Treatment of acute myeloid leukemia carrying inv(2)(p23q13)/<i>RANBP2-ALK</i><i> </i>with crizotinib and the mechanism of resistance to the drug

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  • <i>RANBP2-ALK </i>急性骨髄性白血病に対するクリゾチニブの治療効果と耐性メカニズム

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A 75-year-old woman with acute myeloid leukemia (AML), who carried the inv(2)(p23q13)/RANBP2- ALK fusion gene and monosomy 7 and exhibited nuclear membrane expression of ALK protein, showed florid relapse of AML. Fluorescence in situ hybridization (FISH) of a bone marrow smear slide using an ALK break-apart probe revealed that over 80% of the cells had ALK rearrangement. We obtained her written consent and treated her with crizotinib, an inhibitor of ALK tyrosine kinase. Leukemia cells in the blood rapidly disappeared and ALK rearrangement-positive cells identified by FISH in the bone marrow decreased below the cut-off level. The response at 3 months of crizotinib treatment was comparable to the definition of complete remission (CR) of AML. On day 135 of treatment, however, her AML relapsed. G-banded karyotyping revealed del(1)(p13p22) in addition to inv(2) and −7 after crizotinib. The ALK gene carried the heterozygous mutation c.3806G>C within exon 25, causing p.G1269A amino acid substitution within the kinase domain of ALK. As both del(1)(p13p22) at the cytogenetic level and G1269A at the nucleotide level newly appeared after crizotinib treatment, it is likely that they were secondarily acquired alterations involved in crizotinib resistance. Although the initial response to crizotinib was marked, crizotinib alone was not capable of producing a long-term response. We should have performed consolidating chemotherapy using conventional cytotoxic drugs immediately after the achievement of CR by crizotinib.

Journal

  • Tenri Medical Bulletin

    Tenri Medical Bulletin 18 (2), 80-85, 2015

    Tenri Foundation, Tenri Institute of Medical Research

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