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EXPLORE THE KEY ASPECTS OF
FLT3m+ AML
AML is a heterogeneous disease that arises from
the rapid expansion of myeloid blasts in the bone
marrow of adult patients of which FLT3 is the most
commonly identified gene mutation. 1,2
FLT3m+ AML is associated with poor outcomes
such as shorter duration of remission, shorter DFS,
and shorter OS. 3,4 Multiple factors in FLT3m+ AML
that may contribute to the challenging nature of
the disease have been identified, including 5-13 :
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FLT3-ITD mutations
New target receptor mutations acquired (eg, TKD mutations)
Upregulation (eg, “rebound” FLT3 ligand)
FLT3-independent signal transduction pathway (eg, PI3K)
Activation of another receptor (eg, AXL)
Epigenetic (eg, SHP-1)
Stromal-mediated cytoprotection (eg, impaired pharmacokinetics)
Go to FLT3AML-revealed.com
AML=acute myeloid leukemia; DFS=disease-free survival; FLT3=FMS-like tyrosine kinase 3; ITD=internal tandem duplication;
m+=mutation-positive; OS=overall survival; PI3K=phosphoinositide 3-kinase; SHP-1=Src homology-2-containing protein-tyrosine
phosphatase 1; TKD=tyrosine kinase domain.
2014;120:2142-2149. 7. Baker SD, Zimmerman EI, Wang YD, et al. Emergence of
References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines
polyclonal FLT3 tyrosine kinase domain mutations during sequential therapy with
in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia Version 3.2017.
sorafenib and sunitinib in FLT3-ITD–positive acute myeloid leukemia. Clin Cancer Res.
© National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed
2013;19:5758-5768. 8. Sato T, Yang X, Knapper S, et al. FLT3 ligand impedes the efficacy
08-18-2017. To view the most recent and complete version of the guideline, go online
of FLT3 inhibitors in vitro and in vivo. Blood. 2011;117:3286-3293. 9. Linblad O, Cordero
to NCCN.org. 2. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated
E, Puissant A, et al. Aberrant activation of the PI3K/mTOR pathway promotes resistance
genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079-1089.
to sorafenib in AML. Oncogene. 2016;35:5119-5131. 10. Park IK, Mishra A, Chandler J,
3. Whitman SP, Archer KJ, Feng L, et al. Absence of the wild-type allele predicts poor
Whitman SP, Marcucci G, Caligiuri MA. Inhibition of the receptor tyrosine kinase Axl
prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the
impedes activation of the FLT3 internal tandem duplication in human acute myeloid
internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res.
leukemia: implications for Axl as a potential therapeutic target. Blood. 2013;121:2064-
2001;61:7233-7239. 4. Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal
2073. 11. Park IK, Mundy-Bosse B, Whitman SP, et al. Receptor tyrosine kinase Axl is
tandem duplication associates with adverse outcome and gene- and microRNA-
required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid
expression signatures in patients 60 years of age or older with primary cytogenetically
leukemia. Leukemia. 2015;29:2382-2389. 12. Al-Jamal HAN, Mat Jusoh SA, Hassan R,
normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood.
Johan MF. Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3
2010;116:3622-3626. 5. Fröhling S, Schlenk RF, Breitruck J, et al. Prognostic significance
activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive
of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid
acute myeloid leukemia. BMC Cancer. 2015;15:869. 13. Ghiaur G, Levis M. Mechanisms
leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood.
of resistance to FLT3 inhibitors and the role of the bone marrow microenvironment.
2002;100:4372-4380. 6. Alvarado Y, Kantarjian HM, Luthra R, et al. Treatment with FLT3
Hematol Oncol Clin N Am. 2017;31:681-692.
inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with
development of secondary FLT3–tyrosine kinase domain mutations. Cancer.
© 2017 Astellas Pharma US, Inc. All rights reserved. 077-0064-PM. 12/17
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