Acknowledgements

The valuable assistance of Annett Schmitt and Kirsi Manz is gratefully appreciated. The EUTOS was a common project of the European LeukemiaNet and Novartis Oncology Europe. Novartis Oncology Europe provided financial support for the EUTOS project between 2007 and 2015. This publication is the sole responsibility of the authors, who have complete access to the data.

Compliance with ethical standards

Conflict of interest

The EUTOS project was started as a common enterprise of the European LeukemiaNet and Novartis Oncology Europe. Novartis Oncology Europe provided financial support for the EUTOS project between 2007 and 2015. Susanne Saussele received honoraria from Novartis, Bristol-Myers Squibb, Pfizer, and ARIAD as well as research support from Novartis and Bristol-Myers Squibb. Fausto Castagnetti both received honoraria from and acted as a consultant for Novartis, Bristol-Myers Squibb, Incyte, and Pfizer. Francisco Cervantes was part of the advisory board of Novartis, ARIAD, and Pfizer and of the speaker’s bureau of Novartis, Bristol-Myers Squibb, ARIAD, and Pfizer. Jeroen Janssen declared speaker’s fees from Bristol-Myers Squibb and Pfizer and was part of the advisory board of ARIAD. Jeroen Janssen also received research funding from Novartis. Gabriele Gugliotta reported speaker’s fees from Novartis and Bristol-Myers Squibb. Andreas Hochhaus received research support by Novartis, BMS, Pfizer, and ARIAD. Michele Baccarani acted as a consultant for and received speaker’s fee from Novartis, Bristol-Myers Squibb, ARIAD, and Pfizer. Markus Pfirrmann, Dobromira Evtimova, Verena S. Hoffmann, Rüdiger Hehlmann, and Joerg Hasford declare no conflict of interest.

Ethical approval

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. All studies were approved by the local human investigations committee and performed in accordance with the legal requirements of the corresponding country. Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Markus Pfirrmann
    • 1
    Email author
  • Dobromira Evtimova
    • 1
  • Susanne Saussele
    • 2
  • Fausto Castagnetti
    • 3
  • Francisco Cervantes
    • 4
  • Jeroen Janssen
    • 5
  • Verena S. Hoffmann
    • 1
  • Gabriele Gugliotta
    • 3
  • Rüdiger Hehlmann
    • 2
  • Andreas Hochhaus
    • 6
  • Joerg Hasford
    • 1
  • Michele Baccarani
    • 3
  1. 1.Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE)Ludwig-Maximilians UniversitätMunichGermany
  2. 2.III. Medizinische KlinikUniversitätsmedizin Mannheim, Medizinische Fakultät Mannheim der Universität HeidelbergMannheimGermany
  3. 3.Institute of Hematology and Oncology “L. and A. Seràgnoli”, S. Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly
  4. 4.Hematology Department, Hospital Clinic, IDIBAPSUniversity of BarcelonaBarcelonaSpain
  5. 5.Department of HematologyVU University Medical CenterAmsterdamThe Netherlands
  6. 6.Klinik für Innere Medizin II, Hematology/OncologyUniversitätsklinikum JenaJenaGermany

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