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Cancer Therapy: Clinical

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

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 and Francesco Di Raimondo
Paolo Vigneri
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy.
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  • For correspondence: pvigneri@libero.it
Fabio Stagno
Division of Hematology and Bone Marrow Transplant, University of Catania, Catania, Italy.
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Stefania Stella
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy.
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Alessandra Cupri
Division of Hematology and Bone Marrow Transplant, University of Catania, Catania, Italy.
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Stefano Forte
Mediterranean Institute of Oncology, Viagrande, Italy.
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Michele Massimino
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy.
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Agostino Antolino
Department of Transfusional Medicine, Maria Paternò-Arezzo Hospital, Ragusa, Italy.
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Sergio Siragusa
Division of Hematology, A.O.U. Policlinico “P. Giaccone,” University of Palermo, Palermo, Italy.
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Donato Mannina
Division of Hematology, Papardo Hospital, Messina, Italy.
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Stefana Stella Impera
Division of Oncology and Hematology, ARNAS Garibaldi-Nesima, Catania, Italy.
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Caterina Musolino
Division of Hematology, University of Messina, Messina, Italy.
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Alessandra Malato
Division of Hematology, Cervello Hospital, Palermo, Italy.
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Giuseppe Mineo
Division of Hematology, San Vincenzo Hospital, Taormina, Italy.
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Carmela Tomaselli
Division of Hematology, Civico Hospital, Palermo, Italy.
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Pamela Murgano
Division of Hematology, Sant'Elia Hospital, Caltanissetta, Italy.
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Maurizio Musso
Division of Hematology, La Maddalena Hospital, Palermo, Italy.
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Fortunato Morabito
Division of Hematology, Cosenza, Italy.
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Stefano Molica
Division of Hematology, Catanzaro, Italy.
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Bruno Martino
Division of Hematology, Reggio Calabria, Italy.
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Livia Manzella
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, Catania, Italy.
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Martin C. Müller
Medizinische Fakultät Mannheim, Universität Heidelberg, and Institute for Hematology and Oncology Mannheim, Germany.
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Andreas Hochhaus
Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
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Francesco Di Raimondo
Division of Hematology and Bone Marrow Transplant, University of Catania, Catania, Italy.Department of Surgery, Medical and Surgical Specialties, University of Catania, Catania, Italy.
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DOI: 10.1158/1078-0432.CCR-17-0962
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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); 1–10. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received April 1, 2017.
  • Revision received July 28, 2017.
  • Accepted September 13, 2017.
  • ©2017 American Association for Cancer Research.

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Published OnlineFirst November 13, 2017
doi: 10.1158/1078-0432.CCR-17-0962

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High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib
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 and Francesco Di Raimondo
Clin Cancer Res November 13 2017 DOI: 10.1158/1078-0432.CCR-17-0962

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High BCR–ABL/GUSIS Levels at Diagnosis of Chronic Phase CML Are Associated with Unfavorable Responses to Standard-Dose Imatinib
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 and Francesco Di Raimondo
Clin Cancer Res November 13 2017 DOI: 10.1158/1078-0432.CCR-17-0962
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Clinical Cancer Research
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