High-frequency type I/II mutational shifts between diagnosis and relapse are associated with outcome in pediatric AML: implications for personalized medicine

Abstract

Although virtually all pediatric patients with acute myeloid leukemia (AML) achieve a complete remission after initial induction therapy, 30%-40% of patients will encounter a relapse and have a dismal prognosis. To prevent relapses, personalized treatment strategies are currently being developed, which target specific molecular aberrations. To determine relevance of established AML type I/II mutations that may serve as therapeutic targets, we assessed frequencies of these mutations and their persistence during disease progression in a large group (n ‫؍‬ 69) of paired diagnosis and relapse pediatric AML specimens. In 26 of 42 patients (61%) harboring mutations at either stage of the disease, mutation status changed between diagnosis and relapse, particularly in FLT3, WT1, and RAS genes. Presence or gain of type I/II mutations at relapse was associated with a shorter time to relapse (TTR), whereas absence or loss correlated with longer TTR. Moreover, an adverse outcome was found for patients with activating mutations at relapse, which was statistically significant for FLT3/ITD and WT1 mutations. These findings suggest that mutational shifts affect disease progression. We hence propose that risk stratification, malignant cell detection, and selection of personalized treatment should be based on status of type I/II mutations both at initial diagnosis and during follow-up.

The role of minor subpopulations within the leukemic blast compartment of AML patients at initial diagnosis in the development of relapse

“…Studying pediatric and adult AML patients, we have previously shown that shifts in specific type I/ II molecular aberrations occur frequently in between diagnosis and relapse. 15,16 Here we explored the hypothesis that mutational shifts can be explained by selection and subsequent expansion of leukemic cells from a minor subpopulation of an oligoclonal leukemia-initiating fraction at initial diagnosis, analogous to what has been reported for ALL. 32 We analyzed and compared the mutational profiles of sorted subfractions and proved oligoclonality at initial diagnosis in six out of seven relapsed AML patients.…”

“…16 --19 Regarding mutational shifts, both gains and losses of mutations occur, except for WT1, in which only an apparent gain of mutations was observed. 16,20 Moreover, we showed that the mutational shifts in FLT3/ITD, RAS and WT1 are associated with both the time to relapse (TTR) and overall survival. 16 Differences in genetic aberrations between diagnosis and relapse may be explained by: (1) Continuous accumulation of secondary mutations in (pre-) leukemia initiating cells (LICs), (2) Selection and expansion of a minor, initially undetected clone, from an oligoclonal compartment of leukemia initiating cells at the time of initial presentation.…”

Gene mutations of acute myeloid leukemia in the genome era

“…Comparable analyses of mutation status between the diagnosis and the relapse of AML revealed the loss of class II mutations, such as NPM1 and CEBPA mutations, at the relapse. In contrast, epigenetic modifier mutations are stably identified during the disease progression of AML, while they are frequently acquired at the later stage of MPN, suggesting their multiple oncogenic potency not only for the initiation, but also for progression in myeloid malignancies [22][23][24].…”

“…In vitro and in vivo studies suggest that this class of mutations augments proliferation and survival signals, but does not induce AML but MPN by itself in murine model [21]. Clinically, this type of mutations sometimes emerge or occasionally disappear during clinical course of AML and MDS [22][23][24]. These mutations (so-called class I mutation) are mutually exclusive but not so strictly as the above class of mutations (class II mutation), and not related with AML subtypes except for the preference of KIT mutation to CBF leukemia.…”

Pediatric Acute Myeloid Leukemia

“…However, the newly discovered molecular mutations, such as NPM1 or GATA1 mutations, may also be suitable MRD-targets. (Pine, et al 2005 Some of these targets, such as FLT3 mutations, may not be stable between diagnosis and relapse, and this may result in false-negative results (Bachas, et al 2010), which may also occur in flowcytometry based MRD assessment due to immunophenotypic shifts. Another important issue is the frequency of required sampling post-treatment, as leukemias may differ in the lag-time between molecular and overt relapse, which appears to be translocation/molecular marker dependent.…”