medwireNews: The use of arsenic trioxide instead of idarubicin in combination with all-trans retinoic acid (ATRA) is a feasible option in patients with acute promyelocytic leukaemia, regardless of risk level, suggests a phase III trial.
ATRA plus arsenic trioxide led to significant reductions in the rate of relapse and supportive care needs compared with the chemotherapy-based standard of care, with similar rates of complete remission and overall survival as well as comparable quality of life measures.
In this trial, 235 previously untreated patients harbouring the PML–RARA fusion gene characteristic of acute promyelocytic leukaemia were randomly assigned to receive ATRA either with arsenic trioxide or idarubicin. Fifty-seven patients were categorised as having a high risk of mortality based on a baseline white blood cell count higher than 10 × 109 cells/L.
The researchers explain that the arsenic trioxide administration schedule was different to previous studies, with higher doses given less frequently – at 0.3 mg/kg on days 1–5 of each course and at 0.25 mg/kg twice weekly in weeks 2–8 of the first course and weeks 2–4 of the remaining courses. And at diagnosis, 93% of 30 high-risk patients in the arsenic trioxide arm were given a single infusion of the CD33-targeted immunoconjugate gemtuzumab ozogamicin, while the remainder were offered anthracycline instead.
During a median follow-up of 30.5 months, the 116 patients given arsenic trioxide had a significantly lower cumulative incidence of morphological and molecular relapse at 4 years than the 119 idarubicin-treated patients, at 18% versus 1% and 27% versus 0%, respectively.
Moreover, the arsenic trioxide group required significantly fewer units of blood and platelets, and fewer days in hospital during the first two courses of treatment than the idarubicin group. Arsenic trioxide treatment was also associated with fewer days of intravenous antibiotics, although the relationship was only significant during the first course.
Complete remission rates were comparable between the arsenic trioxide and idarubicin treatment arms, at 94% versus 89%, as were the overall survival rates, at 93% versus 89%, with no significant differences between treatments in either low-risk (95 vs 90%) or high-risk (87 vs 84%) patients.
And although quality of life measures, as assessed with the EORTC QLQ-C30 global health status questionnaire and the Hospital Anxiety and Depression Scale, generally favoured the chemotherapy-free regimen, the differences were mostly not statistically significant, report Alan Burnett (Cardiff University School of Medicine, UK) and colleagues.
The most frequent grade 3 or 4 toxicity in the arsenic trioxide arm after the first course of treatment was elevated levels of liver alanine transaminase (25%), while alopecia (3%) and cardiac adverse events (3%) were most common after the second course. Grade 3 or 4 alopecia was the most frequent symptom after both the first (23%) and second (28%) course in patients given idarubicin. One patient, who received idarubicin, developed treatment-related acute myeloid leukaemia.
Highlighting the inclusion of high-risk patients as the key difference between this and previous trials, Burnett et al conclude in The Lancet Oncology that “de-escalation of therapy in this disease can be implemented, with an associated high cure rate above 90%, without affecting quality of life.”
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