A Multicentre, Randomized Study of FLAG Treatment in China(CHORT).

Introduction: Adult de novo patients with acute myeloid leukemia (AML) may achieve 70%-80% of clinical remission after induction treatment, but unfortunately some proportion of them will get relapse, and the prognosis in these patients is quite poor. Clinicians have been devoted themselves to exploring new effective strategies to re-induce remission in these kind of population including FLAG, which containing fludarabine, cytosine arabinoside (Ara-C), plus granulocyte colony-stimulating factor (G-CSF). FLAG was proved to be one of the most effective salvage treatments in relapsed or refractory AML patients. Our study was designed to assess the efficacy and safety of FLAG in Chinese AML patients and further to compare the clinical efficacy and safety between different dosage of Ara-C in FLAG treatment.

Methods: This is multicentre, open-label, randomized clinical trial. Relapsed or refractory non-M₃ AML patients were randomly assigned to 2 treatment group. Group A: 30mg/m²/d of fludarabine intravenous infusion through d1-d5, plus G-CSF 300μg/d, starting 24 hours before treatment and continuing to d5, 1.0g/m² of Ara-C intravenously infusion from day 1 through 5, abbreviated as FLAG 1.0. Group B: fludarabine and G-CSF were used as same as those in Group A, but dosage of Ara-C increased to 2.0g/m² daily from d1-d5, named as FLAG 2.0.

Results: Between 2006 and 2008, 398 cases of patients from 72 medical centers in China were enrolled into the study with informed consent. 177 cases were entered into analysis, with median age of 39 yrs (range 16–80) and male: female ratio of 1.7:1. 97 cases were assigned into FLAG 1.0 whereas 80 in FLAG 2.0. 73 (41.7%) of patients were diagnosed as M₂, 33(18.9%) in M₄, 33 (18.9%) in M₅, and the other 38 in other subtype of leukemia. And 52/177 cases (29.4%) were in first relapse, while 51 (28.8%) in multi-relapse and 74 (41.8%) in refractory disease. Totally 120 out of 177 patients achieved response remission (67.8%) including 88 (49.7%) in complete remission (CR) and 32 (18.1%) in partial remission (PR). 18 cases (10.2%) had stable disease, 20 (11.3%) had progressive disease, 10 (5.6%) in non-response, and 9 cases died. Among these 9 cases, 8 suffered from serious infection and fatal bleeding during bone marrow suppression and another 1 died due to psychological obstacles. The main side effect during treatment were neutropenia (77.4%, with neutrophil ≤ 0.5×10⁹/L ) , thrombocytopenia (73.4%, with platelet count ≤ 50×10⁹/L), nausea and vomiting (41.8%), and infection (54.8%), but most of them were moderate and the patients got recovery by using supportive treatment. Patients in first relapse had better RR (81.2%) when compared to those in multi-relapse or in refractory disease (55.8% and 64.8%, p=0.004). And, M₂ patients had higher RR (76.8%) than those in M₄ (58.9%) and similar to the response in M₅ patients (76.5%). More of interest, among 80 patients who received FLAG 2.0 treatment, 42 (52.5%) achieved CR, while 45 out of 97 (46%) got CR in FLAG 1.0. And most important, the side effect including the hematological or non-hematological toxicities were comparable between two groups except the neutropenia (82.8%: 71%, p=0.019) and oral ulcer (27.5%:15%, p<0.001).

Conclusion: FLAG was proven to have good clinical efficacy in refractory or relapsed Chinese AML patients with well tolerated toxicities. Enhanced Ara-C dosage (FLAG 2.0) had better clinical response although it didn’t reach to the statistical difference, with comparable and manageable side effects, when compared to those in FLAG1.0 treatment. Long-term follow-up were warranted to properly evaluate the efficacy of FLAG treatment, and to compare the therapeutic benefit between FLAG 1.0 and FLAG 2.0 treatment in these relapsed or refractory AML patients.