***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Internal t and em duplication ( ITD ) mutations in the juxtamembrane domain-coding sequence of the Fms-like tyrosine kinase 3 ( FLT3 ) gene have been identified in 30 % of acute myeloid leukemia ( AML ) patients and are associated with a poor prognosis . The kinase inhibitor sorafenib induces growth arrest and apoptosis at much lower concentrations in AML cell lines that harbor FLT3-ITD mutations than in AML cell lines with wild-type FLT3 . METHODS The antileukemic activity of sorafenib was investigated in isogenic murine Ba/F3 AML cell lines that expressed mutant ( ITD , D835 G , and D835Y ) or wild-type human FLT3 , in primary human AML cells , and in a mouse leukemia xenograft model . Effects of sorafenib on apoptosis and signaling in AML cell lines were investigated by flow cytometry and immunoblot analysis , respectively , and the in vivo effects were determined by monitoring the survival of leukemia xenograft-bearing mice treated with sorafenib ( groups of 15 mice ) . In a phase 1 clinical trial , 16 patients with refractory or relapsed AML were treated with sorafenib on different dose schedules . We determined their FLT3 mutation status by a polymerase chain reaction assay and analyzed clinical responses by st and ard criteria . All statistical tests were two-sided . RESULTS Sorafenib was 1000- to 3000-fold more effective in inducing growth arrest and apoptosis in Ba/F3 cells with FLT3-ITD or D835 G mutations than in Ba/F3 cells with FLT3-D835Y mutant or wild-type FLT3 and inhibited the phosphorylation of tyrosine residues in ITD mutant but not wild-type FLT3 protein . In a mouse model , sorafenib decreased the leukemia burden and prolonged survival ( median survival in the sorafenib-treated group vs the vehicle-treated group = 36.5 vs 16 days , difference = 20.5 days , 95 % confidence interval = 20.3 to 21.3 days ; P = .0018 ) . Sorafenib reduced the percentage of leukemia blasts in the peripheral blood and the bone marrow of AML patients with FLT3-ITD ( median percentages before and after sorafenib : 81 % vs 7.5 % [ P = .016 ] and 75.5 % vs 34 % [ P = .05 ] , respectively ) but not in patients without this mutation . CONCLUSION Sorafenib may have therapeutic efficacy in AML patients whose cells harbor FLT3-ITD mutations Purpose : To determine a safe and biologically active dose of quizartinib ( AC220 ) , a potent and selective class III receptor tyrosine kinase ( RTK ) FLT3 inhibitor , in combination with salvage chemotherapy in children with relapsed acute leukemia . Experimental Design : Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide ( AE ) . A 3 + 3 dose escalation design was used to identify a safe and biologically active dose . Plasma inhibitory assay ( PIA ) testing was performed weekly to determine biologic activity . Results : Toxicities were consistent with intensive relapsed leukemia regimens . One of 6 patients experienced a dose-limiting toxicity ( DLT ) at 40 mg/m2/day ( elevated lipase ) and 1 of 9 had a DLT ( hyperbilirubinemia ) at the highest tested dose of 60 mg/m2/day . Of 17 response evaluable patients , 2 had complete response ( CR ) , 1 complete response without platelet recovery ( CRp ) , 1 complete response with incomplete neutrophil and platelet recovery ( CRi ) , 10 stable disease ( SD ) , and 3 progressive disease ( PD ) . Of 7 FLT3-ITD patients , 1 achieved CR , 1 CRp , 1 Cri , and 4 SD . FLT3-ITD patients , but not FLT3 wild-type ( WT ) patients , had significantly lower blast counts post-quizartinib . FLT3 phosphorylation was completely inhibited in all patients . Conclusions : Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m2/day with near complete inhibition of FLT3 phosphorylation in all patients . The favorable toxicity profile , pharmacodynamic activity , and encouraging response rates warrant further testing of  quizartinib  in children with FLT3-ITD AML . Clin Cancer Res ; 22(16 ) ; 4014–22 . © 2016 AACR Background Patients with acute myeloid leukemia ( AML ) and a FLT3 mutation have poor outcomes . We conducted a phase 3 trial to determine whether the addition of midostaurin — an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation — to st and ard chemotherapy would prolong overall survival in this population . Methods We screened 3277 patients , 18 to 59 years of age , who had newly diagnosed AML for FLT3 mutations . Patients were r and omly assigned to receive st and ard chemotherapy ( induction therapy with daunorubicin and cytarabine and consolidation therapy with high‐dose cytarabine ) plus either midostaurin or placebo ; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo . R and omization was stratified according to subtype of FLT3 mutation : point mutation in the tyrosine kinase domain ( TKD ) or internal t and em duplication ( ITD ) mutation with either a high ratio ( > 0.7 ) or a low ratio ( 0.05 to 0.7 ) of mutant to wild‐type alleles ( ITD [ high ] and ITD [ low ] , respectively ) . Allogeneic transplantation was allowed . The primary end point was overall survival . Results A total of 717 patients underwent r and omization ; 360 were assigned to the midostaurin group , and 357 to the placebo group . The FLT3 subtype was ITD ( high ) in 214 patients , ITD ( low ) in 341 patients , and TKD in 162 patients . The treatment groups were well balanced with respect to age , race , FLT3 subtype , cytogenetic risk , and blood counts but not with respect to sex ( 51.7 % in the midostaurin group vs. 59.4 % in the placebo group were women , P=0.04 ) . Overall survival was significantly longer in the midostaurin group than in the