FLUGAZA trial: Azacitidine vs semi-intensive chemotherapy for older patients with newly diagnosed AML

Patients over 65 who are newly diagnosed with acute myeloid leukemia (AML) currently have a poor prognosis, due to the toxicity and limited efficacy associated with high-intensity chemotherapy. Alternative treatment strategies for this patient group include the use of hypomethylating agents (HMAs). A previous comparative trial (NCT00260832) demonstrated improved survival using the HMA, decitabine, over conventional chemotherapy approaches; supportive care and low-dose cytarabine (LDAC).¹ Since 2011, an adapted semi-intensive regimen from the Programa Español de Tratamientos en Hematología (PETHEMA) group has been used among PETHEMA institutions, with the aim of improving complete remission (CR) and tolerability.² This regimen, FLUGA, combines oral fludarabine and filgrastim with LDAC.

Susana Vives and colleagues recently published the findings from a multicenter, randomized phase III trial (FLUGAZA; NCT02319135) in Cancer, demonstrating the first comparison of overall survival (OS) in elderly patients with newly diagnosed AML treated with either a FLUGA regimen or the HMA, azacitidine, given as monotherapy. We summarize key findings from this study below.²

Study design

Eligibility

• Patients aged ≥65 with newly diagnosed AML, according to the World Health Organization criteria
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status <4
• Patients excluded were those with co-existing illnesses and those previously treated with HMAs or standard chemotherapy for preleukemic conditions.

Treatment schedule

• Patients (n = 283) were randomized 1:1 to receive either azacitidine (n = 142) or FLUGA (n = 141).
• Induction treatment was performed in three cycles followed by six cycles of consolidation, with each cycle lasting 28 days (Figure 1).
• Measurable residual disease (MRD) was observed after Cycle 9 and if patients had MRD ≥0.01%, they continued with the same treatment regimen until relapse or progression. Patients with MRD <0.01% finished treatment and moved onto the follow-up phase.
• The median follow-up of patients alive was 29.1 months in the azacitidine arm and 32.9 months in the FLUGA arm.

AZA, azacitidine; D, day; FLUGA, fludarabine, cytarabine, and filgrastim; IV, intravenous; SC, subcutaneous.
*Data from Vives et al.^2
†D2–5 for patients aged ≥75.

Endpoints

• Primary endpoint was OS at 1 year.
• Secondary endpoints included complete remission (CR) and CR with incomplete blood count recovery (CRi) over nine cycles, 2- and 3-year OS, event-free survival (EFS), disease-free survival, and relapse-free survival in the first, second, and third year.
• Safety data included the number of hematologic and non-hematologic adverse events (AEs).

Key results

Patient characteristics

• Median age: azacitidine arm, 74 (range, 65–90); FLUGA arm, 76 (range, 65–88).  
• There were no significant differences in other baseline characteristics (sex, performance status, AML diagnosis, risk classification, karyotype, and white blood cell counts) between the treatment arms.

Response rates

• Hematological response rate data for the intent-to-treat (ITT) population are summarized in Table 1.

• • CR rate was greater after 3 months in the FLUGA cohort (18% vs 9%; p = 0.038).
  • Overall response rate (ORR; CR + CRi) improved by 9 months for patients treated with azacitidine with no significant difference compared to FLUGA-treated patients (27% vs 33%; p = 0.418).

Table 1. Response data for the ITT population over induction and consolidation treatment*

AZA, azacitidine; CR, complete remission; CRi, CR with incomplete blood count recovery; FLUGA, fludarabine, cytarabine, and filgrastim; ITT, intent-to-treat; ORR, overall response rate. *Data from Vives et al.2
Response	AZA (n = 142)	FLUGA (n = 141)	p value
CR after 3 cycles, %	9	18	0.038
CRi after 3 cycles, %	13	15	—
ORR, %               3 cycles               6 cycles               9 cycles	23 24 29	33 33 33	0.058 0.081 0.418

Survival endpoints

• Overall survival data for the ITT population are summarized in Table 2.

• • OS at 1 year was greater for patients treated with azacitidine compared with FLUGA (47% vs 27%; p = 0.001).                                          
  • 2- and 3-year OS was also greater for the azacitidine arm (19% and 10%, respectively) compared with FLUGA (12% and 5%).
  • Median OS was significantly greater in the azacitidine arm vs the FLUGA arm (9.8 vs 4.1 months; p = 0.005).
  • Median EFS was greater in the azacitidine arm compared with FLUGA (4.9 vs 3 months; p = 0.001).
  • No statistically significant difference was found for all other secondary endpoints.

Table 2. Primary and secondary endpoint data for AZA and FLUGA treatment arms*

AZA, azacytidine; EFS, event-free survival FLUGA, fludarabine, cytarabine, and filgrastim; OS, overall survival. *Adapted from Vives et al.2
Endpoint	AZA (n = 142)	FLUGA (n = 141)	p value
OS (%)               1-year               2-year               3-year Median OS, months	47 19 10 9.8	27 12 5 4.1	0.001 0.005
EFS (%)                 1-year                 2-year                 3-year Median EFS, months	31 9 5 4.9	12 5 1 3.0	0.001

Safety

• The rate of hematological AEs (Grade 3–4) was higher in the FLUGA arm vs the azacitidine arm (23% vs 14%; p = 0.004), however the number of patients with >1 AE was similar between the treatment groups (25% vs 20%; p = 0.376).
• The number of non-hematological AEs (Grade 3–4) was similar between the azacitidine (n = 266) and FLUGA (n = 265) arms.

Table 3.  Grade 3–4 AEs reported within treatment arms*

AE, adverse events; AZA, azacitidine; FLUGA, fludarabine, cytarabine, and filgrastim. *Adapted from Vives et al.2
Grade 3–4 AEs	AZA (n = 142)	FLUGA (n = 141)
Total Grade 3–4 AEs, n	311	346
Hematological AEs, n (%)	45 (14)	81 (23)
Patients with >1 hematological AE, n (%)	29 (20)	35 (25)
Non-hematological AEs, n (%)	266 (86)	265 (77)
Patients with >1 non-hematological AE, n (%)	106 (75)	117 (83)

Conclusion

Data from this comparative study demonstrated improved OS over 3 years with azacitidine monotherapy, compared to a FLUGA semi-intensive chemotherapy regimen, for older patients with treatment-naïve AML. It is important to note, however, that long-term OS (2- and 3-year) was poor for both treatment arms. Although rates of CR were greater after 3 cycles of the FLUGA regimen, there was no significant difference by Cycle 6.

As such, the authors concluded these data demonstrate potential for the use of azacitidine as a backbone in induction and consolidation therapy combinations for elderly patients with AML, as opposed to LDAC.