FDA Approves Oral Azacitidine for Acute Myeloid Leukemia


The FDA has approved oral azacitidine for the continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy who are not able to complete intensive curative therapy.

The FDA has approved oral azacitidine (Onureg, CC-486) for the continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or CR with incomplete blood count recovery following intensive induction chemotherapy who are not able to complete intensive curative therapy.1

“Continued treatment with [oral azacitidine] demonstrated an OS benefit in adults with AML who had achieved first complete remission in the QUAZAR AML-001 study and, notably, it has the potential to do this in a convenient manner, given its once daily oral formulation,” Andrew Wei, MBBS, PhD, QUAZAR AML-001 lead investigator, Alfred Hospital and Monash University, stated in a press release. “This approval should help establish continued treatment with [oral azacitidine] as a standard component of AML therapy for adults who achieved first complete remission following chemotherapy and who cannot proceed to intensive curative therapy, like hematopoietic stem cell transplant.”

The regulatory decision is based on data from the pivotal phase 3 QUAZAR AML-001 trial in which CC-486, an oral formulation of azacitidine, lengthened median overall survival (OS) by 9.9 months versus placebo in patients with AML who were in first remission.2

At a median follow-up of 41.2 months, the median OS was 24.7 months (95% CI, 18.7-30.5) with oral azacitidine versus 14.8 months (95% CI, 11.7-17.6) with placebo; this translated to a 31% reduction in the risk of death with the hypomethylating agent (HR, 0.69; 95% CI, 0.55-0.86; P = .0009). Moreover, the median relapse-free survival (RFS) was 10.3 months versus 4.8 months with oral azacitidine versus placebo, respectively (HR, 0.65; 95% CI, 0.52-0.81; P = .0001).

The FDA stated that the product has warnings and precautions for risks of substitution with other azacitidine products, myelosuppression, increased early mortality in patients with myelodysplastic syndromes (MDS) and embryo-fetal toxicity. The regulatory agency noted that significant differences in the pharmacokinetic parameters exist; As such, this product should not be substituted for intravenous or subcutaneous azacitidine; to do so, could lead to fatal adverse reactions.

Moreover, the FDA noted that new or worsening grade 3 or 4 neutropenia was reported in 49% of patients who received oral azacitidine, and 22% experienced thrombocytopenia. Moreover, febrile neutropenia was experienced by 12% of patients who received the treatment.

"Complete blood counts should be monitored, dosing should be modified as recommended and standard supportive care should be provided if myelosuppression occurs," according to the FDA.

A total of 472 patients were enrolled on the phase 3 QUAZAR AML-001 trial within 4 months of CR or CRi. Patients were randomized to receive daily treatment with oral azacitidine (n = 238) or placebo (n = 234). The hypomethylating agent was given daily for 14 days followed by 14 days off therapy. If a CR/CRi was not maintained, the dose of the agent could then be escalated to 21 days on drug with 7 days of rest.

The median age of the study participants was 68 years, with over two-thirds of patients 65 years of age or older. The most common ECOG performance scores were 0 (47% to 49%) and 1 (42% to 45%). The majority of participants had de novo disease (approximately 90%) and most had intermediate cytogenetic risk (approximately 86%).

The best responses to previous treatment consisted of CR for 79% of patients; for 21% of patients, it was CRi. In the placebo arm, the best responses were CR in 84% of patients and CRi in 16% of patients. Across both treatment arms, about one-fifth of participants had not received consolidation treatment before entering the study. Approximately half of patients had minimal residual disease negativity.

At 1 year, 47% versus 29% of patients in the oral azacitidine and placebo arms, respectively, were free of relapse. Benefits in both RFS and OS were observed across key prognostic patient subgroups.

Moreover, the median treatment duration with oral azacitidine 486 was 12 cycles versus 6 cycles with placebo. Notably, some participants who received oral azacitidine received up to 80 cycles of treatment.

