Melissa Rijken

Bio: Melissa Rijken is an academic researcher from Erasmus University Medical Center. The author has contributed to research in topics: Medicine & Myeloid leukemia. The author has an hindex of 2, co-authored 3 publications receiving 59 citations.

Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia

Abstract: PURPOSE The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)–based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry. METHODS In 161 patients with de novo FLT3-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS). RESULTS NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P < .001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry. CONCLUSION NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

Germline loss of MBD4 predisposes to leukaemia due to a mutagenic cascade driven by 5mC

Abstract: Cytosine methylation is essential for normal mammalian development, yet also provides a major mutagenic stimulus. Methylcytosine (5mC) is prone to spontaneous deamination, which introduces cytosine to thymine transition mutations (C>T) upon replication. Cells endure hundreds of 5mC deamination events each day and an intricate repair network is engaged to restrict this damage. Central to this network are the DNA glycosylases MBD4 and TDG, which recognise T:G mispairing and initiate base excision repair (BER). Here we describe a novel cancer predisposition syndrome resulting from germline biallelic inactivation of MBD4 that leads to the development of acute myeloid leukaemia (AML). These leukaemias have an extremely high burden of C>T mutations, specifically in the context of methylated CG dinucleotides (CG>TG). This dependence on 5mC as a source of mutations may explain the remarkable observation that MBD4-deficient AMLs share a common set of driver mutations, including biallelic mutations in DNMT3A and hotspot mutations in IDH1/IDH2. By assessing serial samples taken over the course of treatment, we highlight a critical interaction with somatic mutations in DNMT3A that accelerates leukaemogenesis and accounts for the conserved path to AML. MBD4-deficiency was also detected, rarely, in sporadic cancers, which display the same mutational signature. Collectively these cancers provide a model of 5mC-dependent hypermutation and reveal factors that shape its mutagenic influence.

Archived bone marrow smears are an excellent source for NGS-based mutation detection in acute myeloid leukemia

Abstract: Acute myeloid leukemia (AML) is a heterogeneous disease as illustrated by the enormous diversity in numbers, types and often patient-specific molecular alterations. The current AML prognostic paradigm classifying patient into three 2017ELN risk groups relies solely on cytogenetic and molecular findings at baseline [1]. Besides the established clinically relevant aberrations, numerous acquired mutations have been revealed in AML [2, 3]. The clinical relevance of many of these somatic mutations is currently unknown because sufficient materials of AML patients carrying these less frequent mutations are lacking. Similarly, studies on the evolution of AML between initial diagnosis and relapse and minimal residual disease (MRD) detection have been hampered by inaccurate sampling during the course of the disease. Here we explored the feasibility of using archived May-Grünwald Giemsa stained bone marrow (MGG-stained BM) slides for next-generation sequencing (NGS)-based mutation detection. MGG-stained BM slides, taken at all clinically relevant time points, are widely available in contemporary biobanks. This study shows that archived MGG-stained BM slides are an excellent source for retrospective molecular analyses of AML, which could certainly be valuable for similar analyses of other hematologic malignancies. We first demonstrated that DNA could be more efficiently isolated from MGG-stained BM slides, in contrast to archived unstained slides (Supplementary Data). Next, we examined whether targeted NGS using the Illumina TruSight Myeloid sequencing panel was feasible on DNA isolated from the MGG-stained BM slides (Supplementary Figs. S1 and S2 and Supplementary Tables S1–S4). We compared the mutation profiles of DNA samples derived from MGG-stained BM slides and matched DNA extracted from Ficoll-purified BM (FPBM) of 18 paired diagnosisrelapse AML cases. In the majority of cases the mutation profiles, i.e., mutation present versus absent, of DNA isolated from the MGG-stained BM slides were identical to FPBM DNA at diagnosis and relapse (Fig. 1a and Supplementary Fig. S3). The majority of MGG-stained slides included were collected after 1997. Interestingly, however, we were able to detected driver mutations in DNA isolated from MGG-stained slides prepared in 1975 (44-year old, Supplementary Data). We did notice variations in variant allele frequencies (VAFs) in few AML samples. A consistently lower VAF in MGG-stained BM DNA as compared to FPBM DNA could be the result of a variety of cells present on MGG-stained BM slides, such as unmutated stromal or differentiated cells. Ficoll purification enriches for mononuclear cells, which would result in increased percentages of blast cells and higher VAFs in FPBM DNA. In few instances VAFs were higher in MGG-stained BM DNA. These differences were mostly seen in genes known to be associated with clonal hematopoiesis, i.e., DNMT3A and TET2 [4, 5]. In these cases more differentiated cells carrying these mutations may have been lost during Ficoll purification resulting in decreased VAFs in the FPBM samples. In 5 out of 18 AML pairs we were able to compare the mutation profiles of MGG-stained slides and FPBM DNA at time of complete remission (CR). Targeted NGS analysis on DNA from both the MGG-stained slides and * Peter J. M. Valk p.valk@erasmusmc.nl

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

Abstract: Abstract The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Clonal hematopoiesis in human aging and disease

Abstract: As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Acute Myeloid Leukemia, Version 2.2021 Featured Updates to the NCCN Guidelines

Abstract: The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.