A Randomized Open-Label Study To Evaluate The Efficacy Of Azacitidine For Post-Remission Therapy Of Acute Myeloid Leukemia In Elderly Patients (QOLESS AZA-AMLE)
Authors: Oliva Esther Natalie , Santarone Stella , Leoni Pietro , Alati Caterina , Volpe Antonio , Cascavilla Nicola , Candoni Anna , Musto Pellegrino , Morabito Fortunato , Di Raimondo Francesco , Cufari Patrizia , Santacaterina Irene , Vincelli Iolanda , Capelli Debora , Freyrie Alessandra , Salutari Prassede , Di Bartolomeo Paolo , Martino Bruno , Ronco Francesca , Cortelezzi Agostino 
Published: October 2019

Abstract

Background
The incidence of acute myeloid leukemia (AML) increases with age. In elderly AML patients, intensive chemotherapy has been associated with complete remission (CR) rates of approximately 45%, considerably lower than in younger patients; the duration of remission is shorter and the early treatment-related mortality is high, 30% to 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 complete response 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 in a cohort of subjects of > 60 years of age with AML, and in CR after conventional induction (“3+7”) and consolidation chemotherapy. Primary objectives are to evaluate overall survival overall survival and DFS at 2 years; secondary objectives are to evaluate the number and length of hospitalizations in the 2 arms in the 2-year post-remission period.

Methods
Approximately 95 patients with the following criteria: newly diagnosed AML with > 30% myeloid marrow blasts, either “de novo” or evolving from a MDS not previously treated with chemotherapeutic agents; no contraindications for intensive chemotherapy and performance status<3 will be included. Thirty-eight patients will be randomized in the post-remission phase 1:1. Standard induction chemotherapy consists of two courses of 3 + 7 with Daunorubicin at a daily dosage of 40 mg/m2 for 3 days (days 1-3) in combination with 100 mg/m2 cytarabine per day as a continuous IV infusion for 7 days (days 1-7). Consolidation consists of cytarabine 800 mg/m2 3 hour infusion bid (days 1-3). Patients in CR are randomized 1:1 to receive best supportive care (BSC) or 5-Aza according to the following schema: 50 mg/sqm s.c. or i.v. for 7 days every 28 days and increase after 1st cycle, if well tolerated, to 75 mg/m2 s.c or i.v. for 7 days (5 + weekend off + 2) every 28 days for further 5 cycles, followed by 6 cycles every 56 days for 2 years post-remission.

Results
At the time of the present report 58 patients have been included in the study. Median age at diagnosis was 72, interquartile range (IQR) 65-75 years, M/F 34/24. During induction-consolidation chemotherapy, 16 patients were relapsed/refractory, 9 patients died, 3 patients were excluded for protocol violation, 3 refused to continue and 8 have not yet reached consolidation treatment. Nineteen patients have been randomized; characteristics of patients are shown in the table. Eighteen patients have reached at least a 4 week follow-up. Amongst these, 11 patients are still in CR at a median observation time of 25.4, IQR 12.9-47.4 weeks. Five patients in the BSC arm have experienced AML recurrence at 7, 8, 13, 21, 49 weeks, respectively, verus 2 patients in the 5-Aza arm at 42 and 47 weeks. DFS is longer in the 5-Aza arm (Figure). Grade 3-4 adverse events included neutropenia in 2 cases in the 5-Aza arm and in 1 case in the BSC arm. There were no hospitalizations related to the adverse events in either arm.

Conclusions
Preliminary results suggest that in elderly AML patients receiving standard induction-consolidation chemotherapy, 5-Aza post-CR is well-tolerated and may prolong survival.

Disclosures:
Oliva: Celgene: Consultancy. Off Label Use: Azacitidine is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with: • intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), • chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder, • acute myeloid leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification.