Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts. Recommendations by the EUTOS cooperative network
Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts. Recommendations by the EUTOS cooperative network
Purpose: Approximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. Methods: BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). Results: In total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Conclusions: Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.
Atypical transcripts, BCR-ABL1, CML, Chronic myeloid leukemia, Molecular monitoring
3081-3089
Schafer, Vivien
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White, Helen
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Gerrard, Gareth
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Mobius, Susanne
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Saussele, Susanne
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Franke, Georg-Nikolaus
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Mahon, Francois X.
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Talmaci, R.
3777adf3-77a9-4a40-afb2-7002c7ad3232
Colomer, Dolors
d98d3237-a7a3-4041-804e-e628892ed687
Soverini, Simona
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Machova-Polakova, Katerina
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Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Ernst, Thomas
96c7805b-c900-4545-9f93-1a83d789cb56
October 2021
Schafer, Vivien
024abf1c-1373-4907-bfe2-794f49044782
White, Helen
2181c0b9-fc3b-407e-95eb-3510524603e5
Gerrard, Gareth
89840fdd-6955-4565-9c75-e6ca296cce30
Mobius, Susanne
6102e263-b8bb-4830-a697-71b573b2186f
Saussele, Susanne
d0f4f232-38a3-4552-83d5-371f95ceac8d
Franke, Georg-Nikolaus
3f9dfe04-b94b-493d-bf62-b3281792a83d
Mahon, Francois X.
ecd1e479-605a-415e-bf53-4b4788206471
Talmaci, R.
3777adf3-77a9-4a40-afb2-7002c7ad3232
Colomer, Dolors
d98d3237-a7a3-4041-804e-e628892ed687
Soverini, Simona
a43c135a-5658-4429-93dc-1855227574a1
Machova-Polakova, Katerina
4e060d78-afa5-47a4-808f-d1fdffe66518
Cross, Nicholas
f87650da-b908-4a34-b31b-d62c5f186fe4
Hochhaus, Andreas
b37b9b7d-85ff-455e-994d-fcc2adf94088
Ernst, Thomas
96c7805b-c900-4545-9f93-1a83d789cb56
Schafer, Vivien, White, Helen, Gerrard, Gareth, Mobius, Susanne, Saussele, Susanne, Franke, Georg-Nikolaus, Mahon, Francois X., Talmaci, R., Colomer, Dolors, Soverini, Simona, Machova-Polakova, Katerina, Cross, Nicholas, Hochhaus, Andreas and Ernst, Thomas
(2021)
Assessment of individual molecular response in chronic myeloid leukemia patients with atypical BCR-ABL1 fusion transcripts. Recommendations by the EUTOS cooperative network.
Journal of Experimental and Clinical Cancer Research, 147 (10), .
(doi:10.1007/s00432-021-03569-8).
Abstract
Purpose: Approximately 1–2% of chronic myeloid leukemia (CML) patients harbor atypical BCR-ABL1 transcripts that cannot be monitored by real-time quantitative PCR (RT-qPCR) using standard methodologies. Within the European Treatment and Outcome Study (EUTOS) for CML we established and validated robust RT-qPCR methods for these patients. Methods: BCR-ABL1 transcripts were amplified and sequenced to characterize the underlying fusion. Residual disease monitoring was carried out by RT-qPCR with specific primers and probes using serial dilutions of appropriate BCR-ABL1 and GUSB plasmid DNA calibrators. Results were expressed as log reduction of the BCR-ABL1/GUSB ratio relative to the patient-specific baseline value and evaluated as an individual molecular response (IMR). Results: In total, 330 blood samples (2–34 per patient, median 8) from 33 CML patients (19 male, median age 62 years) were analyzed. Patients expressed seven different atypical BCR-ABL1 transcripts (e1a2, n = 6; e6a2, n = 1; e8a2, n = 2; e13a3, n = 4; e14a3, n = 6; e13a3/e14a3, n = 2; e19a2, n = 12). Most patients (61%) responded well to TKI therapy and achieved an IMR of at least one log reduction 3 months after diagnosis. Four patients relapsed with a significant increase of BCR-ABL1/GUSB ratios. Conclusions: Characterization of atypical BCR-ABL1 transcripts is essential for adequate patient monitoring and to avoid false-negative results. The results cannot be expressed on the International Scale (IS) and thus the common molecular milestones and guidelines for treatment are difficult to apply. We, therefore, suggest reporting IMR levels in these cases as a time-dependent log reduction of BCR-ABL1 transcript levels compared to baseline prior to therapy.
Text
JOCR Ernst
- Accepted Manuscript
More information
Accepted/In Press date: 12 February 2021
e-pub ahead of print date: 7 March 2021
Published date: October 2021
Additional Information:
© 2021. The Author(s).
Keywords:
Atypical transcripts, BCR-ABL1, CML, Chronic myeloid leukemia, Molecular monitoring
Identifiers
Local EPrints ID: 447062
URI: http://eprints.soton.ac.uk/id/eprint/447062
ISSN: 0392-9078
PURE UUID: d00a1117-779a-4cf5-aa62-f1b9e31b269f
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Date deposited: 02 Mar 2021 17:32
Last modified: 17 Mar 2024 02:54
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Contributors
Author:
Vivien Schafer
Author:
Helen White
Author:
Gareth Gerrard
Author:
Susanne Mobius
Author:
Susanne Saussele
Author:
Georg-Nikolaus Franke
Author:
Francois X. Mahon
Author:
R. Talmaci
Author:
Dolors Colomer
Author:
Simona Soverini
Author:
Katerina Machova-Polakova
Author:
Andreas Hochhaus
Author:
Thomas Ernst
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