RESUMO
Patients with primary hypereosinophilic disorders who are positive for the FIP1L1-PDGFRA fusion gene mutation are highly responsive to therapy with imatinib mesylate. A 35-year-old man with FIP1L1-PDGFRA positive hypereosinophilic syndrome and cardiac involvement, was treated with imatinib 100 mg daily. Hematologic and molecular remission and reversal of end-organ damage was achieved. He was then lost to follow up for 19 months. Imatinib successfully reinduced hematologic and molecular remission but worsening cardiac involvement was not reversed. Our experience and a review of limited literature suggest that imatinib maintenance therapy is necessary despite molecular remission of the FIP1L1-PDGFRA mutation.
Assuntos
Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Adulto , Benzamidas , Humanos , Mesilato de Imatinib , Masculino , Mutação , Piperazinas , Pirimidinas , Indução de RemissãoAssuntos
Antineoplásicos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Masculino , Niacinamida/administração & dosagem , Sorafenibe , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.