TION OF HEMATOLOGY

Current Treatment
Algorithm in
FLT3 Mutated AML
Andrea Marie M. Reyes
Hematology Fellow III
TION OF HEMATOLOGY

Mutational Profile of AML at diagnosis

TION OF HEMATOLOGY

FLT 3 Mutated Acute Myeloid Leukemia

What is FLT3?
• Class 3 transmembrane tyrosine kinase receptor
• Acts as receptor for FLT3 Ligand (FL)
• Once activated  cell proliferation in
hematopoietic cells
TION OF HEMATOLOGY

FLT 3 Mutated Acute Myeloid Leukemia

FLT3 Mutations
• ~30% of AML is FLT3 mutated
• Higher expression, poorer prognosis
• 2 types:
• internal tandem duplication (ITD)
• tyrosine kinase domain (TKD) point mutations
TION OF HEMATOLOGY

FLT 3 Mutated Acute Myeloid Leukemia

FLT3 ITD Mutations
• Internal tandem duplication
• In frame mutations 3-400 base pairs
• Elongated juxtamembrane domain 
activation FLT3
• Poor prognostic factor in RFS and OS
TION OF HEMATOLOGY

FLT 3 Mutated Acute Myeloid Leukemia

FLT3 ITD Mutations
• Prognostic value: ITD length, co-mutations & Allele Ratio
• Allele Ratio (AR) is ratio of ITD mutated allele vs wild type alleles,
value of 0.5 is cut off between low and high AR. AR >0.51 is
unfavorable relapse-free survival and overall survival
• Co-mutations NPM has favorable relapse risk and OS
• 3 Categories:
• Favorable (NPM + wild, NPM + ITD AR <0.5)
• Intermediate (NPM + ITD AR> 0.5, NPM1WT+ITD AR <0.5)
• Adverse (NPM1WT +ITD AR >0.5)
TION OF HEMATOLOGY

FLT 3 Mutated Acute Myeloid Leukemia

FLT3 TKD Mutations
• Point mutations
• Results in proliferation and survival of
AML; Have prognostic value overall AML
patient population
• However not associated with consistent
prognostic impact; AR remains obscure
TION OF HEMATOLOGY

Prognostic Impact of FLT3 Mutations

• Not all FLT—ITD mutations are equal; again influenced AR, co-
mutations, karyotype and ITD length
• Patients with high FLT3-ITD mutations tend to have particularly
unfavorable prognosis, increased risk for relapse and shorter OS.
• Nearly 20% of AML at relapse have a newly detectable FLT3- ITD or
FLT-TKD mutation
TION OF HEMATOLOGY

FLT3 Inhibitors
Integration of FLT3 inhibitors have
lead to improvements in clinical
outcomes in FLT3-ITD+ AML.

Type 1: bind in active and inactive

conformation; against ITD and TKD
mutations
Type 2: inactive conformation;
ITD mutations only
TION OF HEMATOLOGY

First Generation TKI

• Inhibit multiple downstream RTK; lack of specificity to FLT3
• Sunitinib – short lived partial responses (2015)
• Lestaurtinib – no overall clinical benefit (2017)
• Sorafenib
• Midostaurin
TION OF HEMATOLOGY

First Generation TKI

• Sorafenib (type 2: ITD only)
• single agent: only 10% CR (2011)
• addition to standard of care in r/r AML: prolonged EFS, RFS but not OS (2015),
not in elderly patients (2013)
• Addition to standard of care in newly diagnosed: high RR and CR
• SORAML trial, 2014
• FLT AML Post HSCT:
• Relapse post HSCT: 7 of 29 with long lasting remissions
• Maintenance: SORMAIN trial: 85% RFS 90.5% OS compared with 53.3 RFS and 66.2 in
placebo
• Better in AML in CR1 s/p HSCT
TION OF HEMATOLOGY

