Abstract
Residual leukemia is demonstrable by reverse transcriptase-polymerase chain reaction in most patients with chronic myeloid leukemia who obtain a complete cytogenetic response (CCR) to imatinib. In patients who relapse during imatinib therapy, a high rate of mutations in the kinase domain of BCR-ABL have been identified, but the mechanisms underlying disease persistence in patients with a CCR are poorly characterized. To test whether kinase domain mutations are a common mechanism of disease persistence, we studied patients in stable CCR. Mutations were demonstrated in eight of 42 (19%) patients with successful amplification and sequencing of BCR-ABL. Mutation types were those commonly associated with acquired drug resistance. Four patients with mutations had a concomitant rise of BCR-ABL transcript levels, two of whom subsequently relapsed; the remaining four did not have an increase in transcript levels and follow-up samples, when amplifiable, were wild type. BCR-ABL-kinase domain mutations in patients with a stable CCR are infrequent, and their detection does not consistently predict relapse. Alternative mechanisms must be responsible for disease persistence in the majority of patients.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzamides
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Chromatography, High Pressure Liquid
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Codon / genetics
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DNA Mutational Analysis
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DNA, Neoplasm / genetics
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Drug Resistance, Neoplasm / genetics*
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Female
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Follow-Up Studies
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Fusion Proteins, bcr-abl / genetics*
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Fusion Proteins, bcr-abl / physiology
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Humans
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Imatinib Mesylate
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Male
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Middle Aged
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Mutant Proteins / genetics
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Mutant Proteins / physiology*
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Mutation*
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Piperazines / pharmacology*
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Piperazines / therapeutic use
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Structure, Tertiary / genetics
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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RNA, Messenger / genetics
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RNA, Neoplasm / genetics
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Remission Induction
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Reverse Transcriptase Polymerase Chain Reaction
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Treatment Refusal
Substances
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Antineoplastic Agents
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Benzamides
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Codon
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DNA, Neoplasm
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Mutant Proteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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RNA, Messenger
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RNA, Neoplasm
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Imatinib Mesylate
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Fusion Proteins, bcr-abl