FLAG (Fludarabine, Cytarabine, G‐CSF) as a second line therapy for acute lymphoblastic leukemia with myeloid antigen expression: in vitro and in vivo effects

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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 0 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 × 109/l was 16.3 d (range 13–22) and 16.2 d (range 9–29) to platelets>20 × 109/l. 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.

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