First Generation TKI

• Midostaurin (type 1)
• Single agent: limited anti-leukemic activity
• with induction in newly diagnosed: significant improved EFS and OS
• RATIFY Trial (2017) approved FDA
• Improved OS in all FLT3 mutations (TKD, ITD low, ITD high)
• Maintenance therapy: No benefit (2017)
• RADIUS trial (2016)
• Midostuarin in post transplant setting in FLT3 mutated AML s/p allo HSCT
• Improved RFS at 18months after alloHSCT by 13%
• Not clinically significant
TION OF HEMATOLOGY

Next Generation TKI

• First gen lack specificity of FLT3-ITD – transient antileukemic activity
• Next Gen: Gilteritinib, Crenolanib and Quizartinib:
• Higher specificity for FLT3
• Higher potency
• Type 1: both active & inactive: Gilteritinib and Crenolanib
• Type 2: inactive: ITD only: Quizartinib
TION OF HEMATOLOGY

Next Generation TKI

• Crenolanib
• Monotherapy in r/r FLT3 AML: improved OS and CR with no prior FLT3i
• Gilteritinib
• Monotherapy in r/r FLT3 AML : 40% ORR CR 30% (Admiral Trial)
• Post HSCT: Morpho Trial
• Quizartinib
• Single Agent FLT 3 AML: improved CR and ORR in responders
• Salvage r/r AML or post HSCT: improved CR and OS (Quantum-R Trial)
• Common Side Effects
• Diarrhea (37%), anemia (34%), fatigue (33%), increased AST (26%), increased ALT
(19%)
TION OF HEMATOLOGY

On Going Trials
• Ponatinib, FLX925
• None appreciable single agent activity
• Frontline FLT3i with anthracycline/cytarabine induction or HMA
• Intensive Chemotherapy
• Gilteritinib/ Midostaurin + induction/consolidation in newly FLT3 AML
• Ineligible for intensive chemo
• Gilteritinib+ Azacitidine in new FLT AML not eligible for intensive chemo may be
terminated for futility (LACEWING Trial)
• Midostaurin+Azacitidine in newly diagnosed and r/r FLT3 AML: higher RR and remission
duration
• Triplet combination with VNT, FLT3i and chemotherapy (decitabine) 
optimization of dosing due to myelosuppression
TION OF HEMATOLOGY

FLT3 + AML Newly Diagnosed R/R Post HSCT Others

FIRST GENERATION
Sorafenib Monotherapy: No benefit +Chemo: Benefit Benefit (SORAMAIN) Induction: 400 d10-19
Type 2 +Chemo: Benefit (SORAML) except in Elderly Maintenance: 400 BID
ITD Only Post HSCT: 400 OD x2
wks ; 600 OD x 4
weeks; 800 OD
Midostaurin Monotherapy: No benefit +Chemo: Benefit No Benefit (RADIUS) 50mg BID
+Chemo: Benefit (RATIFY) Induction 8-21
Maintenance: 28d
Post HSCT: 28 d
SECOND GENERATION
Gilteritinib Results 2023 Monotherapy: Results 2025 120 OD
(HOVON/AML) Benefit (ADMIRAL) (MORPHO)
Quizartinib Monotherapy: Benefit Monotherapy: Benefit (Quantum-1st) 20mg OD
Type 2 ITD Only (Quantum-R) Benefit (Quantum)
Crenolanib Results 2025 Monotherapy: Results 2025 (AROG) Crenolanib 100 TID
(AROG Pharma) Benefit
TION OF HEMATOLOGY

Treatment Algorithm in FLT3 AML

CONVENTIONAL (ELIGIBLE FOR INTENSIVE CHEMO)
TION OF HEMATOLOGY

Treatment Algorithm in FLT3 AML

MD ANDERSON CANCER CENTER
(ELIGIBLE FOR INTENSIVE CHEMO)

