High BCR-ABL/GUS-IS levels at diagnosis of chronic phase CML are associated with unfavorable responses to standard-dose imatinib
Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. Experimental Design: We correlated BCR-ABL/GUSIS an...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
September 19,2017
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| In: |
Clinical cancer research
Year: 2017, Volume: 23, Issue: 23, Pages: 7189-7198 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-17-0962 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1158/1078-0432.CCR-17-0962 Verlag, Volltext: http://clincancerres.aacrjournals.org/content/23/23/7189 
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| Author Notes: | Paolo Vigneri, Fabio Stagno, Stefania Stella, Alessandra Cupri, Stefano Forte, Michele Massimino, Agostino Antolino, Sergio Siragusa, Donato Mannina, Stefana Stella Impera, Caterina Musolino, Alessandra Malato, Giuseppe Mineo, Carmela Tomaselli, Pamela Murgano, Maurizio Musso, Fortunato Morabito, Stefano Molica, Bruno Martino, Livia Manzella, Martin C. Müller, Andreas Hochhaus, Francesco Di Raimondo |
| Summary: | Purpose: The approval of second-generation tyrosine kinase inhibitors (TKIs) for the first-line treatment of chronic myeloid leukemia (CML) has generated an unmet need for baseline molecular parameters associated with inadequate imatinib responses. Experimental Design: We correlated BCR-ABL/GUSIS and BCR-ABL/ABL transcripts at diagnosis with the outcome—defined by the 2013 European LeukemiaNet recommendations—of 272 patients newly diagnosed with CML receiving imatinib 400 mg/daily. Applying receiver-operating characteristic curves, we defined BCR-ABL/GUSIS and BCR-ABL/ABL levels associated with lower probabilities of optimal response, failure-free (FFS), event-free (EFS), transformation-free (TFS), and overall survival (OS). Results: With a median follow-up of 60 months, 65.4% of patients achieved an optimal response (OR), 5.6% were classified as “warnings,” 22.4% failed imatinib, and 6.6% switched to a different TKI because of drug intolerance. We recorded 19 deaths (6.9%), seven (2.5%) attributable to disease progression. We found that higher BCR-ABL/GUSIS levels at diagnosis were associated with inferior rates of OR (P < 0.001), FFS (P < 0.001), and EFS (P < 0.001). Elevated BCR-ABL/GUSIS levels were also associated with lower rates of TFS (P = 0.029) but not with OS (P = 0.132). Similarly, high BCR-ABL/ABL levels at diagnosis were associated with inferior rates of OR (P = 0.03), FFS (P = 0.001), and EFS (P = 0.005), but not with TFS (P = 0.167) or OS (P = 0.052). However, in internal validation experiments, GUS outperformed ABL in samples collected at diagnosis as the latter produced 80% misclassification rates. Conclusions: Our data suggest that high BCR-ABL transcripts at diagnosis measured using GUS as a reference gene identify patients with CML unlikely to benefit from standard-dose imatinib. Clin Cancer Res; 23(23); 7189-98. ©2017 AACR. |
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| Item Description: | Published first September 19, 2017 IS ist im Titel hochgestellt Gesehen am 17.09.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-17-0962 |