A multicentre, open, non‐comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony‐stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation

Abstract

Summary. The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course.Median survival times were 1´4 years, 3 months and 1´6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Stem cell transplantation after salvage therapy with high-dose cytarabine and amsacrine in adults with high-risk leukaemia

“…Recent interest has focused on the use of FLAG, with CR rates of up to 48% in patients with relapsed and refractory AML and de novo RAEB-t reported in a large series. 18 In patients with HR-ALL, the observed response rates of up to 67% with Ara-amsa are comparable to those reported with the use of multiphase reinduction salvage regimens in patients with relapsed or refractory ALL (62%). 19 Our remission rates are less impressive than those reported by Martino et al 20,21 (78% CR) with the use of a combination chemotherapy (intermediate-dose Ara-C, vindesine, mitoxantrone, cyclophosphamide, prednisolone and methotrexate).…”

Cell proliferation is related to in vitro drug resistance in childhood acute leukaemia

“…Several studies have indeed demonstrated that the in vitro sensitivity to cytarabine of AML cells could be enhanced by preincubation with granulocyte colony-stimulating factor (G-CSF) and/or with granulocyte -macrophage colony-stimulating factor (GM-CSF) (Butturini et al, 1990;Bai et al, 1999). Clinically, pretreatment with G-CSF (as in the FLAG regimen, which is a combination therapy of fludarabine, cytarabine, and G-CSF), seems to be effective and well tolerated in the treatment of poorrisk AML patients (Montillo et al, 1998;Jackson et al, 2001). The efficacy of this therapy, however, has not yet been determined in a controlled, randomised clinical study.…”

Retrospective comparison of clofarabine versus fludarabine in combination with high-dose cytarabine with or without granulocyte colony-stimulating factor as salvage therapies for acute myeloid leukemia

“…1 GCLAC was similar to the FLAG regimen (fludarabine, cytarabine (ara-C) and G-CSF priming), [2][3][4][5][6][7][8][9] with clofarabine substituted for fludarabine. Metabolism of both compounds to their triphosphates may increase synthesis of the triphosphate of ara-C (ara-CTP).…”