scholarly journals Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical trial

2021 ◽  
Vol 5 (3) ◽  
pp. 760-770
Author(s):  
Catia Simoes ◽  
Bruno Paiva ◽  
David Martínez-Cuadrón ◽  
Juan-Miguel Bergua ◽  
Susana Vives ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Intensive Therapy ◽  
Genetic Alterations ◽  
Phase 3 ◽  
Elderly Aml ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Abstract The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase 3 FLUGAZA clinical trial, which randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine (FLUGA) vs 5-azacitidine. After consolidation, patients continued treatment if MRD was ≥0.01% or stopped if MRD was <0.01%, as assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N = 72) was the only independent prognostic factor for relapse-free survival (RFS) (HR, 3.45; P = .002). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR, 0.32; P = .013). Longer overall survival was observed in patients with undetectable MRD after induction though not after consolidation. Although leukemic cells from most patients displayed phenotypic aberrancies vs their normal counterpart (N = 259 of 265), CD34 progenitors from cases with undetectable MRD by MFC carried extensive genetic abnormalities identified by whole-exome sequencing. Interestingly, the number of genetic alterations significantly increased from diagnosis to MRD stages in patients treated with FLUGA vs 5-azacitidine (2.2-fold vs 1.1-fold; P = .001). This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.

scholarly journals Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns

Leukemia ◽  
2021 ◽  
Author(s):  
Tanja Božić ◽  
Chao-Chung Kuo ◽  
Jan Hapala ◽  
Julia Franzen ◽  
Monika Eipel ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Amplicon Sequencing ◽  
Multiparametric Flow Cytometry ◽  
Methylation Patterns ◽  
Cg Dinucleotides ◽  
Measurable Residual Disease ◽  
Acute Myeloid

AbstractAssessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.

AMELIORATE: early intensification in FLT3-mutated acute myeloid leukemia based on peripheral blast clearance – MYNERVA-GIMEMA AML1919 trial

2021 ◽  
Author(s):  
Francesco Mannelli ◽  
Giacomo Gianfaldoni ◽  
Paola Guglielmelli ◽  
Francesco Buccisano ◽  
Roberto Caporale ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Status ◽  
Phase Iii ◽  
Multiparameter Flow Cytometry ◽  
Current Standard ◽  
Disease Category ◽  
Measurable Residual Disease ◽  
Acute Myeloid

AMELIORATE is a Phase III, randomized trial aiming to personalize treatment intensity in FLT3-mutated acute myeloid leukemia. The current study provides an early appraisal of chemosensitivity based on peripheral blasts clearance, as assessed by multiparameter flow cytometry, from baseline to day 4 of induction. This biomarker was previously demonstrated to predict complete remission achievement and measurable residual disease status. For patients experiencing low peripheral blast cells (i.e., ≤2.0 logs), two major adjustments of treatment as compared with current standard of care are envisioned in the experimental arm: the immediate switch to intensified induction with high-doses cytarabine (1500 mg/m2 b.i.d. on days 5–7 of induction); and the early allocation of the patient to high-risk disease category, to be further refined later based on postinduction measurable residual disease status.

Detection and management of acute myeloid leukemia measurable residual disease

2020 ◽  
Vol 27 (2) ◽  
pp. 81-87 ◽  
Author(s):  
Giovangiacinto Paterno ◽  
Maria Ilaria Del Principe ◽  
Adriano Venditti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Measurable Residual Disease ◽  
Acute Myeloid
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