Arsenic Trioxide (ATO) In the Consolidation Treatment of Newly Diagnosed APL - First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian Swiss APL Group

ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL, but this treatment is myelosuppressive and may be associated with long term cardiac toxicity. The use of ATO may allow reduction of the amount of CT (and in particular avoid ara C), and further diminish the relapse risk, especially when used in consolidation treatment (US intergroup study, Powell, ASCO 2008). In a randomized trial, we used ATO for consolidation treatment instead of ara C in standard risk APL (baseline WBC < 10G/L), and in addition to AraC in high risk patients (baseline WBC > 10G/L). ATRA, suggested to reduce the relapse risk when used during consolidation (Sanz, Blood 2008, 112: 3130-4) was also tested in standard risk pts.

In APL 2006 trial (started in Nov, 2006) newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L were randomized between: group A1( standard group) (induction: ATRA 45mg/m2/d until CR with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 12 mg/m2/dx3 and AraC 1g/m2/12h x4d; maintenance during two years: intermittent ATRA 15d/3 months and continuous 6 MP + MTX,); Group A2: same treatment as group A1, but AraC replaced by ATO 0.15 mg/Kg/D D1 to 25 days of both consolidation courses; Group A3: same treatment as group A1, but AraC replaced by ATRA 45 mg/m2 d1 to 15 of both consolidation courses. Pts aged < 70 with WBC > 10G/L (Group C) were randomized between: group C1 (standard group): same treatment as Group A1; group C2: same as C1, but with addition of ATO 0.15 mg/Kg/d d1 to 25 of both consolidation courses, at d1. Pts with WBC > 10 G/L all received intrathecal CT for CNS prophylaxis. This first interim analysis was made at the reference date of 1 Jan 2010, in 186 pts aged < 70 years included in 78 centers before 2009 (141 pts in group A (45/45/51 pts in A1/A2/A3 arms), 45 pts in group C (24/21 pts in C1/21 arms)).

In standard risk patients (group A) 140 (99.3 %) patients achieved CR, and 1 (2%) had early death. After a median follow up of 22.1 months, 1, 0, and 1 pts had relapsed in the A1, A2 and A3 consolidation groups, resp. (18 months cumulative incidence of relapse- CIR-of 0%, 0% and 2%). 2, 2, and 0 pts had died in CR in the A1, A2 and A3 consolidation groups, resp. The median duration of neutropenia and thrombocytopenia during consolidation courses was 43.5 and 44 days, 40 and 35 days, 20 and 25 days after consolidation cycles in groups A1 (AraC), A2 (ATO) and A3 (ATRA), resp (p<0.01). The median overall duration of hospitalization was 51, 59 and 26 days in A1,A2 and A3 groups, respectively. In high risk pts (group C) 45 (100 %) patients achieved CR. After a median follow up of 23.7 months, 1 and 1 pt had relapsed in the C1 and C2 consolidation groups, resp (18 months CIR of 2% and 2%). One and 3 had died in CR in the C1 and C2 consolidation groups, resp. Median duration of neutropenia and thrombocytopenia was 45.5 and 43.5 days, 51.5 and 48 days, after consolidation cycles in groups C1(AraC) and C2 (AraC+ATO), resp. The median overall duration of hospitalization was 53.5, and 65 days in C1 and C2 groups, respectively.

Results of this first interim analysis show that very high CR rates (>95%) can be observed in very multicenter trials in APL, by combining ATRA and anthracycline based CT, while the relapse rate with consolidation and maintenance was very low in all treatments arms, including in pts with WBC > 10G/L. Nevertheless ATO, when combined to high dose CT during consolidation cycles, increased myelosuppression. An amendment further reducing CT in pts receiving ATO is thus being implemented in the trial.

Off Label Use: ATO as 1st line treatment in APL. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.