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434 Clinical Impact of an Accurate Genetic Characterization of Older Acute Myeloid Leukemia Patients: A Report from the Northern Italy Leukemia Group (NILG) Randomized Trial 02/06

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Minimal Residual Disease and Genetic Characterization
Hematology Disease Topics & Pathways:
Diseases, AML, Elderly, Study Population, Clinically relevant, Myeloid Malignancies
Sunday, December 2, 2018: 4:45 PM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Chiara Caprioli, MD1*, Tamara Intermesoli, MD1*, Orietta Spinelli, PhD1*, Silvia Salmoiraghi, MSc1*, Pamela Zanghì, MSc1*, Roberta Cavagna, MSc1*, Anna Michelato, PhD1*, Ksenija Buklijas, MSc1*, Federica Delaini, MSc1*, Elena Oldani, MSc1*, Giacomo Gianfaldoni, MD2*, Dario Ferrero, MD3*, Elisabetta Terruzzi, MD4*, Lorella De Paoli, MD5*, Chiara Cattaneo, MD6*, Erika Borlenghi, MD6*, Irene Cavattoni, MD7*, Monica Tajana, MD8*, Anna Maria Scattolin, MD9*, Daniele Giovanni Mattei, MD10, Paolo Corradini, MD11, Leonardo Campiotti, MD12*, Fabio Ciceri, MD13*, Massimo Bernardi, MD13*, Elisabetta Todisco, MD14*, Agostino Cortelezzi, MD15*, Sergio Cortelazzo, MD16*, Ernesta Audisio, MD17*, Filippo Marmont, MD3*, Alberto Bosi, MD2*, Brunangelo Falini, MD, PhD18*, Chiara Pavoni, Statistician1*, Renato Bassan, MD9*, Alessandro Rambaldi, MD1,19 and Federico Lussana, MD, PhD1*

1Hematology and Bone Marrow Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
2Azienda Ospedaliera Universitaria Careggi, Firenze, Italy
3A.O.U. Città della Salute e della Scienza, Torino, Italy
4Azienda Ospedaliera San Gerardo, Monza, Italy
5Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
6ASST Spedali Civili, Brescia, Italy
7Ospedale San Maurizio, Bolzano, Italy
8ASST Ospedale di Cremona, Cremona, Italy
9Ospedale dell'Angelo e SS. Giovanni e Paolo, Venezia Mestre, Italy
10Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
11Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy
12Dipartimento Medicina Clinica e Sperimentale, Università Insubria, Varese, Italy
13IRCCS Ospedale San Raffaele, Milano, Italy
14Istituto Clinico Humanitas, Rozzano, Italy
15Hematology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Milan, Italy
16Clinica Humanitas/Gavazzeni, Bergamo, Italy
17Department of Oncology and Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy
18Università di Perugia, Perugia, Italy
19Dipartimento di Oncologia-Ematologia, Università degli Studi di Milano, Milano, Italy

Introduction

In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287).

Patients and Methods

Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation.

Results

The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P<0.0001), while 3-years DFS was 73%, 28% and 13% (P<0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P<0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002).

Conclusions

Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment.

Disclosures: Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi: novartis: Consultancy; roche: Consultancy; janssen: Consultancy; abbvie: Consultancy. Rambaldi: Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

*signifies non-member of ASH