title: FLAG (fludarabine, cytarabine, G-CSF) as a second line therapy for acute lymphoblastic leukemia with myeloid antigen expression: in vitro and in vivo effects.
abstract: Thirteen consecutive adult patients with primary refractory (n = 5) or relapsed (n = 8) acute lymphoblastic leukemia (ALL) were treated by an induction schedule (FLAG) consisting of Fludarabine (30 mg/sqm/d) plus high dose Cytarabine (HD-ara-C: 2 g/sqm/d) (d 1-5) and G-CSF (from d O to polymorphonuclear recovery). Patients achieving complete remission (CR) were administered a second FLAG course as consolidation and were then submitted to an individualized program of post-remission therapy, depending on the patient's age and performance status. CR was achieved in 8/12 evaluable cases (67%). The median CR duration was 22.5 w. CR attainment was significantly related to the co-expression of lymphoid and myeloid antigens. ALL/My+ patients achieved CR in 6/6 evaluable cases vs. 2/6 for ALL/My+. In vitro 3H ara-C incorporation into cellular DNA resulted significantly increased by Fludarabine (in 7/9 tested cases) and, furthermore, by the association of Fludarabine G-CSF in 5 evaluable ALL/My+ cases; in contrast, no effect of G-CSF addition to Fludarabine was observed in 4 ALL/My. Myelosuppression was observed in all patients: the median time to neutrophils > 0.5 x 10(9)/1 was 16.3 d (range 13-22) and 16.2 d (range 9-29) to platelets > 20 x 10(9)/1. Nonhematological toxicity was minimal. In conclusion, FLAG is an active and tolerable combination in refractory ALL, particularly in cases with myeloid antigen expression where G-CSF appears to improve efficacy, probably increasing ara-C incorporation into the DNA of leukemic cells.
authors.affiliation: Institute of Hematology, University of Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Visani
authors.forename: P
authors.initials: P
authors.lastname: Tosi
authors.forename: P L
authors.initials: PL
authors.lastname: Zinzani
authors.forename: S
authors.initials: S
authors.lastname: Manfroi
authors.forename: E
authors.initials: E
authors.lastname: Ottaviani
authors.forename: A
authors.initials: A
authors.lastname: Cenacchi
authors.forename: P
authors.initials: P
authors.lastname: Carrara
authors.forename: M
authors.initials: M
authors.lastname: Clavio
authors.forename: M
authors.initials: M
authors.lastname: Gobbi
authors.forename: S
authors.initials: S
authors.lastname: Tura
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000032:analysis / Q000096:biosynthesis*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003231:Conjunctivitis / Q000139:chemically induced / Q000517:prevention & control; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology*; D012074:Remission Induction; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000951:Antigens, Neoplasm; D005938:Glucocorticoids; D009883:Ophthalmic Solutions; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D014740:Vidarabine