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Clin Cancer Res. 2017 Dec 1;23(23):7189-7198. doi: 10.1158/1078-0432.CCR-17-0962. Epub 2017 Sep 19.

High BCR-ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib.

Author information

1
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy. pvigneri@libero.it.
2
Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy.
3
Division of Hematology and Bone Marrow Transplant, University of Catania, Catania, Italy.
4
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
5
Mediterranean Institute of Oncology, Viagrande, Italy.
6
Department of Transfusional Medicine, Maria Paternò-Arezzo Hospital, Ragusa, Italy.
7
Division of Hematology, A.O.U. Policlinico "P. Giaccone," University of Palermo, Palermo, Italy.
8
Division of Hematology, Papardo Hospital, Messina, Italy.
9
Division of Oncology and Hematology, ARNAS Garibaldi-Nesima, Catania, Italy.
10
Division of Hematology, University of Messina, Messina, Italy.
11
Division of Hematology, Cervello Hospital, Palermo, Italy.
12
Division of Hematology, San Vincenzo Hospital, Taormina, Italy.
13
Division of Hematology, Civico Hospital, Palermo, Italy.
14
Division of Hematology, Sant'Elia Hospital, Caltanissetta, Italy.
15
Division of Hematology, La Maddalena Hospital, Palermo, Italy.
16
Division of Hematology, Cosenza, Italy.
17
Division of Hematology, Catanzaro, Italy.
18
Division of Hematology, Reggio Calabria, Italy.
19
Medizinische Fakultät Mannheim, Universität Heidelberg, and Institute for Hematology and Oncology Mannheim, Germany.
20
Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
21
Department of Surgery, Medical and Surgical Specialties, University of Catania, Catania, Italy.

Abstract

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.

PMID:
28928163
DOI:
10.1158/1078-0432.CCR-17-0962
[Indexed for MEDLINE]
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