2013]. of gene expression [DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and disruptor of telomeric signaling-1 (DOT1L) inhibitors], monoclonal antibodies and immunoconjugated toxins, bispecific T-cell engaging (BiTE) antibodies, and chimeric antigen receptor-modified (CAR) T cells. evidence that dasatinib has superior central nervous system (CNS) penetration compared with imatinib [Porkka et al. 2008]. Dasatinib Vegfa is effective against many resistant mutations, with the exception of point mutation T315I [Talpaz et al. 2006]. Nilotinib is another second-generation TKI that has been less studied in both adults and pediatrics, but some reports show efficacy against certain dasatinib-resistant mutations, although not T315I [Jabbour et al. 2008; Sekimizu et al. 2013]. Mesaconine A phase II COG study is investigating the efficacy of nilotinib in pediatric chronic myeloid leukemia (CML), and a multi-institutional phase I study of nilotinib is open for pediatric patients with CML or relapsed/refractory Ph+ ALL (Table 1). The third-generation TKI, ponatinib, is active against the increasingly clinically significant mutation T315I, but toxicities of arterial thrombosis risk were documented [Cortes et al. 2013], temporarily halting its development in clinical trials. As of January 2014, ponatinib is FDA-approved for adults with Ph+ leukemia resistant to other TKIs, now carrying the additional warning of thrombosis. Other classes of kinase inhibitors are being explored in adult Ph+ leukemia in an attempt to prevent the development of resistance, such as the Janus-associated kinase (JAK) inhibitor, ruxolitinib, in combination with nilotinib [ClinicalTrials.gov identifiers: “type”:”clinical-trial”,”attrs”:”text”:”NCT01702064″,”term_id”:”NCT01702064″NCT01702064 and “type”:”clinical-trial”,”attrs”:”text”:”NCT01914484″,”term_id”:”NCT01914484″NCT01914484]. FMS-like tyrosine kinase 3 (FLT3) FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed on human CD34+ hematopoietic stem and early progenitor cells, and FLT3 signaling is central to cell proliferation and differentiation [Small et al. 1994]. FLT3 is aberrantly expressed on the majority of leukemic blasts regardless of CD34 expression [Carow et al. 1996]. Of note, the most consistently overexpressed gene in mixed lineage leukemia-rearranged (MLL-r) infant ALL is wild-type FLT3 [Armstrong et al. 2002]. Also, mutations of FLT3 occur in 20C25% of pediatric AML patients, and result in ligand-independent constitutive activation of the receptor [Kondo et al. 1999; Meshinchi et al. 2001]. Roughly two-thirds of these mutations are internal tandem duplications (ITD) of the juxtamembrane domain of the gene, and the remaining one-third are point mutations of the tyrosine kinase domain Mesaconine (TKD) [Meshinchi et al. 2001; Yamamoto et al. 2001]. Multiple studies have documented decreased overall survival and increased rate of relapse in FLT3-ITD mutant AML [Iwai et al. 1999; Kondo et al. 1999; Meshinchi et al. 2001]. In one study, children with ITD mutations had 8-year Mesaconine overall survival (OS) Mesaconine and EFS rates of 13% and 7%, respectively, compared with an OS of 50% and EFS of 44% for Mesaconine children without ITD mutations [Meshinchi et al. 2001]. A large retrospective review determined that an ITD allelic ratio of 0.4 or higher identified the highest risk group with the worst prognosis, whereas children with allelic ratios 0.4 had similar outcomes to those with wild type FLT3 [Meshinchi et al. 2006]. These data provide strong rationale for the use of FLT3 inhibitors in pediatric acute leukemia. The FLT3 inhibitor lestaurtinib (CEP-701) has shown modest efficacy in adult trials as monotherapy [Smith et al. 2004; Knapper et al. 2006] or in combination with chemotherapy [Levis et al. 2011]. In pediatrics, a phase I trial of lestaurtinib with chemotherapy for relapsed/refractory AML has been completed, though clinical data are not yet published. However, at each dose level, five of six patients tested had 80% inhibition of FLT3 phosphorylation at the majority of lestaurtinib trough time points. Recently completed COG phase III trial AALL0631 investigated lestaurtinib in combination with chemotherapy for newly diagnosed infant ALL. Intermediate-risk (MLL-r and 90 days old) and high-risk (MLL-r and 90 days old) infants were randomized to receive lestaurtinib after induction chemotherapy. Trial efficacy results are pending. Midostaurin (PKC412) is a multi-TKI that has activity against FLT3, and early phase adult clinical trials showed hematological responses in patients with mutant FLT3 [Stone et al. 2005; Fischer et al. 2010]. In pediatrics, a phase I/II clinical trial open in Europe and some US centers is currently recruiting MLL-r infant.