FAI – Fludarabine/Cytarabine/Idarubicin
CLAI – Cladribine/Cytarabine/Idarubicin
Do not recommend to add VNT due to
myelosuppression
Consolidation: FAI/CLAI
Second gen FLT3i –D1-14 induction; continuous during
consolidation
Decision for HSCT
- All intermediate to high risk patients in CR1
then post HSCT maintenance for 2 years
- Low ITD with NPM or TKD is an ongoing
debate
TION OF HEMATOLOGY

Treatment Algorithm in FLT3 AML

CONVENTIONAL (INELIGIBLE FOR INTENSIVE CHEMO)

HMA - Hypomethylating Agent

VNT - Venetoclax
Median OS 13.3 months
TION OF HEMATOLOGY

Treatment Algorithm in FLT3 AML

MD ANDERSON CANCER CENTER
(INELIGIBLE FOR INTENSIVE CHEMO)
HMA – Hypomethylating Agent
VEN – Venetoclax ramp-up
FLT3i – ideally second generation from C1 D1
BMA – C1D14 to avoid overtreatment
Stop FLT3i after D14 in marrow remission
Continue until D21 if blasts>10, cellularity >5%
Repeat BMA D28 to confirm marrow remission
Subsequent Cycles: FLT3i during entire duration but
VNT can be reduced to 14 days if with cytopenia
TION OF HEMATOLOGY

Treatment Algorithm in FLT3 AML

RELAPSED/REFRACTORY
Ideally for clinical trial options (Median OS
<10 months)
If eligible for intensive chemo, plus
remission lasts >12 months, FLT3i +
intensive chemotherapy
Goal: Rapid and Deep Remission
If ineligible, gilteritinib based therapy
(usually with HMA/VNT/Triplet)
If patients relapsed on giltertinib,
combination of azacitidine + sorafenib,
azacytidine + venetoclax or gemtuzumab
TION OF HEMATOLOGY

Mechanisms of Resistance to FLT3

Inhibitors
• Not uncommon
• Primary or Secondary
• Primary – usually TKD mutations, activation of alternative signal
pathways
• Secondary – FLT3 changes (on-target or off-target)
• On target – secondary TKD mutations in type 2 inhibitor
• Off target – clonal evolution even when ITD mutation is lost; mutations in
RAS/MAPK pathway, BCR/ABL fusions
TION OF HEMATOLOGY

Mechanisms of Resistance to FLT3

Inhibitors
• Wild type FLT3 is sensitive to FL and resistant to inhibitors thus
presence of Wild type in FLT-ITD mutations may contribute to
resistance.
• High levels of FL in BM environment during induction can lead to
persistent activity of FLT/MAPK pathway providing survival signals to
leukemic blasts
TION OF HEMATOLOGY

Mechanism of Relapse

REPEAT FLT3 at time of recurrence

Leukemia is not a static condition

Repeat Genomic Analysis at

Relapse is Necessary
TION OF HEMATOLOGY

Clonal Evolution of FLT-ITD AML after

midostaurin
TION OF HEMATOLOGY

Updates
TION OF HEMATOLOGY

EHA JULY 2022

Population 539 patients FLT3-ITD AML Phase III Quantum-First Trial showed addition
of oral FLT3 Inhibitor quizartinib to standard
Similarincreased
chemo incidenceoverall
of toxicities between
survival to 31.9
Exposure Quizartinib 40mg OD on days 8 – 21
Vs Placebo after induction treatment
months inarms. However
adults more patients
with FLT3-ITD+ AML
chemotherapy; Quartinib 40mg OD treated with quizartinib
compared experience
to 15.1 months treatment
for those who
for 14 days plus HIDAC for 4 cycles
emergent
received adverse events alone.
chemotherapy with fatal
(p =outome
0.03)
Outcome Remission
(11.3% vs 9.7%) within 30-60 days of
Method RCT Rates administration.
of complete remission
(Mainlywere similar but
infection)
Follow-Up 3 years and/or HSCT duration of complete response was 3x longer
in quizartinib arm. (38.6mos vs 12.4 mos)