Outcomes with Azacitidine Similar to Other Treatments for Older Patients with AML

Older patients with acute myeloid leukemia (AML) may benefit similarly from treatment with the hypomethylating agent azacitidine as they do to other chemotherapy approaches, according to results from a phase III randomized trial recently published in Blood. These higher-risk patients have a particularly poor prognosis and sometimes only receive palliative care, the authors, led by Prof. Hervé Dombret from the Cardiff University School of Medicine in the United Kingdom, explained.

“There is no universally accepted standard approach to AML treatment for older patients,” Dr. Dombret and co-authors wrote, explaining that those considered “fit” for more intensive induction therapy can have variable rates of survival, and those considered “unfit” are commonly treated with best supportive care or low-dose cytarabine – with less-than-impressive rates of overall survival.

In this international multicenter, randomized, open-label, phase III trial, investigators evaluated the safety and efficacy of azacitidine versus conventional care regimens (CCR) in 488 patients 65 years old or older with newly diagnosed AML and >30 percent of bone marrow blasts who were not considered eligible for hematopoietic stem cell transplantation. Before randomization, one CCR approach (consisting of standard, “7+3” induction chemotherapy, low-dose cytarabine, or supportive care only) was selected by doctors for each patient; patients were then assigned 1:1 to azacitidine (n=241) or CCR (n=247).

Azacitidine (75 mg/m2) was administered once-daily subcutaneously for seven consecutive days per 28-day treatment cycle for at least six cycles. In the CCR arm, 45 patients were assigned to best supportive care, 158 to cytarabine, and 44 to induction chemotherapy.

Baseline demographic and disease characteristics were generally balanced between the treatment arms, with more than half of all patients (54%) 75 years of age or older, and median bone marrow blasts were 72 percent among all patients.

Treatment with azacitidine was associated with a non-significant improvement in survival endpoints, the authors reported. Overall survival (the study’s primary endpoint) was 10.4 months (95% CI 8.0-12.7) in the azacitidine arm versus 6.5 months (95% CI 5.0-8.6) in the CCR arm (HR=0.85; 95 CI 0.69-1.03; p=0.1009).

One-year survival rates with azacitidine and CCR were 46.5 percent and 34.2 percent, respectively (difference = 12.3% [95% CI 3.5%-21.0%]).

Univariate analysis also showed similar trends for azacitidine compared with CCR across all subgroups – including patients with poor-risk cytogenetics and those with prior myelodysplastic syndromes.

Azacitidine was also generally well-tolerated; more than one-half of azacitidine-treated patients received six or more treatment cycles, and one-third received 12 or more. Patients taking cytarabine received a median of four treatment cycles which, the authors noted, “is double the reported median [low-dose cytarabine] in most large clinical trials.”

A total of 69 patients (28.6%) in the azacitidine group and 75 patients (30.4%) in the CCR group went on to receive subsequent AML treatment after discontinuing the randomized study treatment. The most common treatments included – either alone or in combination – a cytarabine-based regimen, azacitidine, and/or decitabine. When adjusted for use of subsequent AML therapy as a time-dependent variable and baseline covariates (including cytogenetic risk, BM blasts, and age), azacitidine improved overall survival compared with CCR (HR=0.69; 95% CI 0.54-0.88]; p=0.0027).

Most patients experienced a treatment-emergent adverse event (TEAE) during the study (99.2% in the azacitidine arm, 100% in the CCR arm). Notably, drug-related TEAEs leading to study discontinuation occurred in 22 patients (9.3%) in the azacitidine arm, 20 patients (13.1%) in the low-dose cytarabine arm, and five patients (11.9%) in the intensive chemotherapy arm. The most frequently reported drug-related AEs in these groups were nausea (27.1%, 22.2%, and 42.9%), neutropenia (19.9%, 22.9%, and 31.0%), and thrombocytopenia (17.4%, 22.2%, and 21.4%), respectively.

During treatment, azacitidine and CCR were associated with general improvement in health-related quality of life.

With regard to the CCR options, patients preselected to receive induction chemotherapy and those who received azacitidine had comparable rates of both overall survival (13.3 vs. 12.2 months, respectively) and one-year survival (55.8% vs. 50.9%). This finding suggests that low-intensity azacitidine treatment may benefit older patients with AML who, though fit for induction chemotherapy, choose to forego intensive therapy, the authors concluded.


Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 May 18. [Epub ahead of print]