title: In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia.
abstract: It is vital to develop effective therapy for children with acute lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer relapse with current protocols. Cellular drug resistance is thought to be an important cause of induction failure and relapse. We performed in vitro tests of bone marrow samples in 196 children with newly diagnosed ALL with a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic cell survival (LCS) rate for dexamethasone and prednisolone. For each single drug, patients were classified into two groups, sensitive or resistant, by median concentration of LD70 or LCS. When patients were classified into three groups by sensitivity to four drugs of DPAV (dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year event-free survival (EFS; 95% confidence intervals) of the super sensitive group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735 (0.609 to 0.863), and that of the relatively resistant group (RR; sensitive to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then investigated the relationship between the above four-drug sensitivity and the time of relapse. The SS and IS patients tended to maintain continuous complete remission, and RR patients tended to undergo induction failure and early and late relapse (P = .004). Initial white blood cell count, immunologic classification, and age were also predictive factors, but the patient numbers showed no statistical correlation between these factors and the four-drug sensitivity groups (SS, IS, and RR). When we took three groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In vitro drug sensitivity testing provides additional prognostic information about childhood ALL, and early detection of drug resistance at the time chemotherapy commences may provide a successful strategy for individualizing treatment, as the results indicate de novo resistance to front-line drugs and suggest alternative, second-line drugs.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hongo
authors.forename: S
authors.initials: S
authors.lastname: Yajima
authors.forename: M
authors.initials: M
authors.lastname: Sakurai
authors.forename: Y
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: R
authors.initials: R
authors.lastname: Hanada
mesh_terms: D015250:Aclarubicin / Q000008:administration & dosage / Q000494:pharmacology; D000293:Adolescent; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000494:pharmacology; D001761:Bleomycin / Q000008:administration & dosage / Q000494:pharmacology; D001853:Bone Marrow / Q000473:pathology; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology; D003630:Daunorubicin / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015993:Life Tables; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology; D008942:Mitoxantrone / Q000008:administration & dosage / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D011239:Prednisolone / Q000008:administration & dosage / Q000494:pharmacology; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D003561:Cytarabine; D001761:Bleomycin; D016685:Mitomycin; D014750:Vincristine; D005047:Etoposide; D015250:Aclarubicin; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone; D008942:Mitoxantrone; C027260:pirarubicin; D001215:Asparaginase; D008558:Melphalan; C011272:perfosfamide; D008727:Methotrexate; D003630:Daunorubicin