Arsenic Trioxide (AS2O3) Therapy for Relapsed Acute Promyelocytic Leukemia (APL): Comparison with a Historic Control Combining All-Trans Retinoic Acid (ATRA) Plus Intensive Chemotherapy.
Authors: Thomas Xavier , Pigneux Arnaud , Raffoux Emmanuel , Huguet Francoise , Caillot Denis , Guerci Agnes , Stamatoullas Aspasia , Reman Oumedaly , Isnard Francoise , Dreyfus Francois , Gratecos Nicole , Bernard Marc , Arkam Yazid , Fenaux Pierre 
Published: April 2020

Abstract
AS2O3 has shown great promise in the treatment of patients with relapsed/refractory APL. We evaluated the results of an As2O3 (Trisenox®)-based treatment strategy proposed to French patients with relapsed APL over the last few years and compared these results to those of our previous strategy combining ATRA with EMA (etoposide + mitoxantrone + AraC) intensive timed-sequential chemotherapy (Thomas et al., Leukemia14:1006, 2000), particularly in the setting of hematopoietic stem cell transplantation (HSCT).
28 consecutive patients (median age, 52 years; range, 21 – 80) with relapsed (relapse 1, R1 = 22 of whom 2 in molecular relapse; R2, R3 or R4 = 6) APL (25 M3, 3 M3v) were treated with AS2O3 between 2002 and 2005. The time from the last complete remission (CR) was 20.5 months (range, 0.9 – 74). Initial treatment was AS2O3 (0.15 mg/kg/day iv) administered alone (n = 25) or combined with ATRA (n = 3) ± idarubicin (n = 1) until CR. Median time to CR was 47 days. Severe toxicities included infection (24%) and APL differentiation syndrome (20%). Median time for granulocytes &gt; 0.5 x 109/l was 15 days (range, 0 – 52). 24 patients (86%) achieved CR after initial AS2O3 treatment. Early death was observed in 2 cases and resistance in 2. CR was followed in 11 patients by at least a second cycle of AS2O3 ± consolidation chemotherapy + maintenance therapy (including ± AS2O3 ± ATRA). The 13 other remitters received HSCT (median time to transplant, 4.7 months): 9 underwent unpurged autologous SCT and 4 genoidentical allogeneic SCT, after at least a second cycle of AS2O3 ± one course of consolidation chemotherapy (n = 5). At a median follow-up of 2.5 years, 22 patients are alive. 4 (16%) have relapsed (median time to relapse, 8.1 months). 80% of patients in continuous CR were PML-RARα negative on sensitive nested RT-PCR. Median LFS was not reached. AS2O3-based therapy resulted in a 2-year LFS of 84%. 2-year OS was 73%. Prognostic factors were HSCT as postremission therapy (p = 0.01) and less than 3 therapeutic lines (p = 0.002). While CR proportions were comparable, 2-year LFS (84% vs 47%) and 2-year OS (79% vs 51%) increased in patients receiving AS2O3-based therapy as compared to the historic control. Severe infections were significantly lower with AS2O3-based regimen (24% vs 54%). When considering only patients receiving HSCT, results showed a benefit with AS2O3-based regimen in terms of 2-year LFS (100% vs 54%) and 2-year OS (100% vs 61%), the historic control showing a high mortality associated with the allogeneic SCT procedure. Our data shows that AS2O3-based therapy induces durable remission in a high proportion of patients with relapsed APL with no major toxicity. The results appear more favorable than those of our previous therapy based on ATRA and intensive timed-sequential chemotherapy particularly in the setting of HSCT. Combination AS2O3 and HSCT regimens are anticipated to further extend survival in relapsed APL.