Consider mutation status in your treatment strategy

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a high degree of recurrent genetic mutations,
several of which have been linked to poor prognosis.1,19 These mutations include FLT3-ITD, ASXL1, RUNX1, TP53,
and KIT.11-14,17,18,20,21,23,24,27

FLT3 is mutated in ≈1/3 of newly diagnosed AML cases, the majority of which are cytogenetically normal AML (CN-AML).1,14,45,48-50 While FLT3 mutations can occur as either internal tandem duplications (ITDs) or point mutations in the tyrosine kinase domain (TKD), ITD mutations are more prevalent.1,45 Additionally, only ITD mutations have been linked definitively to poor prognosis.1,45

Although some studies show an association between
FLT3-TKD mutations and poor prognosis, others show no prognostic impact or favorable outcomes associated with
FLT3 -TKD mutations.1,45

FLT3-ITD

Prevalence: ≈25%11,14
Prognostic impact: Poor1,15,16

FLT3-TKD

Prevalence: ≈7%1,45
Prognostic impact: Undetermined1,45

FLT3-ITD represents a poor prognostic factor compared to FLT3-TKD in AML1,15,16,45

In a recent retrospective analysis of 676 adult patients with de novo AML, survival data showed that FLT3-ITD
mutations were associated with significantly worse prognosis than FLT3-TKD mutations and FLT3 wild type (FLT3 WT).51

5-year overall survival

5-year overall survival

FLT3-ITD   22.6%
FLT3-TKD   46.1%
FLT3 WT   42.4%

FLT3-ITD mutations were present in 20% of patients, and FLT3-TKD mutations were present in 4.7% of patients.

Differential analyses of patients stratified according to age and chromosomal abnormalities also showed a worse prognosis in FLT3-ITD–positive cases compared with FLT3-TKD–positive cases.

AML, acute myeloid leukemia; CN-AML, cytogenetically normal AML; FLT3, FMS-like tyrosine kinase 3; FLT3-ITD, FLT3 internal tandem duplication; FLT3-TKD, FLT3 tyrosine kinase domain; FLT3 WT, FLT3 wild type; ITD/ITDs, internal tandem duplication/internal tandem duplications; TKD, tyrosine kinase domain.
FLT3-ITD mutation:
One of the worst molecular prognostic factors in AML1,16

The FLT3-ITD mutation constitutively activates FLT3 kinase activity, inhibits cell differentiation, and drives proliferation and survival of leukemic cells.16 Patients with AML harboring a FLT3-ITD mutation typically have a significant disease burden presenting as leukocytosis, with high infiltration of bone marrow.48

Due to the aggressive nature of FLT3-ITD AML,1,2,48 prompt, early collaboration and communication among treating and transplant physicians and pathologists is critical in providing comprehensive patient care.

The FLT3-ITD mutation in AML has been associated with significantly shorter49,50,52-55,a:

  • Overall survival (OS)
  • Remission duration
  • Disease- or event-free survival

a Compared with FLT3 wild type.

In an analysis of 854 adult patients with AML, the presence of FLT3-ITD had a significant adverse effect on relapse rate, disease-free survival, and OS.12

Relapse rate
Disease-free survival
OS

In a UK study of 854 younger adult patients mostly with de novo AML from 2 trials, FLT3-ITD mutations were present in 27% of patients. Median follow-up was 52 months.12

AML, acute myeloid leukemia; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; OS, overall survival.

Patients with FLT3-ITD mutations may benefit from HSCT56-58

Allogeneic hematopoietic stem cell transplantation (HSCT) is considered to be an important treatment option in carefully selected patients. In patients newly diagnosed with FLT3-ITD–mutated AML, HSCT has been associated with longer OS, compared with patients who either did not complete HSCT or received chemotherapy.56-58

In a retrospective analysis of 122 patients with AML who received intensive chemotherapy with or without allogeneic HSCT, median overall survival significantly improved in patients with FLT3-ITD who had received allogeneic HSCT compared to patients with FLT3-ITD who had not received allogeneic HSCT (P = 0.006).58

Median OS

Median OS

FLT3 WT/no HSCT (n=59) 40.7 mo
FLT3 WT/HSCT (n=29) 53.4 mo
FLT3-ITD/no HSCT (n=24) 9.8 mo
FLT3-ITD/HSCT (n=10) Not reached

A subgroup analysis of patients with CR1 status also showed significantly longer median OS among patients
with FLT3-ITD who received HSCT compared with patients who did not receive HSCT (not reached vs 17.1 months, P = 0.047).

When HSCT is part of a desired treatment strategy, it is important to collaborate early with transplant physicians and initiate a donor search rapidly.48

Dr Pollyea discusses the therapeutic benefits of HSCT in AML patients classified as intermediate or poor risk

,, Helping more
FLT3-ITD–positive
patients achieve and
maintain remission
is important to
improving long-term
survival in this
poor-risk group. ,,

AML, acute myeloid leukemia; CR1, first complete remission; FLT3-ITD, FMS-like tyrosine kinase 3 internal tandem duplication; FLT3 WT, FLT3 wild type; HSCT, hematopoietic stem cell transplantation; OS, overall survival.

Dr Pollyea discusses prognostic and therapeutic implications of aggressive mutations in AML

,,FLT3-ITD is one of the worst molecular prognostic factors in AML and is the most common poor prognostic marker.,,

What impact do different mutations have on patient outcomes?

Effect On
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Of your newly diagnosed patients with AML, what
percentage do you believe have a FLT3-ITD mutation?
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Reported percentage of patients with AML who
have a FLT-ITD mutation at diagnosis
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References
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