Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors

Abstract

Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk -ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of -ITD mutations, we investigated the effects of-ITD structural features on the response of AML patients to treatment. We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in -ITD-positive AML patients. HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type , whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypicalITDs. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.

Modeling pediatric AML FLT3 mutations using CRISPR/Cas12a- mediated gene editing

“…Consistent with the above data, the IC 50 of D835Y reflects an enhanced level of sensitivity to Gilteritinib. These data reflect the known sensitivities of cells bearing FLT3-ITDs in response to these two TKI inhibitors [17,20,[40][41][42].…”

Prognostic Models Turn the Heat(IT)up on FLT3ITD-Mutated AML

“…In this issue of Clinical Cancer Research, Schwartz and colleagues show that structural features of FLT3-internal tandem duplications (ITDs) mutations, a highly recurrent mutation in acute myeloid leukemia (AML), influence patient responses and overall outcome following both standard cytotoxic chemotherapy and targeted FLT3 inhibitor therapy(1).…”

Targeted Informatics for Optimal Detection, Characterization, and Quantification of FLT3 Internal Tandem Duplications Across Multiple Next-Generation Sequencing Platforms

“…A recent study indicated that nucleotide composition of ITDs, particularly the presence of nontemplated nucleotide content, may impact response to FLT3 inhibition and induction chemotherapy, whereas prior studies have reported inferior outcomes associated with ITDs extending into tyrosine kinase domain 1 or located closer to the C-terminus. 9 , 22 , 33 , 34 By using this algorithm, a case was encountered with a 30-bp ITD at initial diagnosis along with a 180-bp ITD extending into tyrosine kinase domain 1, where the 30-bp ITD subsequently disappeared on treatment while the 180-bp subclone persisted at low level. The clinical significance is uncertain; however, the case highlights the potential utility of comprehensive ITD analysis.…”

“…Although the development of specialized FLT3 -ITD algorithms has improved recognition of mutant reads, few studies have adequately addressed AR estimation and some algorithms are limited to specific NGS platforms. 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 In particular, a trend for AR underestimation by NGS relative to CE has been consistently shown. 17 , 21 , 24 , 25 …”