Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin

Abstract

In the international randomized phase III RATIFY trial, the multi-kinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18-59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients on the midostaurin arm achieved protocol-specified complete remission (CR) and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD) positive AML who were entered on the RATIFY or the AMLSG 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD as well as whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative, but acquired mutations in signaling pathways (e.g. MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD-clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed suggesting either resistance mechanisms bypassing FLT3-inhibition or loss of midostaurin inhibitory activity due to inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD mutated AML under treatment with midostaurin in combination with intensive chemotherapy.

Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias

“…Exome sequencing or targeted sequencing of panels including at least 50–100 genes recurrently mutated in AML can capture partial information on clonal structure. These approaches often compensate their limited coverage compared with WGS with greater depth, allowing more precise assessment of VAFs and more robust clustering of the variants captured [ 5 , 17 , 18 , 19 , 20 ]. Single-colony [ 5 , 6 , 21 ], plate-based single cell [ 22 , 23 ], and more recently, high-throughput, droplet-based genotyping protocols [ 24 , 25 ] have contributed to describe the exact clonal composition of AML ( Figure 1 ).…”

“…This pattern of evolution, often associated with a longer time to relapse, should lead research to consider the post-treatment leukemia as second AML rather than a true relapse [ 20 ]. Genetic mutations can convey resistance to treatment, mainly in the context of targeted therapy [ 18 , 121 , 122 ], but this mechanism might also be involved in chemoresistance [ 19 ]. Resistance to treatment can also be conveyed by a pre-existing stemness program [ 82 , 123 , 124 ] and/or activation of a senescence program [ 52 ].…”

Targeted Therapies for the Evolving Molecular Landscape of Acute Myeloid Leukemia

“…Of note, 59% of patients in the midostaurin arm on RATIFY achieved complete remission, and half of them went on to experience disease relapse. By performing targeted FLT3 analysis and whole exome sequencing on 54 paired patient samples at diagnosis and relapse, Schmalbrock and colleagues have described high rates (46%) of relapse with FLT3-ITD-negative clones [ 50 ]. In these patients, proliferative advantage also seemed to be driven by acquired mutations in common signaling pathways (MAPK).…”

New Drugs Bringing New Challenges to AML: A Brief Review

“…A recent study by Schmalbrock et al provided novel insights into clonal evolution and resistance mechanisms in the RATIFY study. Almost half the midostaurin-treated patients (46%) were FLT3-ITD-negative at the time of disease relapse or progression [14]. In other patients, FLT3 selective pressure propagated mutations in the MAPK pathway, potentially bypassing the effect of FLT3 inhibition [14].…”