The European Commission has granted full marketing authorization to azacitidine tablets for use as a maintenance therapy in adult patients with acute myeloid leukemia who achieved complete remission or CR with incomplete blood recovery after induction therapy with or without consolidation treatment, and who are not eligible for, or do not choose to proceed to, hematopoietic stem cell transplant.
The European Commission has granted full marketing authorization to azacitidine tablets (Onureg) for use as a maintenance therapy in adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or CR with incomplete blood recovery (CRi) after induction therapy with or without consolidation treatment, and who are not eligible for, or do not choose to proceed to, hematopoietic stem cell transplant (HSCT).1
The regulatory decision is supported by data from the phase 3 QUAZAR AML-001 trial (NCT01757535), which showed that the median overall survival (OS) reported with oral azacitidine was 24.6 months (95% CI, 18.7-30.5) vs 14.8 months (95% CI, 11.7-17.6) with placebo (HR, 0.69; 95% CI, 0.55-0.86; P = .0009).2 The median relapse-free survival (RFS) was also significantly longer with oral azacitidine compared with placebo, at 10.2 months vs 4.8 months, respectively (P <.001).3
“The unmet need exists for maintenance therapy options for AML in the European Union, given responses to induction therapy may be of short duration and the risk of relapse is high, especially for patients not eligible for stem cell transplant,” Andrew Wei, MBBS, PhD, lead study investigator, Alfred Hospital and Monash University, stated in a press release. “The approval of [oral azacitidine] by the European Commission has the potential to clinically benefit and change the treatment paradigm of patients with AML, across a range of subtypes.”
The international, randomized, double-blind, phase 3 QUAZAR AML-001 trial enrolled patients who were at least 55 years who had newly diagnosed AML, intermediate or poor cytogenetics, and had experienced first CR or CRi after intensive induction chemotherapy with or without consolidation within 4 months prior to randomization. Patients could not have been eligible for HSCT at the time of screening.
A total of 472 patients were enrolled to the trial, and they were randomized 1:1 to receive oral azacitidine at a once-daily dose of 300 mg (n = 238) or placebo (n = 234). Participants received treatment for 14 days of a 28-day treatment cycle.
The primary end point of the trial was OS, while a key secondary end point was RFS. Additional secondary end points comprised safety and health-related quality of life (HRQoL).
Baseline characteristics were found to be generally well balanced between the treatment arms. In the overall study population, the median age was 68 years (range, 55-86) and the majority had de novo AML (91%) and intermediate-risk cytogenetic characteristics (86%). All participants were given induction treatment with cytarabine-based regimens, in combination with an anthracycline or similar agent, prior to study enrollment.
Additionally, 80% of participants had received at least 1 course of consolidation chemotherapy prior to study entry; 45% of patients received 1 cycle of consolidation, and 31% received 2 cycles. The agents that were most frequently used for consolidation included cytarabine (n = 377/378), idarubicin (n = 95), and daunorubicin (n = 37). In the patients who did not receive consolidation treatment, 25% had received 2 cycles of induction chemotherapy and 85% received 2 or more chemotherapy cycles prior to study enrollment.
The most common toxicities experienced in both treatment arms were gastrointestinal effects that were grade 1 or 2 in severity. Frequent adverse effects reported in the investigative and control arms that were grade 3 or higher included neutropenia (41% vs 24%, respectively) and thrombocytopenia (22% vs 21%).
Additional data from the trial looked at the safety of oral azacitidine specifically in patients who were aged 75 years or older at the time of study entry.3 The agent was found to be well tolerated overall, and rates of individual adverse effects (AEs) were found to be similar between all patients who received the drug and this specific subgroup.
However, a lower incidence of thrombocytopenia was reported in this subgroup vs all patients who received oral azacitidine. Again, gastrointestinal AEs were most frequently experienced in this subgroup; diarrhea was the most comment effect to result in treatment discontinuation.
Although older patients with AML are known to be at increased risk of relapse, oral azacitidine significantly improved both OS (HR, 0.48; 95% CI, 0.25-0.94; P = .0281) and RFS (HR, 0.40; 95% CI, 0.20-0.79; P = .0061) in this patient subgroup.
At the meeting, additional data from the trial demonstrated that patients who relapsed early and who had 5% to 15% blasts and went on to receive escalated 21-day/cycle dosing, tolerated the escalated dose well. Specifically, the dosing was found to reduce blasts to less than 5% in approximately one-fourth of these patients.4
Notably, these patients did not experience an increase in new toxicities following dose escalation. As such, it was concluded that the 21-day dosing schedule for oral azacitidine should be considered for patients with AML who relapse with 15% blasts or less.
Patient-reported health-related quality of life (HRQOL) outcomes with the agent have also reported.5 Data have indicated that patients with CR or CRi who were in first remission after induction chemotherapy experienced numerically low levels of fatigue, and a favorable overall HRQoL at baseline, with scores comparable to those observed in the general populations.
Additionally, HRQoL was found to be preserved in patients who received maintenance treatment with oral azacitidine, remaining at, or slightly above, baseline levels over the entire duration of treatment. Changes from baseline in FACIT-Fatigue and EQ-5D-3L scores were noted to be comparable between the oral azacitidine and placebo arms.
In September 2020, the FDA approved oral azacitidine for the continued treatment of adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy, who were not able to complete intensive curative therapy based on data from QUAZAR AML-001.6 The agent was also approved for use in Canada as a maintenance treatment in adult patients with MAL who achieved CR or CRi after induction therapy with or without consolidation treatment, who are not candidates for HSCT.7