MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure.
In the face of competing tyrosine kinase inhibitors (TKIs), identification of chronic myeloid leukemia (CML) patients expecting favorable response to second-line treatment is warranted. At the time of imatinib resistance, the investigation of multidrug-resistance protein 1 (MDR1) and BCR-ABL yielded the following results: (i) Patients with high MDR1 transcript levels showed superior response at 48 months as compared with low-level MDR1 patients: major molecular response (MMR) in 41% vs 16% (P=0.014), complete cytogenetic response (CCyR) in 58% vs 39% (P=0.044), and progression-free survival (PFS) in 67% vs 46% (P=0.032). (ii) Patients with BCR-ABL(IS) <28% achieved higher MMR rates (48% vs 21%, P=0.009). (iii) PFS at 48 months was associated with in vitro resistance of BCR-ABL kinase domain mutations: 63% (no mutation) vs 61% (sensitive, intermediately sensitive or unknown IC50 (median inhibitory concentration)) vs 23% (resistant, P=0.01). (iv) Single-nucleotide polymorphisms (SNPs) at positions 1236 and 2677 were associated with higher MDR1 expression in comparison to wild type. (v) Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment.
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Agrawal
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Hanfstein
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Erben
Medizinische Klinik III, Onkologie, Hämatologie und Rheumatologie, Universitätsklinikum Bonn (UKB), Bonn, Germany.
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Wolf
Abteilung für Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
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Ernst
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Fabarius
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Saussele
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
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Purkayastha
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
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Woodman
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Hofmann
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Hehlmann
Abteilung für Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany.
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Hochhaus
III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
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Müller
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D034622:RNA Interference; D017211:Treatment Failure; D016896:Treatment Outcome
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib