Effect of Priming with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in Younger Adults with Newly Diagnosed Acute Myeloid Leukemia (AML): A Trial by the Acute Leukemia French Association (ALFA) Group.

Sensitization of leukemic cells with GM-CSF may enhance the cytotoxicity of chemotherapy in younger adults with newly diagnosed AML. In a multicenter randomized trial, 259 patients (median age, 27 years; 15–50) were randomized at baseline to receive a timed sequential induction regimen (DNR 80mg/m²/d d1-3, AraC 500mg/m²/d d1-3 and 500mg/m²/12h d8-10, Mitox 12mg/m²/d d8-9) either without (135 patients) or with GM-CSF (124 patients) administered i.v. at 5μg/kg/d from day 1 to day 10. Patients reaching CR (eventually after salvage therapy combining AraC 3g/m²/12h d1,3,5,7 and Amsa 100mg/m²/d d1-3) and not eligible for allogeneic transplantation in CR1 were then randomized to compare the ALFA-9000 consolidation (Mitox 12mg/m²/d d1-3, VP16 200mg/m²/d d8-10, AraC 500mg/m²/d d1-3,8-10) (Castaigne et al., Blood 2004) to the CALGB postremission chemotherapy, which includes 4 cycles of HD-AraC (3g/m²/12h d1,3,5) followed by 4 additional DNR/AraC courses (Mayer et al, N Engl J Med 1994). Patients initially randomized in the GM-CSF arm received GM-CSF concurrently with chemotherapy during all cycles of consolidation therapy. The effects of GM-CSF on EFS were assessed in the entire cohort and according to distinct prognostic subgroups. After induction therapy, the proportions of CR were not significantly different in the two groups (91% with GM-CSF vs 87% without). After a median follow-up of 3 years, patients receiving GM-CSF had a higher rate of EFS than those who did not receive GM-CSF (3-year EFS, 42% vs 34%, p = 0.06). GM-CSF did not significantly improve OS. Patients with intermediate risk cytogenetics benefited from GM-CSF therapy (3-year EFS, 50% vs 35%, p = 0.05), while GM-CSF did not improve the outcome in the subgroups with favorable (p = 0.8) or unfavorable cytogenetics (p = 0.3). The benefit of GM-CSF in patients with intermediate karyotype was in part related to a lower rate of relapse (29% vs 47% at 3 years, p = 0.05) and a lower TRM (19% vs 23% at 3 years). Patients with abnormal intermediate karyotype benefited more of GM-CSF therapy (3-year EFS, 55% vs 19%, p = 0.03) than those with normal karyotype (3-year EFS, 47% vs 42%, p = 0.4). However, GM-CSF did not significantly improve OS in both groups. The effect of GM-CSF in the intermediate cytogenetic group was increased when considering only patients following the second randomization (consolidation chemotherapy ± GM-CSF) (3-year EFS, 49% vs 31%, p = 0.03; 3-year OS, 65% vs 43%, p = 0.05). GM-CSF also influenced favorably the intermediate group when considering a prognostic classification based on cytogenetics and the number of chemotherapy courses required for achieving CR (Wheatley et al., Br J Haematol 1999) (3-year EFS, 50% vs 34%, p = 0.04; 3-year OS, 63% vs 44%, p = 0.04).

We confirmed here that sensitization of leukemic cells with hematopoietic growth factors is a clinically means of enhancing the efficacy of chemotherapy in younger adult patients with intermediate risk AML.