title: ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases.
abstract: The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.
authors.affiliation: Division of Medical Support, Okayama University Hospital, Okayama, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Aoe
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Michiko
authors.initials: M
authors.lastname: Muraoka
authors.forename: Kana
authors.initials: K
authors.lastname: Washio
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takahide
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masahide
authors.initials: M
authors.lastname: Imada
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Ken
authors.initials: K
authors.lastname: Okada
authors.forename: Ritsuo
authors.initials: R
authors.lastname: Nishiuchi
authors.forename: Takako
authors.initials: T
authors.lastname: Miyamura
authors.forename: Kosuke
authors.initials: K
authors.lastname: Chayama
authors.forename: Misako
authors.initials: M
authors.lastname: Shibakura
authors.forename: Megumi
authors.initials: M
authors.lastname: Oda
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Morishima
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl