General AML

FLAG-IDA for acute myeloid leukemia

The combination of fludarabine, cytarabine and granulocyte colony stimulating factor (FLAG) with idarubicin (FLAG-IDA) is an effective treatment option for patients with newly diagnosed (ND) and relapsed/refractory (R/R) acute myeloid leukemia (AML).1 FLAG-IDA is also used for the treatment of patients with core binding factor (CBF) AML, though it was historically combined with gemtuzumab ozogamicin (GO; FLAG-GO) until GO was withdrawn from the market in the United States.2

During the 61st American Society of Hematology (ASH) Annual Meeting & Exposition, two abstracts focusing on the FLAG-IDA regimen for the treatment of AML were presented. Gautam M. Borthakur, University of Texas MD Anderson Cancer Center, Houston, US, presented results from a study comparing FLAG-IDA to FLAG-GO in patients with CBF AML, whilst Iman Aboudalle, American University of Beirut, Beirut, LB, discussed the results of a phase Ib/II trial investigating if the addition of venetoclax to the FLAG-IDA regimen could improve efficacy in patients with ND and R/R AML.1,2 This article summarizes the results from both presentations.

FLAG regimens for CBF AML2

Patients with CBF AML (with inversion [16] or translocation [8;21]) are highly responsive to high-dose cytarabine and, as such, to the FLAG-IDA and FLAG-GO regimens. Additionally, the presence of unique disease-defining fusion genes (RUNX1-RUNX1T1, CBFB-MYH11) allows measurable residual disease (MRD) monitoring by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) with high sensitivity at 10-5. Three log reduction in fusion transcripts at the end of induction, or four log or more at the end of three cycles, or at the end of all treatments, has previously been shown to be associated with a better remission duration

This current study analyzed the outcomes of ND patients with CBF AML, treated with FLAG-IDA or FLAG-GO for induction (Cycle one) and post-remission consolidation (Cycles 2–7). The study aimed to:

  1. Compare the efficacy of the FLAG-GO regimen to the FLAG-IDA regimen in relation to relapse-free survival (RFS) and overall survival (OS)
  2. Assess the level of MRD reduction as measured by qRTPCR
  3. Evaluate the impact of kinase mutations on clinical outcome

Dosing schedule and measurements

The dosing schedule for both regimens is shown in Table 1. Fusion transcripts, RUNX1-RUNX1T1 or CBFB-MYH11, were assessed at baseline and every 2–3 months via qRTPCR during consolidation.

Table 1. Dosing schedule for FLAG-GO and FLAG-IDA2

 

Induction

Consolidation

FLAG backbone

 

 

Fludarabine

30mg/m2 on Days 1–5

30mg/m2 on Days 1–3

Cytarabine

2g/m2 on Days 1–5

2g/m2 on Days 1–3

G-CSF

5mcg/kg on Days 1–5

5mcg/kg on Days 1–5

Addition of GO vs IDA 

 

 

GO

3mg/m2 on Day one

3mg/m2 in one of the planned six post-remission cycles

IDA

6mg/m2 on Days three and four

6mg/m2 in one of the planned four post-remission cycles

FLAG, fludarabine; cytarabine and granulocyte colony stimulating factor; G-CSF, granulocyte colony stimulating factor; GO, gemtuzumab ozogamicin; IDA, idarubicin

Patient characteristics2

  • Between April 2007 and January 2018, 153 patients with ND CBF AML were treated with FLAG-GO (n= 50) or FLAG-IDA (n= 103)
    • Median age (total cohort): 47 years (range: 19–78)
    • Patients > 65 years: 15%
    • Baseline characteristics of patients in both groups were comparable aside from the presence of KIT mutations which were present in 7% of patients in the FLAG-GO arm and 28% in the FLAG-IDA arm (p= 0.007), and RAS mutations (42% in the FLAG-GO arm and 28% in FLAG-IDA, p= 0.028)

Results2

Best response results are shown in Table 2 below.

