In standard-risk
acute promyelocytic leukemia, recent results have shown that
all-trans retinoic acid plus
arsenic trioxide combinations are at least as effective as classical
all-trans retinoic acid plus
anthracycline-based
chemotherapy while being less myelosuppressive. However, the role of frontline
arsenic trioxide is less clear in higher-risk
acute promyelocytic leukemia, and access to
arsenic remains limited for front-line treatment of standard-risk
acute promyelocytic leukemia in many countries. In this randomized trial, we compared
arsenic,
all-trans retinoic acid and the "classical"
cytarabine for consolidation treatment (after
all-trans retinoic acid and
chemotherapy induction treatment) in standard-risk
acute promyelocytic leukemia, and evaluated the addition of
arsenic during consolidation in higher-risk disease. Patients with newly diagnosed
acute promyelocytic leukemia with a white blood cell count <10x109/L, after an induction treatment consisting of
all-trans retinoic acid plus
idarubicin and
cytarabine, received
consolidation chemotherapy with
idarubicin and
cytarabine,
arsenic or
all-trans retinoic acid. Patients with a white blood cell count >10x109/L received
consolidation chemotherapy with or without
arsenic. Overall, 795 patients with
acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk
acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the
cytarabine,
arsenic and
all-trans retinoic acid consolidation groups, respectively (P=0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. (P=0.001). Among those with higher-risk
acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% (P=0.38) in the
chemotherapy and
chemotherapy plus
arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% (P=0.99). Given the prolonged myelosuppression that occurred in the
chemotherapy plus
arsenic arm, a protocol amendment excluded
cytarabine during consolidation cycles in the
chemotherapy plus
arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of
arsenic in the first-line treatment of
acute promyelocytic leukemia, but probably not concomitantly with intensive
chemotherapy, a situation in which we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).