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Dose-escalation of oral azacitidine provides clinical benefit to acute myeloid leukaemia patients in first remission post induction

The phase III QUAZAR AML-001 trial previously demonstrated the efficacy of oral azacitidine as post-induction maintenance therapy in acute myeloid leukaemia patients, with a significant 31% reduction in the risk of death compared to placebo. New results of this trial reveal that an escalated dose of oral azacitidine in patients with an early relapse (i.e. 5-15% of blasts) constitutes a significant survival benefit, with a restoration of the remission in approximately a quarter of patients.


Currently, the standard-of-care intensive induction chemotherapy (IC) for acute myeloid leukaemia (AML) results in a complete remission (CR) rate of 60-80% in patients <60 years of age, and of 40-60% in patients aged over 60. Unfortunately, however, disease relapse occurs in 80-90% of patients, typically within the first 18 months following remission status. In an attempt to reduce or delay these relapses, several maintenance therapies have been evaluated post IC. The phase III, randomised, international, double-blind QUAZAR AML-001 trial previously demonstrated that post-induction maintenance therapy with oral azacitidine (CC-486) results in a significant improvement in overall (OS) and relapse-free survival (RFS), compared to placebo, in AML patients in remission (median OS: 24.7 vs. 14.8 months; p=0.0009; median RFS: 10.2 vs. 4.8 months; p=0.0001). Eligible patients for this trial were >55 years of age with intermediate or poor risk cytogenetics, an ECOG score of <3, with a CR or CR with incomplete blood count (CRi) after IC +/- consolidation. Within 4 months of achieving a CR/CRi, patients were randomised (1:1) to receive 300 mg CC-486 once daily on days 1-14, repeated every 28 days, or placebo in the same schedule. Every 3 cycles a response evaluation was performed using a bone marrow aspirate. Patients who developed 5%–15% blasts in blood or bone marrow could receive the study drug for 21 days/cycle at the investigator’s discretion. Treatment was continued until >15% blasts, unacceptable toxicity, or until a hematopoietic stem cell transplantation was performed. During ASH 2020, outcome results were presented for the dose-escalated patients.


In total, 238 patients were randomised to receive CC-486, while the remaining 234 received placebo. Overall, 91 patients were identified as having early AML relapse (i.e. 5-15% blasts) and were assigned to the escalated protocol: 51 in the CC-486 arm (22%) and 40 placebo-treated patients (17%), with a median time to dose-escalation of 9.2 and 6.0 months, respectively. Both in the CC-486 and placebo arm, patients received a median of 2 additional treatment cycles, with 43% and 18% receiving 3 or more escalated courses of therapy, respectively. In the escalated cohort, the median OS of CC-486 treated patients was significantly longer than what was seen among placebo-treated patients (median OS: 22.8 and 14.6 months; HR[95%CI]: 0.66[0.42-1.04]; p=0.07), with 1-year survival rates of 80.4% and 59.5%, respectively. Importantly, of 78 evaluable patients with ≥5% blasts, assessed via bone marrow biopsy on or before day 1 of the escalated dosing, 10 (23%) patients in the CC-486 and 4 (11%) patients in the placebo arm achieved a CR/CRi following dose escalation. Moreover, 6 out of 9 patients in the CC-486 arm became minimum residual disease (MRD)-negative (none in the placebo arm).

The most common, any-grade adverse events (AEs) during the escalated dosing phase were febrile neutropenia (CC-486, 24%; placebo 3%), anaemia (22%; 20%), thrombocytopenia (22%; 23%) and neutropenia (20%; 10%). Grade 3/4 AEs were fairly similar across both treatment arms at 31% and 35%, respectively. In total, 4 (8%) of CC-486 treated patients discontinued treatment due to an AEs as compared to 1 in the placebo arm (3%). Assessed via FACIT-Fatigue and EQ-5D-3L instruments, CC-486 dose-escalation did not affect patient-reported fatigue or overall quality of life, compared to placebo.


In the phase III QUAZAR AML-001 trial, approximately a quarter of patients who experienced AML relapse with 5-15% blasts, who were subsequently escalated to a 21-day oral azacitadine dosing schedule, regained CR/CRi. Overall, dose-escalation was well-tolerated, without any new safety concerns. Of note, haematologic AEs first reported during dose escalation may be contributed to by disease relapse. As a result of the efficacy and safety data generated from this study, an escalated, 21-day oral CC-486 dosing schedule should be considered for AML patients who experience relapse with ≤ 15% blasts.


Döhner H, Wei AH, Montesinos P, et al., Escalated dosing schedules of CC-486 are effective and well tolerated for patients experiencing first acute myeloid leukemia (AML) relapse: results from the phase III QUAZAR AML-001 maintenance trial. Presented at ASH 2020; Abstract 111.

Speaker Hartmut Döhner

Hartmut Döhner

Prof. Dr. Med. Hartmut Döhner, Ulm University Hospital, Ulm, Germany


See: Keyslides


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