Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission

N Engl J Med · 2020472 patients (238 oral azacitidine, 234 placebo)

Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al. N Engl J Med. 2020. 383:2526-2537

Study type: Clinical trial
Study name: QUAZAR AML-001
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial (maintenance therapy)
Sample size: 472 patients (238 oral azacitidine, 234 placebo)
Source: N Engl J Med · 2020
Trial registration: NCT01757535

In plain words

In many older patients with acute myeloid leukaemia, the first chemotherapy puts the disease into remission, but it often comes back. This study looked at patients who were in remission after chemotherapy but for whom a bone marrow transplant was not suitable. Taking azacitidine tablets on 14 days of each 28-day cycle raised the median survival from about 15 months to about 25 months and delayed the return of the disease, while quality of life was maintained. The most common side effects were mild to moderate stomach and bowel problems, which is why an anti-sickness medicine is given before each dose in the first two cycles; a drop in white blood cells was also seen more often.

Key results

24.7 vs 14.8 months

Median overall survival (from randomisation)

P<0.001

10.2 vs 4.8 months

Median relapse-free survival

P<0.001

41% vs 24%

Grade 3 or 4 neutropenia

22% vs 21%

Grade 3 or 4 thrombocytopenia

Maintained

Overall health-related quality of life

During treatment with CC-486

Drugs in this study:Azacitidine (Vidaza)

Dose and schedule cards

Oral azacitidine maintenance (QUAZAR)

AML in first CR or CRi after intensive induction, in a patient who cannot complete curative intensive treatment (including transplant)Cycle length: Every 28 daysOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

AML in first CR or CRi after intensive induction, in a patient who cannot complete curative intensive treatment (including transplant)

Drug	Dose	Route	Schedule
Maintenance
Oral azacitidine	300 mg once a day	Oral	Days 1 to 14

Cycle length: Every 28 days
Duration: Until progression or unacceptable toxicity

Antiemetic 30 minutes before each dose for the first 2 cycles. If neutrophils on day 1 are below 0.5×10⁹/L, delay the cycle; febrile neutropenia in 2 consecutive cycles: reduce to 200 mg and, if it recurs, shorten by 7 days. Not interchangeable with subcutaneous or IV azacitidine. Grade 3 or 4 neutropenia occurred in 41% vs 24%.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Oral azacitidine (CC-486)

Oral azacitidine (CC-486) 300 mg once daily for 14 days of each 28-day cycle, as maintenance therapy in first remission after intensive chemotherapy. Treatment duration and dose modifications in the trial: further details in the full text of the paper.

Per the FDA label (Onureg): 300 mg orally once daily on days 1 to 14 of each 28-day cycle; antiemetic 30 minutes before each dose in the first 2 cycles; oral azacitidine must not be substituted for IV or subcutaneous azacitidine.

2Placebo (control group)

Placebo once daily for 14 days of each 28-day cycle.

Source of the regimen details: Abstract of the paper (N Engl J Med 2020) and the FDA label for oral azacitidine (Onureg; DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 55 or older with acute myeloid leukaemia (AML) in first complete remission (with or without complete blood count recovery) after intensive chemotherapy who were not candidates for haematopoietic stem cell transplantation. Median age 68 years (range 55 to 86).

Endpoints

Primary outcome: overall survival.

Secondary outcomes: relapse-free survival and health-related quality of life.

Safety and side effects

The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events: neutropenia 41% with CC-486 versus 24% with placebo and thrombocytopenia 22% versus 21%. Overall health-related quality of life was maintained during treatment. Per the FDA label, an antiemetic is given 30 minutes before each dose in the first 2 cycles.

Clinical significance and place in guidelines

Per the FDA label, oral azacitidine (Onureg) is indicated for continued treatment of adults with AML who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after intensive induction chemotherapy and are not able to complete intensive curative therapy. QUAZAR AML-001 showed that oral maintenance therapy in these patients prolongs both overall and relapse-free survival. The oral formulation is not bioequivalent to injectable azacitidine and, per the label, must not be substituted for IV or subcutaneous azacitidine.

Limitations

Only patients aged 55 and older who were not candidates for haematopoietic stem cell transplantation were enrolled, and the results cannot be generalised to transplant candidates. Grade 3 or 4 neutropenia was more frequent with CC-486. CC-486 is not bioequivalent to injectable azacitidine, and the results cannot be generalised to injectable azacitidine. The study was sponsored by the manufacturer (Celgene).

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.