Minimal residual disease (MRD) detection in acute lymphoblastic leukaemia based on fusion genes and genomic deletions: towards MRD for all

Kuiper, Roland P.; Hoogeveen, Patricia G.; Bladergroen, Reno S.; Dijk, Freerk van; Sonneveld, Edwin; Leeuwen, Frank N. van; Boer, Judith M.; Sergeeva, Irina; Feitsma, Harma; Boer, Monique L. Den; Velden, Vincent H.J. van der

doi:10.1111/bjh.17744

Cited by 6 publications

(7 citation statements)

References 15 publications

(30 reference statements)

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“…This stability enabled us to confirm that all the “new” leukemic subpopulations were indeed new incarnations of the same tumor with changed immunophenotype and several changed molecular characteristics. Moreover, these fusions could serve as stable targets for MRD monitoring [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Semchenkova

Mikhailova

Komkov

et al. 2022

IJMS

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We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.

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Section: Discussionmentioning

confidence: 99%

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Semchenkova

Mikhailova

Komkov

et al. 2022

IJMS

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“…As an alternative to the IG/TR method, fusions often act as primary drivers of ALL that allow for MRD determination by PCR using the fusion transcript or the genomic breakpoint. High correlations between the IG/TR MRD and genomic breakpoint MRD have been shown in multiple studies with various B‐ALL subtypes 11–13 . In a large study focusing on BCR :: ABL1 B‐ALL patients, discordant MRD results between IG/TR PCR and fusion transcript or genomic breakpoint PCR were found for ≈25% of patients.…”

Section: Figurementioning

confidence: 94%

“…A quantitative range of ≤1E‐4 was observed for 72% of the genomic breakpoint assays and 100% of the IG/TR assays and all assays had a sensitivity of ≤1E‐4, similar to that described previously for other patient‐specific fusions and deletions (Figure 1A and 1B). 11 The genomic breakpoint assays with a quantitative range of 5E‐4 exhibited less reproducible amplification (http://links.lww.com/HS/A510). The enhanced quantitative range of IG/TR assays may be attributed to selection of the most optimal target, while genomic breakpoint assays are limited to a single target option, leaving limited options for optimal assay design.…”

Section: Figurementioning

confidence: 99%

“…High correlations between the IG/TR MRD and genomic breakpoint MRD have been shown in multiple studies with various B-ALL subtypes. [11][12][13] In a large study focusing on BCR::ABL1 B-ALL patients, discordant MRD results between IG/TR PCR and fusion transcript or genomic breakpoint PCR were found for ≈25% of patients. This led to the identification of chronic myeloid leukemia (CML)-like disease, characterized by presence of the BCR::ABL1 fusion gene in blood cell lineages other than B-cell in patients presenting with B-ALL.…”

mentioning

confidence: 99%

“…A quantitative range of ≤1E-4 was observed for 72% of the genomic breakpoint assays and 100% of the IG/TR assays and all assays had a sensitivity of ≤1E-4, similar to that described previously for other patient-specific fusions and deletions (Figure 1 A and 1 B). 11 The genomic breakpoint assays with a quantitative range of 5E-4 exhibited less reproducible amplification ( Suppl. Table S3 ).…”

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confidence: 99%

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ABL-class Genomic Breakpoint Q-PCR: A Patient-specific Approach for MRD Monitoring in Acute Lymphoblastic Leukemia

van Outersterp,

van der Velden,

Hoogeveen

et al. 2023

HemaSphere

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A BL-class fusions, in this study defined as fusions of ABL-class kinases other than BCR::ABL1, have been identified in 3%-5% of newly diagnosed pediatric and adult acute lymphoblastic leukemia (ALL). [1][2][3] These fusions comprise driver genes ABL1, ABL2, PDGFRB, or CSF1R fused to a wide range of partner genes. In B-cell ALL (B-ALL), PDGFRB fusions are the most common, whereas ABL1 fusions are the most common in T-cell ALL (T-ALL). [1][2][3] Generally, ABL-class B-ALL patients respond poorly to standard induction therapy. 1 Therefore, these patients receive targeted therapy with tyrosine kinase inhibitors additional to chemotherapy. 4 Accurate monitoring of measurable residual disease (MRD) is critical to evaluate treatment response allowing proper risk stratification and early detection of refractory or relapsed ALL.Determination of MRD by quantitative polymerase chain reaction (Q-PCR) for ALL patients is highly standardized using 2 immunoglobulin and T-cell receptor (IG/TR) rearrangements selected at diagnosis. However, there are some limitations; in particular the lack of identifiable or sensitive IG/TR targets for about 5% of patients [5][6][7][8] and the loss of the selected IG/TR gene rearrangement due to ongoing rearrangements and/or oligoclonality. 7,9,10

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Analysis of measurable residual disease by IG/TR gene rearrangements: quality assurance and updated EuroMRD guidelines

van der Velden,

Dombrink,

Alten

et al. 2024

Leukemia

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Minimal/measurable residual disease (MRD) diagnostics using real-time quantitative PCR analysis of rearranged immunoglobulin and T-cell receptor gene rearrangements are nowadays implemented in most treatment protocols for patients with acute lymphoblastic leukemia (ALL). Within the EuroMRD Consortium, we aim to provide comparable, high-quality MRD diagnostics, allowing appropriate risk-group classification for patients and inter-protocol comparisons. To this end, we set up a quality assessment scheme, that was gradually optimized and updated over the last 20 years, and that now includes participants from around 70 laboratories worldwide. We here describe the design and analysis of our quality assessment scheme. In addition, we here report revised data interpretation guidelines, based on our newly generated data and extensive discussions between experts. The main novelty is the partial re-definition of the “positive below quantitative range” category by two new categories, “MRD low positive, below quantitative range” and “MRD of uncertain significance”. The quality assessment program and revised guidelines will ensure reproducible and accurate MRD data for ALL patients. Within the Consortium, similar programs and guidelines have been introduced for other lymphoid diseases (e.g., B-cell lymphoma), for new technological platforms (e.g., digital droplet PCR or Next-Generation Sequencing), and for other patient-specific MRD PCR-based targets (e.g., fusion genes).

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Minimal residual disease (MRD) detection in acute lymphoblastic leukaemia based on fusion genes and genomic deletions: towards MRD for all

Cited by 6 publications

References 15 publications

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

ABL-class Genomic Breakpoint Q-PCR: A Patient-specific Approach for MRD Monitoring in Acute Lymphoblastic Leukemia

Analysis of measurable residual disease by IG/TR gene rearrangements: quality assurance and updated EuroMRD guidelines

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