title: Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study.
abstract: The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
authors.affiliation: Adult Leukemia Service, Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: J E
authors.initials: JE
authors.lastname: Karp
authors.forename: P J
authors.initials: PJ
authors.lastname: Burke
authors.forename: S D
authors.initials: SD
authors.lastname: Gore
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D003630:Daunorubicin / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D003630:Daunorubicin