Impact of the Type of Anthracycline and of Allogeneic Stem Cell Transplantation in the Treatment of Younger Acute Myeloid Leukemia Patients: Long-Term Follow-up of the EORTC-Gimema AML-10 Trial

FB, FE and SS contributed equally to the work.

Background. The best post-remission treatment for younger acute myeloid leukemia (AML) patients remains controversial (Cornelissen JJ & Blaise D, Blood 2016, 127, 62-70). Most prospective studies comparing autologous (auto-) to allogeneic (allo-) hematopoietic stem cell transplantation (HSCT) have been published with a relatively short follow-up.

Aim. The main objective of this study was to provide a long-term follow-up evaluation of patients previously enrolled in the EORTC/GIMEMA AML-10 study.

Methods. In the EORTC/GIMEMA AML-10 prospective trial, 2157 patients aged 15-60 years were randomized to receive either daunorubicin (DNR) (50 mg/m²/d), mitoxantrone (MXR) (12 mg/m²/d), or idarubicin (IDA) (10 mg/m²/d) on days 1, 3 and 5 in addition to standard-dose cytarabine and etoposide for induction chemotherapy. A second cycle of induction was administered in patients who achieved a partial response while patients who achieved a CR or a CR with incomplete counts recovery (CRi) after 1 or 2 courses of induction chemotherapy received consolidation chemotherapy with the same anthracycline as in the induction course plus intermediate dose cytarabine. Young (≤ 45 years old) patients were then scheduled to receive an allo-HCT in first CR/CRi if they had an HLA-identical sibling donor or an auto-HCT otherwise. Median follow-up at the time of the initial report was 5.6 years (Mandelli et al., J Clin Oncol 2009, 27, 5397-5403). For the current analyses, cytogenetics were centrally reviewed and re-classified using the UK Medical Research Council (MRC) classification.

Results. In the current report, median follow-up was 11 (95% CI, 9-15) years. The 5-, 10-, 15- and 20-year overall survival (OS) rates were 33.2%, 30.1%, 28.0% and 26.1% respectively. No significant difference between the 3 randomized groups regarding OS was observed (Table 1). In young patients, the OS was comparable in the 3 treatment groups, whereas, in older patients, who had generally a worse outcome, OS was prolonged in the MXT and IDA groups as compared to the DNR group (Table 1). As expected, the initial MRC cytogenetic risk group had an important impact on OS. Within each subgroup, treatment outcomes were quite homogeneous (Table 1).

The impact of auto- versus allo-HCT was assessed in a cohort of 839 patients ≤ 45 years old who achieved a CR/CRi after induction chemotherapy, who generally received consolidation chemotherapy, and who were HLA-typed. A total of 330 patients had an HLA-identical sibling (donor group) while the remaining 509 patients had not (Table 2). The 10- and 15-year DFS and OS rates from CR were approximately 10% higher in patients with a donor as compared to those without (Table 2). Assessing the impact of donor availability on the DFS according to cytogenetic risk group, we observed that patients with a donor had a higher 10- and 15- yr DFS rates in all but those in the favorable MRC cytogenetic subgroup (table 2).

Among patients aged 46-60 years, 635 reached CR/CRi. The outcomes (DFS and OS) of CR/CRi patients with a donor were only marginally prolonged as compared to those without a donor, which can be explained by the positive effect of decreased relapse rate being neutralized by an increased risk of death in CR/CRi. The 10- and 15-yr DFS rates were increased by 6-11% in the MXR and IDA groups as compared to the DNR (overall logrank P=0.12); the HR (MXR vs DNR) was 0.88 (99% CI, 0.66-1.17), and the HR (IDA vs DNR) was 0.79 (99% CI, 0.58-1.06). The 10- and 15-yr OS rates were also increased, by 7-14% in the MXR and IDA groups as compared to the DNR (overall logrank P=0.04); the HR (MXR vs DNR) was 0.86 (99% CI, 0.64-1.16) and the HR (IDA vs DNR) was 0.74 (99% CI, 0.54-1.10).

Conclusions. Long-term follow-up of the EORTC/GIMEMA AML-10 trial confirmed that, overall, similar outcomes were obtained by using either DNR, MXR or IDA. In young patients without favorable cytogenetic features, who reached CR/CRi, the long-term outcome of those with a HLA-identical donor, who generally received AlloHSCT, was improved as compared to those without a donor. In older patients who reached CR/CRi, allo-HSCT and auto-HSCT yielded similar outcomes; however, MXR and IDA administered during induction and consolidation, provided better results than DNR.

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