Table 2. Responses by regimen2

 

Total cohort

FLAG-GO

FLAG-IDA

p value

N

153

50

103

-

CR/CRi, n (%)

153 (99)

50 (96)

103 (100)

0.14

Early death

2 (3)

2 (4)

0

-

Molecular response

Three-log reduction after induction

68/140 (49)

30 (65)

38 (40)

0.01

Four-log reduction after Cycle 3

68/131 (52)

30 (75)

38 (42)

< 0.001

Four-log reduction at end of therapy 

83/123 (67)

36 (92)

47 (56)

< 0.001

RFS

RFS at a median follow-up of 65 months, %

Not reported

87%

67%

0.015

CR, complete remission; CRi, complete remission with incomplete blood count recovery; FLAG-GO, fludarabine cytarabine, granulocyte colony stimulating factor with gemtuzumab ozogamicin; FLAG-IDA, fludarabine cytarabine, granulocyte colony stimulating factor with idarubicin; RFS, relapse-free survival

Multivariate analysis comparing FLAG-GO to FLAG-IDA found significant associations as shown in Table 3. Interestingly, the presence of KIT or any kinase mutation (KIT, RAS or FLT3) did not impact RFS

Table 3. Significant associations with RFS and OS by multivariate analysis2

Outcome

Factor

Impact

p value

HR

95% CI

RFS

Age

Worsened

0.001

1.03

1.01–1.05

RFS

Regimen (FLAG-GO)

Improved

0.046

0.392

0.157–0.983

RFS

Three-log reduction in fusion transcripts post-induction

Improved

0.026

0.412

0.189–0.897

RFS

Four-log or higher reduction in fusion transcripts at end of treatment

Improved

0.001

0.3

0.15–0.63

OS

Age

Worsened

0.002

1.035

1.013–1.058

OS

Four-log or higher reduction in fusion transcripts at end of treatment

Improved

0.02

0.41

0.19–0.87

FLAG-GO, fludarabine, cytarabine, granulocyte colony stimulating factor with gemtuzumab ozogamicin; HR, hazard ratio; OS, overall survival; RFS, relapse-free survival

Fusion transcript ratios2

This study confirmed previous results that a reduction of fusion transcript ratio led to in improvement in RFS. Additionally, a four-log reduction of fusion transcript ratio at the end of therapy was associated with both RFS (p= 0.001) and OS (p= 0.013). FLAG-GO was the only predictor for achievement of optimal qRTPCR response at all time points.

This study has demonstrated that both FLAG-GO and FLAG-IDA regimens can induce high response rates in patients with newly diagnosed CBF AML. Other key takeaways include:2

  • The FLAG-GO regimen resulted in better RFS and a higher reduction in fusion transcript ratio when compared to FLAG-IDA
  • Age, and a four-log reduction or more of transcript ratios, are predictors for OS
  • Kinase mutations did not lead to reduced RFS
  • Monitoring fusion transcripts may help identify patients with better chances of sustained remissions
Phase Ib/II study of FLAG-IDA + venetoclax1

Study design and objectives1

  • Primary aims:
    • Phase Ib: assess the safety and tolerability of FLAG-IDA + venetoclax in patients with R/R AML (N= 16)
    • Phase II: evaluate overall response rate (ORR) by modified International Working Group AML criteria in patients with ND or R/R AML
      • Target enrolment is 25 patients per cohort
      • Results reported here are for patients enrolled and treated up to data cut-off (ND; n= 14 and R/R; n= 10)
    • Secondary analyses were for duration of response (DoR), OS, and RFS
    • Exploratory endpoints included MRD assessment by flow cytometry and biomarker analysis

Patient characteristics1

Eligible patients had AML or high-risk myelodysplastic syndrome, an Eastern Cooperative Oncology Group (ECOG) score of two or less, and adequate organ function. At data cut-off, 40 patients had been enrolled with a median age of 48 years (range: 21–72), and 18% of patients over the age of 60. Patients had received a median of two prior therapies (range: 1–4), 40% had adverse cytogenetics and 38% had received prior allogeneic stem cell transplant (allo-SCT).

