Arsenic Trioxide (ATO) and ATRA with Limited Chemotherapy (CT) in Newly Diagnosed Standard Risk APL in the Elderly. a Report By the French Belgian Swiss APL Group (APL 2006 trial)

Background.Treatment of APL in the elderly with conventional ATRA-anthracycline based CT regimens is associated, like in younger patients, with very few relapses, but high death rates (CR rate of 87.3%, 10-year CIR of 9.3%, 21.7% deaths in CR, and a 10-year OS of 58% in patients aged> 65 years in our previous APL trials ;Blood 2010 115:1690). Recent results have shown that, in standard risk APL, ATRA+ATO combinations (without CT) are at least as effective as classical ATRA + CT regimens while being less myelosuppressive (Lo Coco, NEJM 2014; Burnett, Lancet Oncol, 2015) thus constituting a very appealing approach for elderly patients. However, when our APL 2006 trial started, the feasibility of treatment of APL without CT was unknown. Furthermore, access to ATO still remains limited for frontline treatment of APL in most countries. We present results of APL 2006 trial, where we combined ATO to ATRA and reduced CT in patients aged older than 70 with standard risk APL (baseline WBC <10G/L).

Methods. Between 2006 and 2015, newly diagnosed APL patients (pts)>70 years with WBC <10 G/L received induction treatment with ATRA 45mg/m2/d until CR and Idarubicin (Ida) 9 mg/m²/d on days 3, 5 and 7, a first consolidation course with Ida 9 mg/m²/dx3 combined with ATO 0.1 mg/kg/d during 25 days, a second consolidation course with ATO (same schedule)and ATRA during 15 days, followed by maintenance during 2 years with intermittent ATRA continuous 6 MP + MTX, plus 15 days ATO cycles every 3 months during the first maintenance year. In Sept 2010, after inclusion of 55 patients, because mortality in CR was still high (10/51 CR pts) while no relapse was observed, consolidation CT was reduced to one day of Ida during the first consolidation cycle. The primary endpoint was event-free survival (EFS) from CR achievement. We present here results at the reference date of Jan, 1, 2016. Results. Median age of the 123 pts included (after excluding one diagnosis error) was 73.6 years (range 70-88.4), with 56 % males. 113 (92%) pts achieved CR, 4 (3%) had resistant leukemia, and 6 (5%) had early death from sepsis (n=3), and multiorgan failure (n=3). Of the 113 CR pts, 3 relapsed (5-year cumulative incidence of relapse of 2.9%), with no significant difference across periods (p= 0.10, Gray's test). 14 (12%) patients died in CR, including 4/62 (4%) accrued after vs 10/51 (20%) before the amendment (p= 0.045, Fisher's test). Causes of death in CR were sepsis (n=4 before and 2 after amendment), bleeding (n=5 before and 1 after), general deterioration (n=1 before) and prostate cancer (n=1 after). 5-year OS was 80% (95%CI, 73-88%) and 5-year EFS was 80% (95%CI, 73-88%), with no difference according to period (p=0.71 and p=0.80 by the log-rank test, respectively). Mean time to ANC>1 G/L and platelets> 50G/l after the first consolidation course was 16.2 and 11.9 days in the original vs 5.6 and 4.0 days in the amended protocol (p<0.0001 and p<0.0001), while the second consolidation course was not associated with myelosuppression.

Conclusion. In this very old patient population (>70 years) with standard risk APL, addition of ATO, that allowed reduction of the amount of CT administered, was associated with high CR rates, without any increase (and a possible reduction) in the relapse rate compared to our previous experience with ATRA-CT regimens. However, reduction of mortality in CR with this regimen was only seen when consolidation CT was reduced to one single day of Ida. This is further evidence of the role of ATO in a patient population in whom myelosuppression must be avoided.