Abstract
Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25–3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09–7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.
Highlights
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a rapidly evolving treatment paradigm
NPM1 mutation occurred in 28% (n = 253/916), FLT3-ITD in 25% (n = 226/916); FLT3 tyrosine kinase domain mutations (FLT3-TKD) in 8% (n = 71/910); IDH1 in 8% (n = 68/842) and IDH2 in 11% (94/842)
IDH1 R132H associated with NPM1 positivity more commonly than other IDH1 R132 codon mutations: 90% (n = 27/30) versus 26% (n = 10/38), p
Summary
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a rapidly evolving treatment paradigm. The majority of patients remain incurable, long-term remissions can be achieved in roughly one-third of these patients. The identification of prognostic markers bears outstanding relevance for optimizing treatment strategy. Measurable residual disease (MRD) after induction therapy and before hematopoietic stem cell transplantation is an independent, post-diagnosis prognostic indicator of relapse and survival. The application of molecular genetics and multiparametric flow cytometry are recommended for monitoring. Requirements for a reliable molecular genetic MRD marker are the following: (i) mutation burden fluctuates in parallel with leukemic tumor burden: present at disease onset, disappearing in remission and re-emerging at relapse, (ii) available method with the capability of achieving high sensitivity [1,2,3]
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