A combination strategy of all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) and idarubicin showed a significant improvement in event-free survival compared with standard ATRA and anthracycline-based chemotherapy in patients with newly diagnosed, high-risk acute promyelocytic leukemia (APL), according to results of the phase III APOLLO trial. Further analysis of the APOLLO trial may support the implementation of this regimen as the new standard of care in patients with high-risk APL.
Pioneered by the APL0406 trial, prior investigations have demonstrated the superiority of combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) over standard ATRA and chemotherapy (CHT) as front-line management of low/intermediate risk acute promyelocytic leukaemia (APL). However, the efficacy of ATRA/ATO in high-risk APL (HR-APL), defined as >109/L white blood cell counts (WBC) at diagnosis, has not been studied within randomised trials so far. Therefore, the objective of the APOLLO trial was to prospectively compare the efficacy of the ATRA-ATO regimen versus the standard of care (ATRA-CHT) in patients with HR-APL.
The European, randomised, open-label, phase III APOLLO study enrolled patients with newly diagnosed high-risk APL aged 18-65 years. In the ATRA-ATO arm, patients received treatment with idarubicin (2x 12 mg/m2) on days 1 and 3 plus ATRA (45 mg/m2 daily) and ATO (0.15 mg/kg) until complete response. Consolidation consisted of 4 courses of ATO 5 days/week, 4-weeks-on/ 4-weeks-off, for a total of 4 courses, in parallel with ATRA 2-weeks-on/2-weeks-off (7 courses). Patients in the ATRA-CHT arm received the standard AIDA (ATRA+idarubicin) induction followed by 3 cycles of CHT-based consolidation as well as maintenance. The primary endpoint was event-free survival (EFS) after 2 years. Key secondary endpoints included overall survival (OS), measurable residual disease (MRD), safety and quality of life.
Between 2016 and 2022, a total of 133 patients were included in the APOLLO study. It was originally planned to include 280 participants but the study was prematurely discontinued in August 2022 due to slow recruitment during the Covid-19 pandemic and expiration of the study drug reserved for the trial. A total of 131 patients were analyzed: 68 in the ATRA-ATO group and 63 in the ATRA-CHT group. Patients had a median age of 46 years, 51.9% were male and the median white blood cell concentration was 36 x 109/L. At a median follow-up of 31 months, the two-year EFS rate was 88% in the ATRA-ATO group and 70% in the ATRA-CHT group (p= 0.02). The two-year OS rates were 93% and 87%, respectively (p= 0.17). The expected five-year EFS (87% vs. 55%; p= 0.003) and five-year OS rates (93% vs. 82%; p= 0.17) showed a similar trend. Complete response was achieved in 93% of patients in the ATRA-ATO group and in 90% of patients in the ATRA-CHT group (p= 0.654). In total, 1.7% of patients in the ATRA-ATO group vs. 5.5% of patients in the ATRA-CHT group had no achievement of molecular remission after the last consolidation course (p= 0.268). Furthermore, the cumulative incidence of relapse was significantly higher in the ATRA-CHT group than in the ATRO-ATO group (14.0 vs. 1.6%, p= 0.011).
Regarding safety, grade 1-4 thrombocytopenia was reported in 15% of patients in the ATRA-ATO group and in 22% of patients in the ATRA-CHT group. Grade 3-4 neutropenia occurred in 22% of patients in the ATRA-ATO group and in 46% of patients in the ATRA-CHT group. Premature death was reported in 7% vs. 10% of patients, respectively. Causes of early death were intracranial bleeding in 3 and 4, sepsis in 0 and 2, thrombosis in 1 and 1 and respiratory insufficiency due to hyperleukocytosis in 1 and 0 patients in the ATRA-ATO and ATRA-CHT arm, respectively.
First-line therapy with ATRA-ATO with two initial doses of idarubicin results in superior EFS compared to conventional ATRA-CHT in patients with high-risk acute promyelocytic leukaemia. Further analysis of the APOLLO trial may support the implementation of this regimen as the new standard of care in this setting.
Reference
Platzbecker U, et al. First results of the APOLLO trial: a randomized phase III study to compare ATO combined with ATRA versus standard AIDA regimen for patients with newly diagnosed, high-risk acute promyelocytic leukemia. Presented at EHA 2024; Abstract S102.
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