placebo group ( hazard ratio for death , 0.78 ; one‐sided P=0.009 ) , as was event‐free survival ( hazard ratio for event or death , 0.78 ; one‐sided P=0.002 ) . In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored , the benefit of midostaurin was consistent across all FLT3 subtypes . The rate of severe adverse events was similar in the two groups . Conclusions The addition of the multitargeted kinase inhibitor midostaurin to st and ard chemotherapy significantly prolonged overall and event‐free survival among patients with AML and a FLT3 mutation . ( Funded by the National Cancer Institute and Novartis ; Clinical Trials.gov number , NCT00651261 . PURPOSE To assess the toxicity , pharmacokinetics , and pharmacodynamics of multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in children with relapsed/refractory leukemia . PATIENTS AND METHODS Twelve patients with acute leukemia ( 11 with acute myeloid leukemia [ AML ] ) received sorafenib on days 1 to 7 and then concurrently with cytarabine ( 1 g/m(2 ) ) and clofarabine ( stratum one : 40 mg/m(2 ) , n = 10 ; stratum two [ recent transplantation or fungal infection ] : 20 mg/m(2 ) , n = 2 ) on days 8 to 12 . Sorafenib was continued until day 28 if tolerated . Two sorafenib dose levels ( 200 mg/m(2 ) and 150 mg/m(2 ) twice daily ) were planned . Sorafenib pharmacokinetic and pharmacodynamic studies were performed on days 7 and 8 . RESULTS At sorafenib 200 mg/m(2 ) , two of four patients in stratum one and one of two patients in stratum two had grade 3 h and -foot skin reaction and /or rash as dose-limiting toxicities ( DLTs ) . No DLTs were observed in six patients in stratum one at sorafenib 150 mg/m(2 ) . Sorafenib  inhibited the phosphorylation of AKT , S6 ribosomal protein , and 4E-BP1 in leukemia cells . The rate of sorafenib  conversion to its metabolite sorafenib  N-oxide was high ( mean , 33 % ; range , 17 % to 69 % ) . In vitro , the N-oxide potently inhibited FLT3-internal t and em duplication ( ITD ; binding constant , 70 nmol/L ) and the viability of five AML cell lines . On day 8 , sorafenib  decreased blast percentages in 10 of 12 patients ( median , 66 % ; range , 9 % to 95 % ) . After combination chemotherapy , six patients ( three FLT3-ITD and three FLT3 wild-type AML ) achieved complete remission , two ( both FLT3-ITD AML ) had complete remission with incomplete blood count recovery , and one ( FLT3 wild-type AML ) had partial remission . CONCLUSION Sorafenib in combination with clofarabine and cytarabine is tolerable and shows activity in relapsed/refractory pediatric AML PURPOSE To determine the efficacy and toxicity of the combination of sorafenib , cytarabine , and idarubicin in patients with acute myeloid leukemia ( AML ) younger than age 65 years . PATIENTS AND METHODS In the phase I part of the study , 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination . We then treated 51 patients ( median age , 53 years ; range , 18 to 65 years ) who had previously untreated AML with cytarabine at 1.5 g/m(2 ) by continuous intravenous ( IV ) infusion daily for 4 days ( 3 days if > 60 years of age ) , idarubicin at 12 mg/m(2 ) IV daily for 3 days , and sorafenib at 400 mg orally twice daily for 7 days . RESULTS Overall , 38 ( 75 % ) patients have achieved a complete remission ( CR ) , including 14 ( 93 % ) of 15 patients with mutated FMS-like tyrosine kinase-3 ( FLT3 ; the 15th patient had complete remission with incomplete platelet recovery [ CRp ] ) and 24 ( 66 % ) of 36 patients with FLT3 wild-type ( WT ) disease ( three additional FLT3-WT patients had CRp ) . FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients ( P = .033 ) . With a median follow-up of 54 weeks ( range , 8 to 87 weeks ) , the probability of survival at 1 year is 74 % . Among the FLT3-mutated patients , 10 have relapsed and five remain in CR with a median follow-up of 62 weeks ( range , 10 to 76 weeks ) . Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity . CONCLUSION Sorafenib can be safely combined with chemotherapy , produces a high CR rate in FLT3-mutated patients , and inhibits FLT3 signaling We conducted a phase I study using midostaurin ( 25 or 50 mg orally twice daily ) , all-trans retinoic acid ( ATRA ) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML . 10 patients received the combination and no dose-limiting toxicities were observed . Two patients ( 22 % ) achieved complete remission and 1 patient ( 11 % ) achieved complete remission with incomplete count recovery . Pharmacokinetic data showed that the 25 mg dosing of midostaurin achieved therapeutic levels with no significant interaction between midostaurin and ATRA . With evidence of activity of ATRA in NPM1-mutated AML and midostaurin in FLT3-ITD AML , this combination warrants further investigation Activating mutations of FMS-like tyrosine kinase 3 ( FLT3 ) are present in approximately one third of patients with acute myeloid leukemia ( AML ) and are associated with adverse prognosis . The important role played by FLT3 in the survival and proliferation of blasts , and its overexpression in most patients with AML , make FLT3 an attractive therapeutic target . We undertook a phase 2 trial of the FLT3-selective tyrosine kinase inhibitor lestaurtinib ( CEP701 ) used as monotherapy in untreated older patients with AML not considered fit for intensive chemotherapy , irrespective of FLT3 mutation 
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Conclusion Our study showed that combined use of FLT3 inhibitors improved OS and that the FLT3 status of AML patients could affect their sensitivity to FLT3 inhibitors in terms of CR and ORR