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505 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

Program: Oral and Poster Abstracts
Type: Oral
Session: Acute Myeloid Leukemia - Therapy, excluding Transplantation
Monday, December 6, 2010: 2:45 PM
311 EFGH (Orange County Convention Center)

Lionel Ades1, Emmanuel Raffoux, MD, PhD2*, Sylvie Chevret3*, Arnaud Pigneux, MD, PhD4*, Xavier Thomas5*, Dominique Bordessoule6, Norbert Vey7*, Agnès Guerci8*, Thierry Lamy9*, Christian Récher, MD10*, Beatrice Muller11*, Olivier Tournilhac, MD, PhD12*, Cécile Pautas13*, Jean-Yves Cahn, MD14, Jacques Delaunay15*, Eric Deconinck16*, Bruno Quesnel17*, Stephane de Botton18*, Aspasia Stamatoullas19*, Christine Chomienne, MD, PhD20*, Herve Dombret, MD, PhD21, Laurent Degos22* and Pierre Fenaux, MD, PhD23

1French-Belgian-Swiss APL group, Bobigny, France
2Hôpital Saint-Louis APHP University Paris VII, Paris, France
3Dbim, hopital saint Louis, Paris, France
4Hopital du Haut-Lévèque, Pessac, France
5Department of Hematology, Hôpital Edouard Herriot, Lyon, France
6Hématologie Clinique et Thérapie Cellulaire, CHU Limoges, Limoges, France
7Institut Paoli Calmettes, Marseille, France
8CHU Nancy, Nancy, France
9CHU Rennes, Rennes, France
10Service d'Hématologie clinique, CHU Purpan, Toulouse, France
11University Hospital Berne, Bern, Switzerland
12Service d'hématologie adultes et thérapie cellulaire, CHU Clermont-Ferrand, Clermont Ferrand, France
13Hôpital Henri Mondor, AP-HP, Université Paris 12, Créteil, France
14Onco-Hematologie, CHU-Grenoble, Grenoble, Cedex O9, France
15Hematology Department, CHU de Nantes, Nantes, France
16CHU Besancon, Besancon, France
17CHU Huriez, Lille, France
18Institut Gustave Roussy, Villejuif, France
19Centre Becquerel, Rouen, AK, France
20Institut Universitaire d'Hématologie, INSERM UMR-S 940, Paris, France
21Hematology department, Saint-Louis Hospital, AP-HP, Paris 7 University, Paris, France
22Hôpital Saint Louis, Paris, France
23Hôpital Avicenne, AP-HP, Université Paris 13, Bobigny, France

Background: 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.

Methods: 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)).

Results: 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.

Conclusion: 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.

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

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