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

Apr 21, 2021
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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.

Figure 1. Dosing schedule for a 28-day cycle for each treatment 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, 6590); FLUGA arm, 76 (range, 6588).  
  • 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.

  1. Thomas XG, Dmoszynska A, Wierzbowska A, et al. Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML. J Clin Oncol. 2011;20-29(15_suppl):6504. DOI: 1200/jco.2011.29.15_suppl.6504
  2. Vives, S. Martínez‐Cuadrón D, Bergua Burgues J, et al. A phase 3 trial of azacitidine versus a semi‐intensive fludarabine and cytarabine schedule in older patients with untreated acute myeloid leukemia.  2021. Online ahead of print. DOI: 10.1002/cncr.33403

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