Is Arsenic Trioxide (ATO) Required in the Treatment of Standard Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL 2006) By the French Belgian Swiss APL Group
Authors: Ades Lionel , Thomas Xavier , Guerci-Bresler Agnes , Emmanuel Raffoux , Spertini Olivier , Vey Norbert , Lamy Thierry , Récher Christian , Pigneux Arnaud , Bordessoule Dominique , Deconinck Eric , Gardin Claude , Tournilhac Olivier , Lambert Jean-Francois , Chevallier Patrice , de Botton Stephane , Lejeune Julie , Dombret Hervé , Chevret Sylvie , Fenaux Pierre 
Published: October 2019

Abstract
Background: ATO is very effective in the treatment of APL and recent results have shown that ATRA+ATO combinations (without CT) were at least as effective as classical ATRA + anthracycline based chemotherapy (CT) while being less myelosuppressive (Lo Coco, NEJM 2014, Burnett, Lancet Oncol, in press). However, access to ATO remains limited for frontline treatment of APL in most countries, which must mainly rely on ATRA+CT combination. In those combinations, investigators have suggested that the amount of CT could be reduced and the incidence of relapses further diminished by introducing ATRA (Sanz) or ATO (Powell) during consolidation cycles. In a randomized trial (APL 2006 trial), we compared for consolidation treatment (after ATRA CT induction treatment) ATO, ATRA and the "classical" Ara C in standard risk APL (ie with baseline WBC < 10G/L).
Methods: Between 2006 and 2013 newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L , after an induction treatment consisting of ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3, were randomized for consolidation between AraC, ATO and ATRA. The AraC group ( standard group) received a first consolidation course with, Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7, a second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d, and a maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group, but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of an analysis made at the reference date January 1st 2014 in the 398 pts aged < 70 years with WBC<10G/L included before 1/1/2012. The primary endpoint was event free survival (EFS) from CR achievement. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary endpoints.
Results: Among the 398 included pts, 7 were excluded for diagnosis error, 96% achieved CR, 12 (3%) had early death (from bleeding (n=1), sepsis (n=6), Thrombosis (n=4), cardiac arrest (n=1)) and 4 (1%) had resistant leukemia. 353 pts were randomized for consolidation (118, 118 and 117 in the AraC, ATO and ATRA arms, respectively). Pre-treatment characteristics were well balanced between the 3 consolidation groups. Overall, 4, 0, and 7 pts had relapsed (p=0.03) and 6, 5, and 5 pts (p=0.93) had died in CR in the AraC, ATO and ATRA consolidation groups, respectively. Causes of death in CR were sepsis (n=4) and hemorrhage (n=2), AML/MDS (n=5), relapse of a previous cancer (n=2), other (n=2). Two of the 6 deaths in CR related to myelosuppression occurred in each arm. Of the 5 patients who developed AML/MDS, 2, 1 and 2 had been treated in the AraC, ATO and ATRA arms, respectively. Five-year EFS from randomization was 90.8% [85.5; 96.5], 92.5% [87.6; 98.4] and 86.8% [79.7; 94.5] (p=0.52), 5y CIR was 3.89% [0.08 ; 7.69], 0% [0 ; 0], 7.41% [1.96 ; 12.87] (p=0.03) and 5 year OS was 93.6% [89.1; 98.3]%, 92.8% [87.6; 98.4]% and 91.9% [85.4; 98.9] (p=NS), in the AraC, ATO and ATRA consolidation groups, respectively. Median time to ANC >1 G/L after the first consolidation course was 24, 24 and 17 in the AraC, ATO and ATRA group, respectively (AraC vs ATO: p= 0.96; ATO vs ATRA: p<0.0001). Similarly, time to ANC >1 G/L after the second consolidation course was 23, 19 and 13 days (AraC vs ATO: p= 0.02; ATO vs ATRA: p <0.0001).
Median duration of hospitalization after the first and the second consolidation course were 32d, 29d, 32d (p= NS) and 30d, 17d, 15d in the AraC, ATO and ATRA group, respectively (p<0.0001).
Conclusion: Very high CR rates are now obtained in standard risk APL on a very large multicenter basis using classical ATRA and anthracycline based CT combinations, with very few relapses. On the other hand, our results strongly suggest that relapse rates observed with regimens without ATO, although they are low, can be significantly further reduced by addition of ATO. The Ida-ATRA consolidation regimen in particular, while carrying reduced toxicity, was associated with a relapse rate of 7.4%. Our results therefore advocate systematic introduction of ATO in the first line treatment of standard risk APL, but probably not concomitantly with CT, a situation where we found myelosuppression to be significant.

Disclosures
Guerci-Bresler: ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Deconinck:NOVARTIS: Other: Travel for international congress; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; ROCHE: Research Funding; LFB loboratory: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.