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A.J. Ambinder and M. Levis
Table 2. A list of non-canonical, activating mutations that have been found in de novo acute myeloid leukemia or in patients that progressed on treatment with a FLT3 inhibitor. The last column provides a prediction of each mutation’s likely sensitivity to types of FLT3 inhibitors based upon in vitro studies.
Mutation
S451F10 Y572C10
V579A/G10,90,91
F590G, Y591D92 D593N91
F594L90 Q598_Y599del93
F621L94 A627P94 M664I95
N676Δ9,96,97 A680V11,98
F691I/L65,99 G697R97
S840GS102 N841102–105
Time of Onset
De novo De novo
De novo De novo De novo De novo De novo
De novo
De novo
Acquired resistance to type 2 inhibitor
De novo, acquired resistance De novo, acquired resistance
Acquired resistance to type 1 and 2 inhibitors
De novo, acquired resistance to type 2 inhibitors
De novo
De novo, acquired resistance to type 2 inhibitors
De novo, acquired resistance to type 2 inhibitors
De novo
De novo
De novo, acquired resistance to type 2 inhibitors
R834Q10
Anticipated Sensitivity to FLT3 Inhibitors
Relatively resistant to most FLT3 inhibitors Sensitive to type 1 and 2 inhibitors
Sensitive to type 1 and 2 inhibitors Sensitive to type 1 and 2 inhibitors Sensitive to type 1 and 2 inhibitors Sensitive to type 1 and 2 inhibitors Sensitive to type 1 and 2 inhibitors
Sensitive to type 1 and 2 inhibitors Relatively resistant to most FLT3 inhibitors Relatively resistant to type 2 inhibitors
Relatively resistant to most FLT3 inhibitors
Unknown
Relatively resistant to most FLT3 inhibitors Relatively resistant to most FLT3 inhibitors
Resistant to type 2 inhibitors, sensitive to type 1 inhibitors
Resistant to type 2 inhibitors, sensitive to type 1 inhibitors
Resistant to type 2 inhibitors, sensitive to type 1 inhibitors
Resistant to type 2 inhibitors, sensitive to type 1 inhibitors Resistant to type 2 inhibitors, sensitive to type 1 inhibitors Resistant to type 2 inhibitors, sensitive to type 1 inhibitors
Functional Impact
Extracellular Domain
Constitutive kinase activation by unknown mechanism
Juxtamembrane Domain
Loss of JM autoinhibitory function
Loss of JM autoinhibitory function Loss of JM autoinhibitory function Loss of JM autoinhibitory function Loss of JM autoinhibitory function Loss of JM autoinhibitory function
ATP Binding Pocket of TK Domain 1
Unknown
Unknown Altered inhibitor binding
Biases activation loop toward
active conformation Unknown Altered inhibitor binding Altered inhibitor binding
Activation Loop of TK Domain 2
Constitutive active conformation
Constitutive active conformation
Constitutive active conformation
Constitutive active conformation Constitutive active conformation Constitutive active conformation
D835Δ52,100,101 I836Δ91
Y842Δ106,107
JM: juxtamembrane; TK: tyrosine kinase.
Can allo-transplant be deferred for some?
Our improved capacity to prognosticate and to monitor disease status, as well as the availability of potent FLT3 inhibitors, may obviate the benefits of alloHSCT in a select population of patients with mFLT3 AML. As previ- ously discussed, there is already some compelling evi- dence that patients with low mFLT3-ITD allelic ratio and NPM1 mutations may not derive a survival benefit from alloHSCT.23,34 However, we believe the data are insuffi- cient to provide a broad recommendation against alloHSCT for any particular subset of patients with mFLT3 AML. There are still a number of other variables of prognostic significance including ITD length, the presence of co-mutations, and the presence of MRD that are not consistently or reliably measured in clinical practice and which remain unaccounted for in current decision models. In the face of such uncertainty, we continue to recom- mend alloHSCT for the vast majority of patients with mFLT3 AML.
Alternative immunotherapy approaches
Thus far, efforts to target FLT3 have largely focused on inhibiting its signaling; however, we may also be able to
take advantage of the near ubiquity of FLT3 expression (either mutant or wild type) on AML leukemic blasts and the narrow expression profile on healthy cells. Several immunotherapeutic approaches are being pursued to tar- get the FLT3 receptor. A trial of a monoclonal FLT3 anti- body is currently recruiting (clinicaltrials.gov identifier: NCT02789254). One group has developed an anti-FLT3 antibody-drug conjugate.87 FLT3-CD3 bispecific antibodies have also been developed and at least one has been demonstrated to be safe in an animal model.88 FLT3 specific chimeric antigen receptor T-cell (CAR-T) and T-cell modi- fied T-cell therapies are in development as well. In vitro data even suggest a rationale for combining these immunother- apeutic strategies with FLT3 inhibitors. mFLT3 leukemic cell lines treated with a FLT3 inhibitor increased their expression of FLT3 on their cell surfaces, which translated into better T-cell mediated cytotoxicity.89
Conclusions
FLT3 signaling plays a central role in the pathogenesis of AML. Over the last 2 decades, the presence of FLT3-acti- vating mutations has impacted prognostication and guid- ed management decisions. The development of more
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