Survival Improvement for Acute Myeloid Leukemia Patients Treated in Routine Practice By Intensive Chemotherapy Between 2000 and 2014
Authors: Bertoli Sarah , Bérard Emilie , Tavitian Suzanne , Huynh Anne , Borel Cecile , Guenounou Sarah , Luquet Isabelle , Delabesse Eric , Sarry Audrey , Laurent Guy , Attal Michel , Huguet Françoise , Récher Christian 
Published: October 2019

Abstract
Acute Myeloid Leukemia (AML) is one of the hematological malignancies in which no key development in specific treatment has been achieved in opposition to B-cell malignancies or CML. Yet, few recent studies have reported an improvement in overall survival (OS) of adult AML patients (pts) (Sant, Lancet Oncol 2014; Derolf, Blood 2009; Pulte, Haematologica 2008). However, these studies are mainly based on registries or compilation of clinical trials and reasons for this improvement are not defined. We analyzed the outcome of AML pts treated between 2000 and 2014 by intensive chemotherapy in order to determine whether there has been an improvement in OS over time and independently of classic prognostic factors.
From January, 1st, 2000 to December, 31st, 2014, 976 AML pts received intensive chemotherapy at the Toulouse University Hospital. With regards to routine practice evolution, voriconazole or caspofungin were used from 2003 as prophylaxis of fungal infections (Chabrol, Haematologica 2010), then posaconazole from 2008. Indications for alloSCT have evolved from geno to pheno-identical (Id) in first complete response (CR) and more recently to haplo-Id in high risk pts, whereas autologous-SCT was progressively abandoned. Molecular stratification for alloSCT indications based on NPM1, FLT3-ITD and CEBPA mutations started from 2006. A specific unit dedicated to acute leukemia was created in the Hematology department in 2005. Starting from 2010, dexamethasone was added to chemotherapy in pts with WBC>100 or >50 G/L with leukostasis. Since therapeutic strategies differed between younger and older pts, we analyzed separately the outcome of pts <60y (n=513) and pts 60y+ (n=463) according to 2000-2004, 2005-2009 and 2010-2014 periods.
In pts <60y, there were no differences in median age (47.9, 47.3 and 50.5y), secondary AML (19.7; 18.2 and 15.7%), PS>1 (22.8, 10.5 and 24.2%), median WBC count (11, 13 and 9 G/l), favorable/unfavorable karyotypes (14.0/25.6, 15.5/22.7 and 11.5/21.0%), FLT3-ITD (23.7, 20.7 and 22.9%) or NPM1 mutations in intermediate-cytogenetic risk (24.5, 33.6, 33.3%) according to 2000-2004; 2005-2009 and 2010-2014 periods. Median FU of pts still alive was 67.4 months (84.0, 74.1 and 38.1 months for 2000-2004, 2005-2009 and 2010-2014, respectively). Patients were censored at 7 years. Table 1 shows response to induction, treatment distribution and outcome. There were no differences in term of cumulative incidence (CI) of death in CR1 or non-relapse mortality in allografted pts over time. However, multivariate analyses with regards to d60 death (HR 0.43, 95% CI, 0.17-1.13; p=0.089), CI of relapse (SHR 0.72, 95%CI 0.50-1.03; p=0.071) and disease-free survival (HR 0.76, 95%CI 0.54-1.06; p=0.104) showed a trend for better outcome in the 2010-2014 period than in 2000-2004. The period of time was significantly associated with a better OS (p=0.031) with HR of 0.92 (95%CI 0.70-1.20; p=0.536) and 0.68 (95%CI, 0.50-0.92; p=0.012) for 2005-2009 and 2010-2014 respectively, compared to 2000-2004. The 2010-2014 period effect was still significant in multivariate analysis when adjusted on age (≥50y), secondary AML, cytogenetics and WBC >50 G/L (HR 0.62, 95%CI 0.46-0.85; p=0.003).
Characteristics of pts 60y+ were: median age (68.0, 68.7 and 66.9y), secondary AML (34.6; 20.2 and 25.7%), PS>1 (28.4, 20.0 and 21.7%), median WBC count (10.7, 8.3 and 11.2 G/l), favorable/unfavorable karyotypes (3.1/24.2, 3.8/21.3 and 4.8/19.8%), FLT3-ITD (12.0, 25.9 and 21.2%) or NPM1 mutations in intermediate-cytogenetic risk (41.3, 34.6, 32.8%) according to 2000-2004; 2005-2009 and 2010-2014 periods. Median FU of pts still alive was 52.5 months (84.0, 70.6 and 35.6 months for 2000-2004, 2005-2009 and 2010-2014, respectively). There was no difference in OS over time (table 2). However, there was a significant interaction between period of time and WBC in the multivariate analysis for OS meaning that the 2010-2014 period had an impact only in pts with WBC > 50 G/L (HR 0.41, 95%CI 0.24-0.71; p=0.002). The same interaction was also found for CR achievement (OR 3.90, 95%CI 1.30-11.7; p=0.015).
Progresses have been made in each phase of the therapeutic course of younger AML pts (less early deaths, more alloSCT without increased NRM, less relapses, more second remissions) resulting in survival improvement. In older pts, though outcome of hyperleukocytic patients has improved, significant advances remain to be made.

Disclosures
Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Attal:sanofi: Consultancy; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; amgen: Consultancy, Research Funding. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding.