Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)

Abstract

As all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO-based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA-anthracycline for low-/intermediate-risk patients, or ATRA-ATO-anthracycline versus ATRA-anthracycline-cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of -5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI -0.07 to 6.97), confirming noninferiority (P < 0.001). Using the Kaplan-Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups (P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5], P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-chemotherapy (https://www.clinicaltrials.gov/, NCT01987297).

Keywords: acute promyelocytic leukemia; all-trans retinoic acid; arsenic trioxide; consolidation therapy; risk stratification.

Fig. 1.

Enrollment, randomization, and disposition of patients. hCR, hematological complete remission.

Fig. 2.

Kaplan–Meier plot of clinical outcomes. Disease-free survival curves of patients in ATO or non-ATO groups (A) with low-, intermediate-, and high-risk disease, respectively (B–D). Overall survival of 855 patients enrolled (E) and cumulative incidence of relapse (F) with low-, intermediate-, and high-risk disease. Treatment protocol of ATO group (Low risk: ATRA+ATO, Intermediate risk: ATRA+ATO, High risk: ATRA+ATO+IDA/DNR). Treatment protocol of non-ATO group (Low risk: ATRA+IDA/DNR, Intermediate risk: ATRA+IDA/DNR, High risk: ATRA+IDA/DNR+Ara-C). IDA, idarubicin; DNR, daunorubicin; Ara-C, cytarabine.

Fig. 3.

Treatment protocol and patients’ allocation. ATRA 25 mg⋅m⁻²⋅d⁻¹; ATO 0.16 mg⋅kg⁻¹⋅d⁻¹; IDA 8 mg⋅m⁻²⋅d⁻¹; DNR 45 mg⋅m⁻²⋅d⁻¹. *For low- and intermediate-risk patients who did not achieve mCR after consolidation therapy at two successive times of detection within 1 mo apart, they would be enrolled cross-over in the other group to receive three more courses of high-risk consolidation therapy. IDA, idarubicin; DNR, daunorubicin; Ara-C, cytarabine; hCR, hematological complete remission.