An effective and chemotherapy-free strategy of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia in all risk groups (APL15 trial)

Abstract

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

Fig. 1. Study design.

ATRA all-trans retinoic acid. ATO arsenic trioxide, CHT chemotherapy, HCR hematological complete remission, MCR Molecular complete remission. In the ATRA-ATO group, synchronous administration of mannitol and ATO was used to prevent central nervous system leukemia in high-risk patients. In the ATRA-ATO-CHT group, the chemotherapy regimen was as follows: IDA (idarubicin) at a dose of 8 mg/m²/day on days 2, 4, 6 or DNR (daunorubicin) at a dose of 45 mg/m²/day on days 2, 4, 6, 8 plus Ara-C(cytosine arabinoside) at a dose of 150 mg/m²/day on days 1-7. The bone marrow testing included morphology and molecular evaluation.

Fig. 2. Trial profile.

CHT chemotherapy.

Fig. 3. Survival outcomes for all APL patients.

A Disease-free survival. B Event-free survival. C Overall survival.

Fig. 4. Survival outcomes for high-risk APL patients.

A Disease-free survival. B Event-free survival. C Overall survival.