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.

Superiority of anthracycline‐free treatment in standard‐risk acute promyelocytic leukemia: A systematic review and comparative epidemiological analysis

“…From a therapeutic perspective, opportunities center around confirming and optimizing current protocols. While the APL15 trial has provided initial evidence for non‐inferiority of chemotherapy‐free treatment in all‐risk APML, 8,9 additional randomized controlled trials are required to confirm these findings—especially in dissimilar population groups. Furthermore, an oral arsenic formulation has been commercially available for APML treatment in Chinese populations since 2009 with studies demonstrating non‐inferiority of the formulation compared to intravenous ATO 53 .…”

“…informed consent gained [8], outcome measures reliable [9], outcome measures valid [10], intervention described in detail [11], contamination avoided [12], cointervention avoided [13], statistical reporting of results [14], appropriate statistical analysis [15], clinical importance reported [16], drop-outs reported [17], appropriate conclusions [18], clinical implications reported [19], study limitations acknowledged [20]. Studies were rated as poor (<7 points), moderate (7-11 points), good (12-15 points), very good (16-18 points), or excellent quality (19-20 points).…”

“…[7][8][9]24,32,34,35,40 Consolidation treatment with ATRA/anthracyclines was assessed in six studies with DFS from 77% (2-year) to 93% (7-year), 10,[32][33][34][36][37][38][39] ATO/ATRA/anthracyclines was assessed in one study with DFS of 98% (2-year), 31,42 and ATO/ATRA was assessed in six studies with DFS from 91% (4-year) to 96% (7-year). [7][8][9][10]24,32,34,35,40 Grade 3-4 treatment toxicity was reported in seven studies. [7][8][9][10]24,31,32,34,35,40,42 Typically, anthracycline-based regimens were more likely to cause hematological or infection-related adverse events (up to 96% 10 and 55% 7,24 of patients, respectively).…”

“…[7][8][9][10]24,32,34,35,40 Grade 3-4 treatment toxicity was reported in seven studies. [7][8][9][10]24,31,32,34,35,40,42 Typically, anthracycline-based regimens were more likely to cause hematological or infection-related adverse events (up to 96% 10 and 55% 7,24 of patients, respectively). Conversely, regimens containing ATO were more likely to cause liver injury and QTc prolongation (up to 63% 40 and 16% 40 of patients respectively).…”

“…The resulting 30 articles were assessed in full, with 13 articles excluded (including all 3 studies identified in reference list searching) due to use of other chemotherapeutics (n = 11) and the retrospective nature of the study (n = 2). Subsequently, 17 articlesdescribing 12 distinct trials-were identified and included in the qualitative synthesis [7][8][9][10]24,[31][32][33][34][35][36][37][38][39][40][41][42].…”