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