title: Two groups of Philadelphia chromosome-positive childhood acute lymphoblastic leukemia classified by pretreatment multidrug sensitivity or resistance in in vitro testing.
abstract: The development of effective chemotherapy is imperative for children with Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) because of the poor prognosis of this condition. Initial cellular drug resistance is thought to be an important cause of induction failure and early relapse. We carried out in vitro tests using a methyl-thiazol-tetrazolium assay on bone marrow samples from 274 children with newly diagnosed ALL. Sixteen children (5.8%) had Ph-positive results of cytogenetic analysis. We examined in vitro drug resistance to 14 agents and found that leukemic cells in Ph ALL were significantly more resistant than were cells in non-Ph ALL to melphalan, bleomycin, etoposide, mitoxantrone, L-asparaginase, and vinblastine. With the prednisolone, L-asparaginase, and vincristine (PAV) combination of drugs, 10 of the 16 Ph patients with ALL (62.5%) showed relative resistance (RR) (sensitivity to only 1 or to none of the 3 drugs) at initiation of treatment. These 10 patients experienced significantly poorer event-free survival (EFS) than did the 6 patients with supersensitivity (SS) (defined as sensitivity to all 3 or to 2 of the 3 drugs, P = .019). Leukemic cells from RR patients were found to be multiresistant to 12 drugs with 2.0- to 58.4-fold RR compared with cells from SS patients. This PAV sensitivity delineates initially sensitive and resistant groups. Of these, the SS subgroup of Ph ALL patients may be curable with chemotherapy and stem cell transplantation. For EFS improvement in the RR group, it may be necessary to use a new chemotherapy approach from initiation.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Japan. hongot@hama-med.ac.jp
authors.forename: Teruaki
authors.initials: T
authors.lastname: Hongo
authors.forename: Shuichi
authors.initials: S
authors.lastname: Okada
authors.forename: Noriko
authors.initials: N
authors.lastname: Inoue
authors.forename: Sayuri
authors.initials: S
authors.lastname: Yamada
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yajima
authors.forename: Chieko
authors.initials: C
authors.lastname: Watanabe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fujii
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horikoshi
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents