Genomic markers of midostaurin drug sensitivity in FLT3 mutated and FLT3 wild-type acute myeloid leukemia patients
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// Mara W. Rosenberg 1 , 2 , Kevin Watanabe-Smith 1 , 2 , Jeffrey W. Tyner 1 , 4 , Cristina E. Tognon 1 , 2 , 3 , Brian J. Druker 1 , 2 , 3 and Uma Borate 2 1 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA 2 Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA 3 Howard Hughes Medical Institute, Portland, OR, USA 4 Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, OR, USA Correspondence to: Mara W. Rosenberg, email: rosenberg.mara@gmail.com Keywords: acute myeloid leukemia; drug sensitivity; midostaurin; drug resistance; FLT3 Abbreviations: AML: acute myeloid leukemia; FLT3-ITD: FLT3-internal tandem duplication; TKI: tyrosine kinase inhibitors; ELN Guidelines: European Leukemia Network Guidelines Received: April 23, 2020 Accepted: June 05, 2020 Published: July 21, 2020 ABSTRACT Acute myeloid leukemia (AML) is a heterogeneous malignancy with the most common genomic alterations in NPM1, DNMT3A, and FLT3. Midostaurin was the first FLT3 inhibitor FDA approved for AML and is standard of care for FLT3 mutant patients undergoing induction chemotherapy [ 1 , 2 ]. As there is a spectrum of response, we hypothesized that biological factors beyond FLT3 could play a role in drug sensitivity and that select FLT3-ITD negative samples may also demonstrate sensitivity. Thus, we aimed to identify features that would predict response to midostaurin in FLT3 mutant and wild-type samples. We performed an ex vivo drug sensitivity screen on primary and relapsed AML samples with corresponding targeted sequencing and RNA sequencing. We observed a correlation between FLT3-ITD mutations and midostaurin sensitivity as expected and observed KRAS and TP53 mutations correlating with midostaurin resistance in FLT3-ITD negative samples. Further, we identified genes differentially expressed in sensitive vs. resistant samples independent of FLT3-ITD status. Within FLT3-ITD mutant samples, over-expression of RGL4, oncogene and regulator of the Ras-Raf-MEK-ERK cascade, distinguished resistant from sensitive samples. Overall, this study highlights the complexity underlying midostaurin response. And, our results suggest that therapies that target both FLT3 and MAPK/ERK signaling may help circumvent some cases of resistance.Keywords:
Midostaurin
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Objective:To explore the possibility of secondary neoplasia following long term combined chemotherapy.Methods:Sister chromatid exchanges(SCE)were investigated in 44 patients with adult leukemia.Rusults:Frequencies of SCE in patients with de novo leukemia,relapsed leukemia and chronic myeloid leukemia(CML)were significant higher than health controls.The five patients(5/16)with complete remission showed higher SCE frequencies,those were mainly the patients received more than nine courses of combined chemotherapeutic regimens received more than nine courses of combined chemotherapeutic regimens.Conclusion:The patients with de novo leukemia,relapsed leukemia and CML have DNA damage in diagnosis,long term combined chemotherapy may cause the DNA instability in partial patients.
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The prognostics implications of patients with acute myeloid leukemia harboring non-canonical FLT3 is unknown. The use of tyrosine kinase inhibitors in this patient population has not been previously reported. We report successful targeted therapy against non-ITD, non-D835 driver FLT3 alterations in two patient case studies with acute myeloid leukemia.
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The T315I mutation is especially challenging as it confers resistance to all first- and second-generation tyrosine kinase inhibitors. We present here a chronic myeloid leukemia patient harboring the T315I and E255V BCR-ABL1 mutation successfully achieved deep molecular response with a combined treatment of dasatinib and IFN-α. To our knowledge, this is the second case of a T315I-bearing chronic myeloid leukemia patient displaying satisfactory response to the combination therapy of dasatinib and IFN-α.
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