Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) in the Elderly: A Joint Analysis of the French -Belgian-Swiss and PETHEMA Groups.
Authors: Ades Lionel , Montesinos Pau , Chevret Sylvie , Vellenga Edo , Raffoux Emmanuel , Rayon Chelo , Díaz-Mediavilla Joaquim , Thomas Xavier , Chevallier Patrice , Rivas Concha , Guerci Agnes , Amutio Elena , Huguet Francoise , Arias Jesus , Vey Norbert , Deben Guillermo , Meyer Sandrine , Novo Andres , Ferrant Augustin , Bergua Juan , Rigon Mathieu Resche , de la Serna Javier , Dombret Herve , Castaigne Sylvie , Fenaux Pierre , Sanz Miguel A. 
Published: October 2019

Abstract
Abstract 845

Background:
ATRA combined to anthracycline-based chemotherapy (CT) for induction and consolidation followed by prolonged maintenance is a standard treatment of newly diagnosed APL, but the outcome and prognostic factors in the elderly are less well established than in younger patients (pts).

Methods:
We performed a joint analysis of elderly pts included in two subsequent trials of the PETHEMA group (LPA96 and LPA99) and and on the French -Belgian-Swiss APL group (APL93 and APL2000). In the PETHEMA trials, pts received induction therapy with ATRA and idarubicin (Ida 12 mg/m2/d, d2,4,6,8), consolidation with 3 anthracycline monochemotherapy courses (2 with Ida and 1 with mitoxantrone, with ATRA and higher idarubicin dose for Sanz's int and high risk pts in LPA99 trial), and 2-year maintenance with intermittent ATRA and continuous low-dose CT (6MP + MTX). In APL 93 and 2000 trials: pts received induction therapy with ATRA and DNR (60mg/m2/d ×3d)+AraC, (200 mg/m2/d×7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d × 3) + AraC (1-2 g/m2/12h × 8) course (omitted in pts >65y) and the same maintenance as in PETHEMA trials. Median follow up was 75 and 42 months in PETHEMA and APL trials, respectively.

Results:
1575 consecutive newly diagnosed APL pts were enrolled in the 4 trials, including 1288 (81%), 105 (6.6%), 91 (5.7%) and 91 (5.7%) aged <60, 60-65, 65-70, and >70, respectively (ie 287 pts (18%) older than 60). CR rates in these age groups were 94.6%, 84.8%, 81.8% and 78.4% (p=0.0002). All failures were due to early death, except one due to resistant leukemia, in a younger adult. The 5-year cumulative incidence of relapse was 16.5%, 19.1% ,11.9% and 13.5% in pts <60, 60-65, 65-70 and >70, respectively (p= 0.63). The 5-year OS in these age groups was 85.8%, 68.7%, 63.8% and 56.4% (p<0.0001). The 5-year rate of death in CR , mainly resulting from myelosuppression during post induction treatment, increased with age, from 3.1%, 11.8%, 14.6% up to 17.9% in patients <60, 60-65, 65-70 and >70 years, respectively (p<0.0001). By multivariate analysis stratified on the trial (APL and LPA), better OS was associated with age <60 (HR 2.645, p<0.0001), female gender (HR 0.77, p=0.05), lower WBC (HR 1.007, p<0.0001) and higher platelets (HR 0.996, p=0.03).
In pts >60 yrs, by multivariate analysis, early death was associated with increased WBC (p=0.046), and increased creatinine level (p=0.002). Higher CIR was associated with increased WBC (p=0.002) . In patients older than 60 years, age had no significant impact on CR rate and survival. Finally, no significant differences in outcome were seen between French Belgian Swiss and PETHEMA trials.

Conclusion:
In pts older than 60, classical APL treatment with ATRA combined to anthracycline based CT followed by prolonged maintenance gives no initial leukemic resistance and similar relapse rate as in younger pts, but significantly lower OS due to a higher incidence of early deaths and of deaths in CR compared with younger pts. Higher WBC counts are associated with an increased incidence of both early deaths and deaths in CR. Improvement in prognosis, therefore, requires better supportive care during induction treatment, while reduction of the amount of myelosuppressive drugs during post induction treatment may be required to reduce deaths in CR.

Disclosures:
Fenaux: CELGENE: Research Funding; AMGEN: Research Funding.