Dosing schedule1

  • Induction/consolidation with FLAG-IDA:
    • Fludarabine: 30mg/m2 intravenously (IV) on Days 2–6
    • Cytarabine, 1.5g/m2 IV on Days 2–6
    • Idarubicin: IV on Days 4–6:
      • R/R AML: 6mg/m2
      • ND AML: 8mg/m2
    • Filgrastim: 5mcg/kg daily on Days 1–7
  • Oral administration of venetoclax in the dose escalation (3+3) phase:
    • Dose level one (n= 8): 200mg on Days 1–21
      • Cytarabine: 2mg/m2
      • Due to increased toxicity (sepsis and/or bacteremia), the dosing for dose level two was amended
    • Dose level two (n= 5): 200mg on Days 1–14
      • Cytarabine: 1.5mg/m2
    • Dose level three (n= 3): 400mg on Days 1–14
      • Cytarabine: 1.5mg/m2
    • A venetoclax dose of 400mg on Days 1–14 was deemed to be safe for the phase II portion, with 1.5mg/m2 of cytarabine
  • Maintenance: venetoclax monotherapy (400mg) continuously, for patients not continuing to allo-SCT for up to one year

Results1

  • Median number of cycles received: two (range: 1–4)
  • All patients were evaluable for response (Table 4)
  • Sixteen patients subsequently received an allo-SCT
    • R/R AML: n= 10
    • ND AML: n= 6
  • Three patients in the phase Ib portion proceeded to venetoclax maintenance
    • Median number of maintenance Cycles: two (range: 1–3)

Table 4. Phase Ib/II responses to FLAG-IDA + venetoclax by patient population1

 

Phase Ib

Phase II

Patient population

R/R AML

R/R AML

ND AML

N

16

10

14

ORR, n (%)

12 (75)

7 (70)

13 (93)

Best response of CR+CRi, n (%)

12 (75)

7 (70)

12 (85)

MRD-negativity by flow cytometry, n (%)

9 (56)

5 (50)

11 (85)

Best response after one cycle, n (%)

10 (83)

6 (85)

13 (100)

CR+CRi, complete remission + complete remission with incomplete blood count recovery; MRD, measurable residual disease; ND, newly diagnosed; ORR; overall response rate; R/R, relapsed/refractory

  • R/R AML cohort
    • Median follow-up: 5.2 months (range: 1.1–15.8):
    • OS (n= 26): 9.4 months
    • RFS (n= 19): 13.4 months
  • ND AML cohort
    • Median follow-up: 5.5 months (range: 1.7–8)
    • OS and RFS: not reached (NR)

Safety1

  • No tumor lysis syndrome events occurred
  • Adverse events (AEs) grade ≥ 3 are shown in Table 5
  • Mortality:
    • Thirty-day mortality: 0%
    • Sixty-day mortality:
      • ND AML: 0%
      • R/R AML: 11% (two of three were due to progressive disease)
    • In patients with R/R AML (treated in both phase Ib/II parts of the study [n= 26]), 10 went on to allo-SCT, three relapsed, three died in complete remission (CR) and three are active on study
    • In the ND AML population (n= 14) no patients have died, with six proceeding to allo-SCT, none relapsing, one withdrawing consent, and six remaining active on study

Table 5. SAEs occurring in ≥ 10% of patients1

AE, %

Grade 3–4

Grade 5

Infections

32

4

Bacteremia

18

0

Hypokalemia

18

0

Hypophosphatemia

16

0

ALT increase

10

0

This study concluded that FLAG-IDA, in combination with venetoclax, is efficacious in patients with R/R AML and fit patients with ND AML. The phase II portion of the study is ongoing with a longer follow-up required to establish a survival benefit.

Conclusion1,2

Both studies reported here have shown that FLAG-based regimens have an important role in the treatment of AML, including in the ND and R/R setting, and in various subtypes of AML such as CBF AML. Moving forward, longer follow-up is required to understand if there is a survival benefit when venetoclax is added to FLAG-IDA, and monitoring of fusion transcript levels in CBF AML may be used to help identify patients more likely to experience sustained remissions.

References
  1. Aboudalle I. et al., A Phase Ib/II Study of the BCL-2 Inhibitor Venetoclax in Combination with Standard Intensive AML Induction/Consolidation Therapy with FLAG-IDA in Patients with Newly Diagnosed or Relapsed/Refractory AML. Oral abstract #176: 61st American Society of Hematology (ASH) Meeting & Exposition, Florida, US
  2. Borthkaur G.M. et al., Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin (FLAG-GO) Regimen Results in Better Molecular Response and Relapse-Free Survival in Core Binding Factor Acute Myeloid Leukemia Than FLAG and Idarubicin (FLAG-Ida). Oral abstract #290: 61st American Society of Hematology (ASH) Meeting & Exposition, Florida, US

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