General AML

FLAG-Ida or daunorubicin combined with clofarabine in high-risk acute myeloid leukemia – data from the AML17 trial

The UK National Cancer Research Institute (NCRI) AML17 trial (ISRCTN55675535) was a large prospective phase III multicenter study for patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome that ran consecutively between May 2002 and December 2014 in the United Kingdom, Denmark, and New Zealand and addressed several randomized questions.1 In this AML17 trial, the safety and efficacy of daunorubicin combined with clofarabine (DClo) was prospectively compared with fludarabine/cytosine arabinoside (ara-C)/granulocyte stimulating factor (G-CSF) and idarubicin (FLAG-Ida) in patients with high-risk AML. The results of this part of the AML17 trial were reported in Leukemia by Alan K. Burnett and colleagues.2

Three-hundred and eleven patients with high-risk AML were randomized after having received the first induction course, which could have been ara-C/daunorubicin/etoposide alone (n = 39) or in combination with gemtuzumab ozogamicin 3 mg/m2 (n = 29) or 6 mg/m2 (n = 22) with the daunorubicin dose being 60 mg/m2 (n = 78) or 90 mg/m2 (n = 78). Patients were randomized 2:1 to receive up to three courses of DClo (daunorubicin 50 mg/m2 on days 1, 3 and 5 and clofarabine 20 mg/m2 days 1–5, n = 207) or FLAG-Ida (fludarabine [30 mg/m2 days 2–6], ara-C [2 g/m2] G-CSF [263 µg days 1–7] and idarubicin [8 mg/m2 days 4–6], n = 104). The main objectives of the study were the number of patients delivered to transplant and overall survival (OS).

Key findings:
  • Median follow-up: 47.4 months (range, 3.1–74.7 months)
  • Outcomes shown below are representative of DClo and FLAG-Ida arms, respectively
    • 5-year OS: 26% vs 44%, HR = 1.40 (95% CI, 1.05–1.86), P = 0.02
    • 5-year cumulative incidence of relapse: 51% vs 39%, HR = 1.38 (95% CI, 0.95–2.01), P = 0.09
    • 5-year relapse-free survival (RFS): 25% vs 44%, HR = 1.40 (95% CI, 1.03–1.91), P = 0.09
  • One-hundred and seventy-five patients (56%) received a transplant
    • Number of patients receiving transplant in the DClo and FLAG-Ida arms: 58% vs 53%, OR = 0.83 (95% CI, 0.52–1.34), P = 0.4
  • Outcomes shown below are representative of DClo and FLAG-Ida arms, respectively, censored at the time of transplant
    • 4-year OS: 25% vs 28%, HR = 1.27 (95% CI, 0.87–1.85), P = 0.2
    • RFS post-transplant was worse in patients in the DClo arm compared to FLAG-Ida: 39% vs 69%, HR = 1.69 (95% CI, 1.19–3.21), P = 0.008
  • Myelosuppression was significantly higher in patients in the FLAG-IDA arm than in the DClo arm
    • Neutrophil recovery to 1.0 x 109/l was longer in the FLAG-Ida arm than DClo arm: 40 vs 32 days, P = 0.005
    • Platelet recovery to 100 x 109/l was longer in the FLAG-Ida arm than DClo arm: 61 vs 45 days, P = 0.16

In summary, there was no significant difference in the number of patients delivered to transplant in both the DClo and FLAG-Ida arms. However, FLAG-Ida led to a better OS in patients than DClo, which the researchers say might be due to the better RFS observed in patients after transplant.

The authors concluded that compared to DClo, FLAG-Ida was superior in patients with high-risk AML. They, however, suggested that the resulting prolonged cytopenia from the FLAG-Ida regimen can “cause unpredictable difficulties and scheduling of transplant” and thus advised that “checking the marrow status 10–14 days after the chemotherapy and proceeding to transplant irrespective of count recovery may be the optimal option”.

References
  1. Knapper S. et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017 Mar 2; 129(9): 1143–1154. DOI:   10.1182/blood-2016-07-730648. Epub 2016 Nov 21.
  2. Burnett A. K. et al. A comparison of FLAG-Ida and daunorubicin combined with clofarabine in high-risk acute myeloid leukaemia: data from the UK NCRI AML17 Trial. Leukemia. 2018 Jun 6. DOI: 10.1038/s41375-018-0148-3. [Epub ahead of print]. 
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