Azacitidine As Post-Remission Therapy in Elderly Patients with Acute Myeloid Leukemia Significantly Prolongs Disease-Free Survival: Interim Results from a Prospective, Randomized, Open-Label, Phase III Multicenter Trial
Authors: Oliva Esther Natalie , Alati Caterina , Salutari Prassede , Freyrie Alessandra , Candoni Anna , Simeone Erica , Ventura Giovanna , Cortelezzi Agostino , Capelli Debora , Leoni Pietro , Di Bartolomeo Paolo , Marino Antonio Giovanni , Cufari Patrizia , Di Raimondo Francesco , Mauro Elisa , Volpe Antonio , Cascavilla Nicola , Musto Pellegrino , Morabito Fortunato , Niscola Pasquale , Specchia Giorgina , Ronco Francesca 
Published: October 2019

Abstract
Background: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%), which partially explains a median survival of 7 to 12 months. Several studies have suggested that maintenance therapy may improve CR duration and long-term, disease-free survival (DFS). Grovdal et al (2010) treated 60 elderly patients with high-risk myelodysplastic syndrome (MDS) or AML with cytarabine-based induction therapy resulting in CR in 24 patients who continued on to 5-Azacitidine (5-Aza) maintenance therapy. The median duration of CR was 13.5 months. The median OS for the 5-Azacitidine-treated group was 20 months.
Aims: The present phase III, prospective, randomized, open-label, multicenter trial is designed to assess the efficacy of post-remission treatment with 5-Aza versus best supportive care (BSC) in 54 patients > 60 years of age with AML in CR after conventional induction (3+7) and consolidation chemotherapy. Primary endpoint is the difference in DFS at 2 and 5 years between; secondary endpoints are the difference in overall survival (OS) at 2 and 5 years, the number and length of hospitalizations and quality of life in the 2 arms in the 2-year post-remission period.
Methods: Patients with newly diagnosed AML with > 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with a performance status < 3 are included. Standard induction chemotherapy consists of two courses of "3+7" (Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7). Patients in CR receive consolidation with cytarabine 800 mg/m2 3 hour infusion bid days 1-3. Patients in CR are randomized 1:1 to recieve best supportive care (BSC) or 5-Aza according to the following schema: 50 mg/m2 s.c. or i.v. for 7 days (5 + weekend off + 2) every 28 days and increase dosing after 1st cycle, if well tolerated, to 75 mg/ m2 for further 5 cycles, followed by cycles every 56 days for 4 years and six months post-remission.
Results: At the time of the present interim analysis 88 patients have been included in the study. Median age at diagnosis was 71, interquartile range (IQR) 66-75 years, male/female 45/43. During induction-consolidation chemotherapy, 31 patients were relapsed/refractory, 14 died, 5 refused to continue, 3 were excluded for protocol violation, 1 was lost to follow-up and 6 have not yet reached consolidation treatment. Twenty-eight patients have been randomized and 9 have more than 1 year follow-up (7 5-Aza patients, 2 BSC patients). The characteristics of randomized patients are shown in the table. The median observation time is 42.3 weeks and 12 patients are still in CR. Twelve patients in the BSC arm have experienced AML recurrence versus 4 patients in the 5-Aza arm at 9,17,42,56 weeks, respectively. Median DFS in the BSC arm is shorter (14 weeks, IQR 9-50 weeks) compared to that observed in the 5-Aza arm (median not reached at 2 years, P=0.008; Figure 1). At 2 years post-randomization 10 patients have died: 4 in 5-Aza arm versus 6 in BSC arm. All deaths occurred after AML recurrence. Median OS in 5-Aza arm is not reached at 2 years, versus 57 weeks, IQR 25-NA weeks in the BSC arm (P= 0.219, Figure 2). Grade 3-4 adverse events in the 5-Aza arm included neutropenia in 3 cases and one hospitalization for pericarditis, concomitant to AML recurrence. No serious adverse events were experienced in the BSC arm.
Conclusions: Preliminary results indicate that in elderly AML patients receiving standard induction-consolidation chemotherapy, 5-Aza post-CR is well-tolerated and significantly prolongs DFS. The trial is ongoing and may provide further insight on the impact of post-remission 5-Aza treatment on OS in this elderly population.
Figure 1 Figure 1.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
Oliva: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Speakers Bureau. Off Label Use: Azacitidine is indicated for treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.. Musto:Celgene: Advisory Board Other, Honoraria.