FLT3

Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML

Patients with acute myeloid leukemia (AML) who also have an FMS-like tyrosine kinase 3 (FLT3) activating mutation tend to have poorer outcomes in terms of survival and initial therapy failure.1 These patients are less likely to respond to salvage chemotherapy, which has prompted research into FLT3 tyrosine kinase inhibitors as treatment options. Gilteritinib is a highly selective oral inhibitor of FLT3 that works against the two mutant FLT3 subtypes, the internal tandem duplication (ITD) and the tyrosine kinase domain (TKD). It has demonstrated a sustained inhibitory effect in 41% of patients with FLT3-mutated relapsed or refractory (R/R) AML at a dose of ≥80mg per day during a phase I-II study (NCT02014558; previously reported on the AML global portal here).2

Alexander Perl of the University of Pennsylvania, Abramson Comprehensive Cancer Center, Philadelphia, PA, US, and colleagues, recently published the results of their randomized phase III study (ADMIRAL, NCT02421939) in the New England Journal of Medicine, which compared gilteritinib to salvage chemotherapy (SC) in patients with FLT3-mutated R/R AML.1

A total of 371 patients with R/R AML were included in the study, all of whom had either the FLT3 ITD or TKD (D835 or I836) mutations. Patients were randomly allocated in a 2:1 ratio to either 120mg per day gilteritinib (n= 247), rising to 200mg per day in the case of no complete response (CR), or SC (n= 124). Both gilteritinib and SC were given in 28-day cycles.

Patients in the SC arm were allocated to receive one of the following four chemotherapy regimens, based on their response to previous treatment: mitoxantrone, etoposide, and cytarabine (MEC); fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida); low-dose cytarabine (LDAC); or azacitidine. MEC and FLAG-Ida were deemed high intensity regimens, while LDAC and azacitidine were low intensity. Those patients receiving high-intensity SC were assessed for the need of a further cycle of treatment on day 15, and then for a response to treatment on day 1 of cycle 2. Patients in the gilteritinib arm and those receiving low-intensity SC were given treatment until evidence of lack of benefit, or toxic effects forced cessation of treatment. Response was assessed in these patients on day 1 of cycles 2 and 3 and then every two to three cycles after this. Primary outcomes were overall survival (OS) and CR with full or partial hematologic recovery (CRi).

Patient characteristics:

  • In total, 60.6% of patients had R/R AML, with the remaining 39.4% having primary refractory disease
  • In total, 83.8% of patients had received anthracycline-based induction therapy, 12.4% had a previous treatment with a FLT3 inhibitor and 19.9% of patients had relapsed after hematopoietic stem cell transplantation (HSCT)

Key findings

  • Amongst patients receiving high-intensity SC, 94.1% had just one cycle of treatment
  • The median duration of low-intensity SC was 4 weeks (LDAC range, 2–31 days, azacitidine range, 1–26 days)
  • The median number of cycles of gilteritinib was 5 (range, 1–33)
  • Common reasons for therapy discontinuation:
    • Gilteritinib: lack of efficacy (50.2%), death (14.6%), or adverse events (11.3%)
    • SC: relapse/progression/lack of efficacy (39.5%), withdrawal by patient (8.1%), clinician decision (8.9%), or death (8.1%)

Efficacy

  • Median OS:
    • Gilteritinib: 9.3 months
    • SC: 5.6 months
    • Comparison: p<0.001
  • OS at 1 year:
    • Gilteritinib: 37.1%
    • SC: 16.7%
    • Comparison: hazard ratio (HR)= 0.64 (95% confidence interval [CI], 0.49–0.83)
  • Subgroup Analysis of OS: Longer OS with gilteritinib vs SC was sustained regardless of high/low intensity chemotherapy, FLT3 mutation type, previous use of FLT3 inhibitors, cytogenetic risk status (except in the unfavourable category), response to first-line therapy (though there was no clear benefit of gilteritinib in patients with primary refractory disease without allogeneic HSCT), or Eastern Cooperative Oncology Group (ECOG) score status (Table 1). Also, co-mutations (with commonly occurring mutations NPM1 [46.6%] and DNMT3A [31.0%]) did not alter the longer survival observed with gilteritinib vs SC
  • More patients in the gilteritinib group had an HSCT than in the SC group (25.5% vs 15.3%), yet the OS seen with gilteritinib was sustained when data were censored at time of HSCT (HR for death 0.58; 95% CI, 0.43–0.76)
  • Response rates (overall study population):
    • Gilteritinib: CR was 21.1% and CR/CRi was 34.0%
    • SC: CR was 10.5% and CR/CRi was 15.3%
  • Response rates (primary refractory AML group):
    • Gilteritinib: CR/CRi was 31.6%
    • SC: CR/CRi was 20.8%
  • Response rates (FLT3 ITD group):
    • Gilteritinib: CR was 20.5%
    • SC: CR was 9.7%
  • Median event free survival (EFS):
    • Gilteritinib: 2.8 months
    • SC: 0.7 months
  • Transfusion independence: 79.8% of patients in gilteritinib arm were transfusion-dependent at randomization, and of those 34.5% became transfusion-independent

