Human NPM1 blocking peptide

Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a clinical course predicted by recurrent cytogenetic abnormalities and/or gene mutations. The NPM1 insertion mutations define the largest distinct genetic subset, similar to 30% of AML, and is considered a favorable risk marker if there is no (or low allelic ratio) FLT3 internal tandem duplication (FLT3 ITD) mutation. However, similar to 40% of patients with mutated NPM1 without FLT3 ITD still relapse, and the factors that drive relapse are still not fully understood. We used a next-generation sequencing panel to examine mutations at diagnosis; clearance of mutations after therapy, and gain/loss of mutations at relapse to prioritize mutations that contribute to relapse. Triple mutation of NPM1, DNMT3A and IDH1/2 showed a trend towards inferior overall survival in our discovery dataset, and was significantly associated with reduced OS in a large independent validation cohort. Analysis of relative variant allele frequencies suggests that early mutation and expansion of DNMT3A and IDH1/2 prior to acquisition of NPM1 mutation leads to increased risk of relapse. This subset of patients may benefit from allogeneic stem cell transplant or clinical trials with IDH inhibitors.

FLT3-ITD and FLT3-TKD mutations were observed in approximately 20 and 10% of acute myeloid leukemia (AML) cases, respectively. FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. The majority of cases gain secondary resistance either by on-target and off-target abnormalities. On-target mutations (i.e., FLT3-TKD) such as D835Y keep the TK domain in its active form, abrogating pharmacodynamics of type II FLT3 inhibitors (e.g., midostaurin and quizartinib). Second generation type I inhibitors such as gilteritinib are consistently active against FLT3-TKD as well as FLT3-ITD. However, a "gatekeeper" mutation F691L shows universal resistance to all currently available FLT3 inhibitors. Off-target abnormalities are consisted with a variety of somatic mutations such asNRAS,AXLandPIM1that bypass or reinforce FLT3 signaling. Off-target mutations can occur just in the primary FLT3-mutated clone or be gained by the evolution of other clones. A small number of cases show primary resistance by an FL-dependent, FGF2-dependent, and stromal CYP3A4-mediated manner. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.