Azacitidine versus decitabine for patients with naïve AML not eligible for intensive chemotherapy

Elderly and unfit patients with treatment naïve acute myeloid leukemia (TN-AML) who are ineligible for intensive chemotherapy have limited available treatments, and thus, very poor outcomes. The standard of care in this patient population is between two hypomethylating agents (HMAs), azacitidine (AZA) and decitabine (DEC), which have both been approved in Europe and US for AML patients who are ineligible for intensive chemotherapy or hematopoietic cell transplant. Nevertheless, a study comparing the efficacy and safety of AZA and DEC in this disease setting was missing. Therefore, Amer Zeidan and colleagues conducted a comparative study using prospective data from the largest global randomized trial in this patient population, ASTRAL-1, to directly compare AZA to DEC in patients receiving these two treatments.^1,2

Methods

Data from the randomized phase III, ASTRAL-1 study were used to compare the clinical efficacy and safety of AZA versus DEC in older and unfit patients with TN-AML. This trial prospectively analyzed 815 patients with TN-AML who were ineligible for intensive chemotherapy, including patients who were aged ≥ 75 years or had major comorbidities and an Eastern Cooperative Oncology Group (ECOG) performance status of 2–3.

In ASTRAL-1, patients were randomized 1:1 to either guadecitabine (n = 408), a next generation HMA or treatment of choice (ToC; n = 388) with AZA (dose of 75 mg/m²/day; Days 1–7; n = 171), or DEC (20 mg/m²/day; Days 1–5; n = 167), or low-dose Ara-C (LDAC) (20 mg; Days 1–10). The baseline variables, as shown in Table 1, were well balanced with no statistically significant differences between the AZA and DEC treatment arms.

An independent central pathologist who was blinded to randomization determined AML diagnoses and responses to treatment based on the International Working Group (IWG) 2003 criteria. The co-primary endpoints were complete response (CR) rates, overall survival (OS).

The median follow-up was 25.5 months and patients had a median of six treatment cycles for AZA (range, 1–31), and five for DEC (range, 1–34).¹

Table 1. Baseline characteristics in patients receiving azacitidine or decitabine²

AML, acute myeloid leukemia; BM, bone marrow; ECOG PS, Eastern Cooperative Oncology Group Performance Status; WBC, white blood count
Characteristics	Azacitidine (N = 171)	Decitabine (N = 167)
Median age (range)	76 (59–94)	76 (60–87)
Males, %	61	56
ECOG PS, % 0–1 2–3	53 47	46 54
Secondary AML, %	38	37
Poor risk cytogenetics, %	38	34
Total WBC ≥ 20.000/µL, %	15	13
BM blasts > 30%	64	71
TP53 mutation, %	11.7	11.4

Results

Efficacy

The intention-to-treat (ITT) analyses showed that there was no difference in clinical response between AZA and DEC with no statistically significant differences when accounting for covariates such as treatment cycles, age, secondary AML, or genetic subgroups, including FLT3-ITD, NPM1, CEBPA, TP53. The response rates for AZA and DEC are shown in Table 2. In brief, the CR rates were 17.5% vs 19.2% (p = 0.78), respectively, and the overall CR (CR + CRp + CRi) was 22.2% vs 25.1% (p = 0.53) for AZA vs DEC respectively. The median OS was 8.7 vs 8.2 months for AZA vs DEC, respectively; see Table 3. 

Table 2. Response rates from treatment with azacitidine or decitabine^1,2

CR, complete response; CRc, composite CR; CRi, CR with incomplete blood count recovery; CRp; CR with incomplete platelet recovery
Response rate	Azacitidine (n = 171)	Decitabine (n = 167)	p value
Median number of cycles (range)	6 (1–31)	5 (1–34)
CR, %	17.5	19.2	0.78
CRp, %	1.2	1.2
CRi, %	3.5	4.8
CRc (CR + CRi + CRp), %	22.2	25.1	0.53

Table 3. The overall survival of patients treated with azacitidine or decitabine²

CI, confidence interval; HR, hazard ratio; OS, overall survival
Survival	Azacitidine (n = 171)	Decitabine (n = 167)	p value (95% CI)	HR
Median OS, months	8.7	8.2	0.81 (0.77–1.23)	0.97
1-year survival, %	39	32
2-year survival, %	15	14

Safety

There was no statistically significant difference in the incidence of Grade ≥ 3 adverse events (AEs) between AZA vs DEC, including febrile neutropenia (29% vs 26%), thrombocytopenia (18% vs 23%) or all-cause 30-day mortality (12% vs 8%). Treatment with AZA showed a trend for higher all-cause 60-day mortality of 21% vs 13% for DEC (p = 0.08), which was not statistically significant. The incidence of fatal serious AEs was also higher in patients treated with AZA, 38% vs 26%, but this was not thought to be treatment related. See Table 4 for the safety profile of patients treated with AZA or DEC.   

Table 4. The safety profile of patients treated with azacitidine or decitabine²

AE, adverse event *Neutropenia difference p value was 0.06 †Fatal serious AE difference p value was 0.02 ¥60-day mortality difference p value was 0.08
Adverse event	Azacitidine (n = 171)	Decitabine (n = 167)
Grade ≥ 3 AEs with ≥ 10% incidence
Febrile neutropenia, %	29	26
Pneumonia, %	23	19
Thrombocytopenia, %	18	23
Neutropenia, %*	16	25
Anemia, %	16	19
Sepsis, %	14	12
Serious AE leading to death, %†	38	26
All-cause 30-day mortality, %	12	8
All-cause 60-day mortality, %¥	21	13

Conclusion

This study is the largest study comparing the clinical outcomes from patients with TN-AML ineligible for intensive chemotherapy who received AZA and DEC as treatment. The patient population was reflective of real life with an ECOG PS 2–3, and the baseline characteristics were well balanced between the two treatment arms. The results of this study showed that there were no significant differences in CR, overall CR, OS, or safety between AZA and DEC in this patient subset.