With regard to safety, toxicities proved to be consistent with what have been reported with injectable azacitidine. Treatment discontinuation associated with adverse effects (AEs) proved to be infrequent. No treatment-related deaths were reported. The most commonly observed all-grade AEs with the hypomethylating agent included nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3/4 toxicities reported with oral azacitidine versus placebo included neutropenia (41% vs 24%, respectively), thrombocytopenia (23% vs 22%), anemia (14% vs 13%), diarrhea (5% vs 1%), vomiting (3% vs 0%), fatigue (3% vs 1%), and nausea (3% vs 0.4%).

Additional results from the trial focused on the safety of the agent specifically in patients who were 75 years of age or older at the time of study entry were presented during the 2020 ASCO Virtual Scientific Program. Overall, the hypomethylating agent was found to be well tolerated, and rates of individual AEs were found to be generally similar between all patients who received the drug and this specific subgroup.3

Notably, a lower incidence of thrombocytopenia was observed in this population compared with all patients who received oral azacitidine. Gastrointestinal effects were the most commonly reported toxicities in this subgroup, with diarrhea being the most comment effect to lead to treatment discontinuation.

Although older patients with AML are known to be at increased risk of relapse, oral azacitidine was found to result in statistically significant improvements in 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 population.

At the meeting, additional data from the trial demonstrated that patients who relapsed early who had 5% to 15% blasts and went on to receive escalated 21-day/cycle dosing tolerated the escalated dose well; the dosing was observed 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, investigators concluded that the 21-day dosing schedule for the hypomethylating agent should be considered for patients with AML who relapse with 15% blasts or less.

Finally, patient-reported health-related quality of life (HRQOL) outcomes were also reported. Results showed that patients with CR or CRi who were in first remission following induction chemotherapy reported numerically low levels of fatigue and a favorable overall HRQOL at baseline, with scores comparable to those of the general populations.5

Notably, HRQOL was preserved in patients who received maintenance treatment with the agent, remaining at, or slightly above, baseline levels over the entire treatment duration. Changes from baseline in FACIT-Fatigue and EQ-5D-3L scores were comparable between oral azacitidine and placebo.

“The FDA approval of [oral azacitidine] is the culmination of over a decade of research and 13 preclinical and clinical trials. We are grateful to the patients, families and caregivers who participated in and supported these trials, and who ultimately made today’s advancement possible,” Giovanni Caforio, MD, chairman and chief executive officer at Bristol Myers Squibb, added in the release. “This milestone is representative of our commitment to helping patients with hard-to-treat cancers live longer, and the approval of [oral azacitidine] as an oral therapy option for patients is more relevant now than ever as the world continues to navigate the COVID-19 pandemic.”


  1. US Food and Drug Administration approves Onureg (azacitidine tablets), a new oral therapy, as continued treatment for adults in first remission with acute myeloid leukemia. FDA. September 1, 2020. Accessed September 1, 2020. https://bwnews.pr/2QJJsx1.
  2. Wei AH, Döhner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission. Blood. 2019;134(suppl 2):LBA-3. doi:10.1182/blood-2019-132405
  3. Ravandi F, Wei A, Dohner H, et al. CC-486 is safe and well-tolerated as maintenance therapy in elderly patients (≥75 years) with acute myeloid leukemia (AML) in first remission following induction chemotherapy: results from the phase III QUAZAR AML-001 trial. J Clin Oncol. 2020;38(suppl 15):7530. doi:10.1200/JCO.2020.38.15_suppl.7530
  4. Dohner H, Wei A, Montesinos P, et al. Escalated dosing schedules of CC-486 for patients experiencing first acute myeloid leukemia (AML) relapse: results from the phase III QUAZAR AML-001 maintenance trial. J Clin Oncol. 2020;38(suppl 15):7513. doi: 10.1200/JCO.2020.38.15_suppl.7513
  5. Roboz GJ, Dohner H, Pocock C, et al. Health-related quality of life (HRQoL) in the phase III QUAZAR-AML-001 trial of CC-486 as maintenance therapy for patients with acute myeloid leukemia (AML) in first remission following induction chemotherapy (IC). J Clin Oncol. 2020;38(suppl 15):7533. doi:10.1200/JCO.2020.38.15_suppl.7533
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