Revisiting the role of measurable residual disease in FLT3 mutated acute myelogenous leukemia

Figures & data

Figure 1. Molecular MRD targets in patients with FLT3 mutated AML in the NCRI AML19 trial [8]. 55% of patients had co-occurring NPM1 mutations, and approximately 15% patients had fusion transcripts (i.e. CBFB:MYH11, RUNX1:RUNX1T1, NUP98:NSD1, or other rare fusion genes), while for the remaining 30% of patients no validated molecular MRD target was present.

Table 1. Studies assessing molecular MRD monitoring in FLT3 mutated AML. the table summarizes the most important clinical studies assessing MRD in FLT3 mutated AML and includes performed methods, sample source, the time point of monitoring, and the main conclusion of the study.

Methods	Source	n	Timepoint	Main findings	References
NGS DNA sequencing for FLT3-ITD and TKD	PB	339 + 412*	Pre allo-HSCT	Persistence of FLT3-ITD was associated with increased relapse rates and worse survival	[18]
PCR-NGS for FLT3-ITD	BM or PB	104	Pre allo-HSCT	FLT3-ITD MRD positivity was associated with increased risk of relapse and poorer overall survival	[17]
NGS-based FLT3-ITD	BM or PB	161	After two cycles of induction chemotherapy	NGS-based detection of FLT3-ITD MRD identified patients with profound risk of relapse and mortality post-transplant	[19]
NGS-based FLT3-ITD	BM or PB	321	After one or two cycles of induction chemotherapy	MRD negativity associated with better prognosis, but the FLT3 inhibitor quizartinib increased overall survival in MRD positive patients	[20]
NGS-based FLT3-ITD	BM or PB	142	After two cycles of induction chemotherapy	MRD negativity was the strongest independent favorable prognostic factor for relapse and overall survival	[21]
NGS-based FLT3-ITD	BM	356	Pre and post allo-HSCT	MRD negativity was associated with increased relapse free survival, but the FLT3 inhibitor gilteritinib increased relapse free survival in MRD positive patients	[22]

*Patients in discovery and validation cohort.

Abbreviation: FG, fusion genes; RT-qPCR, real time- quantitative polymerase chain reaction, NGS, next generation sequencing; BM, bone marrow; PB; peripheral blood; MRD; measurable residual disease, allo-HSCT, allogeneic hematopoietic stem cell transplantation.

Table 2. Advantages and disadvantages using NGS as an MRD marker for FLT3 mutated AML.

Advantages	Disadvantages
Applicable to all FLT3 mutated AML patients. Highly sensitive. ctDNA allows for use of blood. Potential for standardization of multiplexed platforms. Information of clonal evolution if other mutations tracked. May allow early clinical intervention, i.e. proceeding to allo-HSCT or introducing FLT3 inhibitors.	Still lack of standardization and validation. FLT3-ITD negative relapse can occur. In need of bioinformatic advanced competence. Time consuming. Expensive.

Othman J, Potter N, Mokretar K, et al. FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML. Leukemia. 2023;37(10):2066–2072. doi: 10.1038/s41375-023-01994-x

 PubMed Web of Science ®Google Scholar

Dillon LW, Gui G, Page KM, et al. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. JAMA. 2023;329(9):745–755. doi: 10.1001/jama.2023.1363

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Loo S, Dillon R, Ivey A, et al. Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome. Blood. 2022;140(22):2407–2411. doi: 10.1182/blood.2022016567

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Grob T, Sanders MA, Vonk CM, et al. Prognostic value of FLT3-internal tandem duplication residual disease in acute myeloid leukemia. J Clin Oncol. 2023;41(4):756–765. doi: 10.1200/JCO.22.00715

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Perl AE, Erba H, Montesinos P, et al. Quantum-first trial: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)–Specific measurable residual disease (MRD) clearance assessed through induction (IND) and consolidation (CONS) is associated with improved overall survival (OS) in newly diagnosed (nd) FLT3-ITD+ AML patients (pts). ASH Annual Meeting & Exposition, Abstract no 832; San Diego, CA, US; 2023.

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Rucker FG, Bullinger L, Cocciardi S, et al. Next-generation sequencing-based measurable residual disease monitoring in acute myeloid leukemia with FLT3internal tandem duplication treated with intensive chemotherapy plus midostaurin. European Hematology Association Hybrid Congress 2023, Abstract no S135; Frankfurt, Germany; 2023.

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Levis MJ. ilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3. J Clin Oncol. 2024. Epub ahead of print.

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