MANAGEMENT OF FLT3-ITD POSITIVE AML

Dr. Md. Mahamudul Hasan

Phase B Resident

FLT3 MUTATIONS IN ACUTE MYELOID LEUKAEMIA : KEY CONCEPTS AND EMERGING CONTROVERSIES.

Fronntiers in Oncology journal

Published on 2020

FMS LIKE TYROSIN KINASE 3(FLT3)

• A member of receptor tyrosin kinase family.
• Widely expressed in haemopoietic proginator cell and overexpressed in AML blast.
• FLT3 receptor activates upon binding to FLT3 ligand.
• After activation

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• Dimerize and leading to conformational change
• Cellular proliferation
• Inhibition of apoptosis and differentiation

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FLT3 subdivided into

1. Internal Tandem duplicate(ITD)- 25%
2. Tyrosin Kinase Domain (TKD) – 5%
1. High AR ( FLT3-ITD to FLT3-WT ) >0.5 associated with higher risk.
2. Low AR associated with favourable risk in patient with a co-occurrent with nucleophosmin 1 (NPM 1) mutation.

FLT3 testing technique

• Fluorescence lebeled PCR( Highly specific >99%)
• Whole genome sequencing
• Whole exom sequencing
• Multiplex targeted NGS
• Karyogene
• PCR based

OVERVIEW OF CURRENTLY ESTABLISHED FLT3 BINHIBITORS

1. First generation FLT3 inhibitors:

Midostaurin

Sorafenib

Sunitinib, Lestaurtinib, Tandutinib

2) Second generation FLT3 inhibitors:

Quizartinib

Giltertinib

Crenolanib

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MIDOSTAURIN

• It was first FLT34 inhibitor to be studied in AML.
• Has limited efficacy when it was used alone.
• Along with combination therapy it is more promising.
• It is recommended by FDA in combination with standard induction and consolidation chemotherapy in adult <60 years.

MIDOSTAURIN

• Median overall survival of 74.7 month in patient receiving midostaurin plus chemotherapy VS 25.6 month in patient receiving chemotherapy vs placebo.
• In older age >70 year , it does not significantly impact outcomes , and dose reduction of midostaurin is recommended .

MIDOSTAURIN

Side effects:

Haematologic : Cytopenia including febrile neutropenia.

Constitutional : Pyrexia , flu like symptom.

Cardiac: cardiac failure.

GI : Abdominal pain, nausea , vomiting, diarrhoea,stomatitis, abnormal liver function.

SORAFENIB

• It has efficacy as single agent.
• Study shows FLT3-ITD R/R AML response of Sorafenib monotherapy was 23-92%.
• It does not have regulatory approval for AML but can be used off-label in US as it is approved for hepatocellular, renal cell and thyroid cancer.

SORAFINIB

Side effects:

Haematologic : Cytopenia ,differentiation syndrome.

Constitutional : Fatigue (may be seveare)

Cardiac : Hypertension , cardiac ischemia.

GI : Diarrhoea.

Dermatological : Rash,Erythema,hand-foot skin reaction.

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QUIZARTINIB

• Quizartinib monotherapy is considered a standard of care option in R/R FLT3-ITD mutated AML.
• Side effects : Cardiotoxicity ( QTc prolongation).
• It’s regulatory approval was granted in Japan.

QUIZARTINIB

Side effects:

Haematological: Cytopenia,abnormal bruising,bleeding, differentiation syndrome.

Cardiac : QTc prolongation.

GI : Abdominal pain, nausea,anorexia .

RESISTANCE OF FLT3 INHIBITORS

• Despite relative success responses are frequently short lived and therapeutic resistance poses an ongoing challenges.
• Resistance broadly subdivided into intrinsic and extrinsic mechanism.

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RESISTANCE

Intrinsic resistance further sub-divided into:

• On target secondary mutation within FLT3
• Off target mutation in downstream or parallel signaling pathway.

NOVEL FLT3 INHIBITOR COMBINATIONS

Overcome the resistance and provide durable is to use FLT3 inhibitor and Novel combinations with other anti-leukaemic agents.

Novel agent available are:

• Hypomethylating agent
• Venetoclax
• Proteosome Inhibitors

HYPOMETHYLATING AGENTS

Well established FLT3 inhibitor combination is with the Hypomethylating agent : Azacytidine

Decitabine

• Multiple trial have demonstrated the combination of Midostaurine and HMA to be feasible in adult with FLT3 mutated AML who are unfit for chemotherapy.

HMA

• Sorafenib plus HMA have also been shown effective for R/R or newly diagnosed FLT3 positive AML.
• Second generation FLT3 inhibitor with HMA is under trial in case of both newly diagnosed or R/R AML.

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VENETOCLAX

Venetoclax is an inhibitor of the anti apoptotic protein Bcl-2.

• Venetoclax demonstrated synergestic anti-Leukaemic activity with Midostaurine.
• Studies shows FLT3-ITD mutated blast have higher Bcl-2 expression in comparison to FLT3-WT.

VENETOCLAX

• Quizartinib along with Venetoclax and Decitabine is thought to be very much effective in FLT3 positive R/R AML .

PROTEOSOME INHIBITORS

Proteosome inhibitor alone or in combination with Midostaurine or Sorafenib are found effective in clinical trial.

TREATMENT ALGORITHM

TREATMENT ALGORITHM

TREATMENT ALGORITHM