Early Deaths (ED) in Acute Promyelocytic Leukemia (APL) in France: A Retrospective Multicenter Study in 355 Patients (pts)
Authors: Rahmé Rami , Thomas Xavier , Recher Christian , Vey Norbert , Delaunay Jacques , Deconinck Eric , Bordessoule Dominique , Micol Jean-Baptiste , Stamatoullas Aspasia , Mariette Clara , Pautas Cécile , Bories Pierre , Marolleau Jean-Pierre , Hunault-Berger Mathilde , Fegueux Nathalie , Raffoux Emmanuel , Dombret Hervé , Chevret Sylvie , Degos Laurent , Fenaux Pierre , Ades Lionel 
Published: October 2019

Abstract
Abstract 890

Background:
While, with the combination of ATRA and anthracycline-based chemotherapy, 90–95% of APL pts included in APL clinical trials achieve complete remission (CR), it has been suggested that the actual early death (ED) rate may be as high as 15–17%, many pts being unable to enter clinical trials (Park JH, Blood 2011, Lehmann S, Leukemia. 2011 ). In some cases, an important delay in starting ATRA was also incriminated in ED (Altman, Blood 2011). We assessed the early outcome of newly diagnosed APL pts diagnosed in 16 large French centers during a period of 5 years, included or not in a clinical trial.

Methods:
16 French University hospitals retrospectively provided data on all their APL pts diagnosed between Dec 2006 and Dec 2011, included or not in APL 2006 trial, the only active French APL trial during that period, which randomly assessed the role of ATO and ATRA during consolidation treatment, after ATRA – anthracycline based chemotherapy induction, and which had no upper age limit for inclusions. Every effort was made to collect all cases, by checking all APL diagnoses made in the lab and including pts admitted directly to ICU or to departments other than that of hematology, to avoid any bias. Intervals between first blood count, hospital admission and ATRA onset were particularly analyzed. ED was defined as death within 30 days of admission, irrespective of its cause.

Results:
355 cases of newly diagnosed APL were seen during that period: 52% men, median age 52 years (range 16 –87). 26% of the pts had WBC >10 G/L. 65.6% pts were included in APL 2006 trial and 34.4% not included. Reasons for non-inclusion in APL 2006 trial were: 32 patients refusing or unable to give consent (9%), 20 initial admissions in ICU (5.6%), 20 older age and/or comorbidities (5.6%), 8 previous cancer (2.3%), 11 contraindications to anthracyclines (3.1%), 5 other exclusion criteria (pregnancy, HIV, poor socioeconomic conditions) (1.4%), 2 deaths before ATRA onset (0.6%), 2 CNS bleeding at admission (0.6%) and 22 unknown reasons (6.2%). Pts not included were characterized by older age (median 62 vs 48 y, p < 0.0001) but a similar proportion of pts with high WBC (31% vs 24%,p=0.16). 20/33 (61%) pts aged ≥ 75 and 19/26 (73%) pts initially admitted in ICU were not included in APL 2006 trial. Median interval from first abnormal blood count to hospitalization was < 1 day (1 d and > 1 d in 20% and 22% pts, respectively), from hospitalization to ATRA onset < 1 day (1 d and > 1 d in 24.5% and 25% pts respectively) and from bone marrow aspirate to ATRA onset < 1 day (<1 d, 1 d, and > 1d in 66%, 19%, 15% pts respectively), without significant difference between pts included and not included in APL 2006.
316 (89.8%) pts reached CR, 1 had resistant leukemia and 35 pts (9.9%) had ED. 8 of the 35 ED (2.2% of the whole population) occurred before ATRA onset. Causes of ED in pts who received ATRA were: differentiation syndrome (DS) (n=5), CNS bleeding (n=4), sepsis (n=7), myocardial infarction (n=2), multiple organ failure (n=4), uncertain (n=5). No significant differences in the incidence of ED were seen based on the various intervals analyzed (from first blood count to hospital admission, admission to ATRA onset, BM aspirate to ATRA onset). In particular, ATRA onset within <1, 1 and >1 day of hospitalization was associated with ED rates of 9.4%, 7% and 8%, respectively (p=0.961). ED was seen in 3% (7/233) of pts included in APL 2006 trial and 23% (28/122) of non protocol pts (p < 0.0001), and the CR rate was 97% and 77% in APL trial and non protocol pts (p < 0.0001). In particular, in pts aged ≥ 75, the ED rate was 0% and 30% in protocol and non protocol pts, respectively (p=0.06). Still, overall, 16/26 (61.5%) of the pts admitted directly in ICU, 27/33 (82%) of the pts aged ≥ 75, and 77/92 (83.7%) of the pts with WBC > 10G/L achieved CR.

Conclusions:
(1) A large majority of APL pts are rapidly admitted to hospital and rapidly treated with ATRA in France, with an overall CR rate of 89.8%. (2) One third of the pts are not included in clinical trials, especially due to their age or critical condition, and their outcome is less favorable than that of protocol patients (77% versus 97% CR). On the other hand, 61.5% of the pts directly admitted to ICU and 82% of those aged ≥ 75 y achieved CR. (3) Our overall early death rate (9.9%) appears inferior to those published in several recent studies.

Disclosures:
No relevant conflicts of interest to declare.