Safety

  • The most common adverse events that were grade ≥3 were:
    • Gilteritinib: febrile neutropenia (45.9%), anemia (40.7%), or thrombocytopenia (22.8%)
    • SC: febrile neutropenia (36.7%), anemia (30.3%), or decreased platelet count (24.8%)
  • Serious adverse events (SAEs): There were 181 (out of 246 patients evaluated) SAEs in the gilteritinib arm and 15 (out of 109 patients evaluated) in the SC arm
    • Incidence of exposure-adjusted SAEs was 7.11 events per patient-year in the gilteritinib group and 9.24 events per patient-year in SC group
  • Treatment discontinuation: Gilteritinib related adverse events leading to the discontinuation of treatment were reported in 27 patients. The most common events included elevated aspartate aminotransferase level (4 patients), elevated alanine aminotransferase level (3 patients), or pneumonia (3 patients)
    • The most common fatal adverse events considered to be gilteritinib-related were pneumonia (3 patients), large intestine perforation (2 patients) and septic shock (2 patients)
    • In the SC group, the most common fatal adverse events were sepsis (2 patients), and respiratory failure (2 patients)
  • Cause of death: There were 251 deaths (of 355 patients in safety population), 69.1% of the gilteritinib group, and 74.3% of the SC group
    • Common fatal events in both groups were disease progression (12.2% of gilteritinib group, 4.6% of SC group) and infection (11.4% of gilteritinib group, 6.4% of SC group)

Table 1: Subgroup analysis

Subgroup

Gilteritinib

SC

HR for death (95% CI)

No. of events/total no. of patients

Preselected SC

High intensity

Low intensity

 

96/149

75/98

 

52/75

38/49

 

0.66 (0.47–0.93)

0.56 (0.38–0.84)

FLT3 mutation type

FLT3 ITD alone

FLT3 TKD alone

FLT3 ITD and FLT3 TKD

Other

 

145/215

16/21

6/7

4/4

 

81/113

8/10

0

1/1

 

0.62 (0.47–0.82)

0.69 (0.29–1.64)

Not evaluated

0.70 (0.06–7.92)

Previous FLT3 inhibitor use

Yes

No

 

26/32

145/215

 

11/14

79/110

 

0.70 (0.35–1.44)

0.62 (0.47–0.82)

Cytogenetic risk status

Favorable

Intermediate

Unfavorable

Unknown

 

3/4

119/182

22/26

27/35

 

1/1

63/89

7/11

19/23

 

0.70 (0.06–7.92)

0.60 (0.44–0.82)

1.63 (0.69–3.85)*

0.46 (0.25–0.84)

Response to first line therapy

Relapse ≤ 6 months after allo-HSCT

Relapse > 6 months after allo-HSCT

Primary refractory disease without allo-HSCT

Relapse ≤ 6 months after cCR and no allo-HSCT

Relapse > 6 months after cCR and no allo-HSCT

 

24/31

10/17

70/98

47/67

20/34

 

16/17

4/8

28/48

28/34

14/17

 

0.38 (0.20–0.75)

0.86 (0.26–2.80)

0.99 (0.63–1.55)

0.49 (0.30–0.80)

0.49 (0.25–0.98)

ECOG performance status score

0 or 1

≥ 2

 

138/206

33/41

 

78/105

12/19

 

0.60 (0.45–0.79)

0.87 (0.45–1.69)

The Kaplan-Meier method along with the Greenwoord formula was used to determine hazard ration (HR) for death and 95% confidence intervals (CI). Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5; higher score indicates lower functional status, and 5 indicates death.

Allo-HSCT; Allogeneic hematopoietic stem-cell transplantation. cCR; composite complete remission (CR plus CRi plus CR with incomplete platelet recovery). * = favors SC over gilteritinib, the remaining HRs favoured gilteritinib

Alexander Perl and colleagues highlighted the improved OS and remission rates achieved by gilteritinib compared to SC in this patient group. They also commented on the limited statistical power of the multiple comparisons made in the subgroup analysis but went on to state that gilteritinib consistently conveyed a survival benefit across the many subgroups assessed. The authors pointed out some limitations of the study, including the trial design that may have resulted in a potentially inaccurate estimate of response duration in the SC group. In addition, trial enrolment took place before the wider use of another FLT3 inhibitor, midostaurin, as a first-line treatment in combination with chemotherapy. Therefore, any resistance to FLT3 inhibitor therapy that this may have generated would not have been well captured. Perl and colleagues went on to state that any survival advantage associated with gilteritinib following allogeneic HSCT in this study was difficult to assess. Other ongoing studies will elucidate the role gilteritinib in first-line induction treatment (NCT02752035), as a maintenance therapy following induction or consolidation therapy (NCT02927262), and as a post-allogeneic HSCT maintenance therapy (NCT02997202). The group concluded that gilteritinib offers longer survival and higher remission rates than SC in patients with R/R FLT3 mutated AML, a group in which limited options are available.

Alexander Perl was interviewed by the AML Global Portal at the European Hematology Association (EHA; June 2019) where he discussed the early results of this study (which can be viewed here), and the interim study results summary that can be reached here.

Related AML Global Portal articles include a summary of the current landscape of FLT3 inhibitors (presented by Catherine Smith of the University of California San Francisco, US, at the Society of Hematologic Oncology (SOHO) in October 2019) and an interview with Mark Levis of John Hopkins University, Baltimore, US, on maintenance therapy with gilteritinib at the American Society of Oncology Annual Meeting (ASCO; June 2018).

References
  1. Perl A.E. et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. DOI: 10.1056/NEJMoa1902688
  2. Perl A.E. et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017 August; 18(8): 1061-1075. DOI: 10.1016/S1470-2045(17)30416-3
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!