Acute lymphoblastic leukemia clonal distribution between bone marrow and peripheral blood

Fries, Carol; Adlowitz, Diana G.; Spence, Janice M.; Spence, John P.; Rock, Philip; Burack, W. Richard

doi:10.1002/pbc.28280

Cited by 7 publications

(4 citation statements)

References 22 publications

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“…These studies reported on 16–183 paired peripheral blood and bone marrow samples and detected a complete concordance of 69–97%. Four of these seven studies either included or were exclusively performed in patients with lymphoid neoplasms [ 40 , 42 , 44 , 45 ], five did not report how many days were allowed between the peripheral blood and bone marrow samples, two reported up to 334 days between the sampling, and the sensitivity of the NGS analyses and/or the mean (min–max) coverage were rarely reported. Nevertheless, these important studies underscore the relevance and the real-world clinical need to be able to diagnose and monitor treatment response without repeated bone marrow evaluations.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, a real-world clinical need exists to be able to use an alternative or surrogate sample, to be able to obtain information on the mutational status of a patient’s disease. In this regard, research groups around the world have assessed whether the genetic information required for an integrated diagnosis and/or treatment monitoring may also be obtained from analysis of the peripheral blood of patients with various hematologic malignancies ( Table 1 and Table S1 ) [ 20 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

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Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

Jansko-Gadermeir

Leisch

Gassner

et al. 2023

Cancers

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Background: Next generation sequencing (NGS) has become indispensable for diagnosis, risk stratification, prognostication, and monitoring of response in patients with myeloid neoplasias. Guidelines require bone marrow evaluations for the above, which are often not performed outside of clinical trials, indicating a need for surrogate samples. Methods: Myeloid NGS analyses (40 genes and 29 fusion drivers) of 240 consecutive, non-selected, prospectively collected, paired bone marrow/peripheral blood samples were compared. Findings: Very strong correlation (r = 0.91, p < 0.0001), high concordance (99.6%), sensitivity (98.8%), specificity (99.9%), positive predictive value (99.8%), and negative predictive value (99.6%) between NGS analyses of paired samples was observed. A total of 9/1321 (0.68%) detected mutations were discordant, 8 of which had a variant allele frequency (VAF) ≤ 3.7%. VAFs between peripheral blood and bone marrow samples were very strongly correlated in the total cohort (r = 0.93, p = 0.0001) and in subgroups without circulating blasts (r = 0.92, p < 0.0001) or with neutropenia (r = 0.88, p < 0.0001). There was a weak correlation between the VAF of a detected mutation and the blast count in either the peripheral blood (r = 0.19) or the bone marrow (r = 0.11). Interpretation: Peripheral blood samples can be used to molecularly classify and monitor myeloid neoplasms via NGS without loss of sensitivity/specificity, even in the absence of circulating blasts or in neutropenic patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

Jansko-Gadermeir

Leisch

Gassner

et al. 2023

Cancers

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“…This strategy is ideal for lymphocytic leukemias, as every T and B cell undergoes VDJ recombination to generate functional B and T cell receptors; the specific sequence of the rearrangement in the receptor is unique to an individual B or T cell. ALL results from the abnormal expansion of typically 1-5 B or T cell clones, each of which will have a unique VDJ sequence ( 11 , 12 ). ClonoSEQ uses NGS methods to sequence the genomic DNA of cells isolated from patient blood and bone marrow samples to identify clonally expanded VDJ sequences and detect as few as one leukemic blast per million cells.…”

Section: Introductionmentioning

confidence: 99%

Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia

Sampathi

Chernyavskaya²,

Haney³

et al. 2022

Front. Oncol.

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BackgroundAcute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL.MethodsWe present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status.ResultsQuantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample.ConclusionsThe Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.

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“…This strategy is ideal for lymphocytic leukemias, as every T and B cell undergoes VDJ recombination to generate functional B and T cell receptors as part of the cell’s maturation, and the specific sequence of the rearrangement in the receptor is unique to an individual B or T cell. ALL results from the abnormal expansion of typically 1-5 T or B cell clones, each of which will have a unique VDJ sequence (10, 11). ClonoSEQ identifies clones based on a major expansion of that particular VDJ sequence within the patient’s blood and bone marrow samples at leukemia diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Nanopore sequencing methods detect cell-free DNA associated with MRD and CNS infiltration in pediatric Acute Lymphoblastic Leukemia

Sampathi

Chernyavskaya

Haney

et al. 2021

Preprint

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Acute Lymphoblastic Leukemia (ALL) patients that have minimal residual disease (MRD) after therapy or infiltration of ALL into the central nervous system (CNS) are considered high risk. These patients are often given intensified and/or additional rounds of chemotherapy in the hopes of eliminating their disease. Current methods to diagnose MRD and CNS infiltration rely on detecting ALL cells in patient samples using pathology, flow cytometry, or isolation of ALL genomic DNA for next-generation sequencing. However, blasts may be present in the patient but not detectable in a bone marrow biopsy or cerebrospinal (CSF) fluid sample, leading to incorrect or delayed patient diagnosis. We have developed a nanopore sequencing assay to detect B-ALL-associated cell-free DNA in patient blood and CSF samples. Quantitation of B-cell specific VDJ recombination events in cell-free DNA samples defined B-ALL clonal heterogeneity. Monitoring cfDNA in blood and CSF samples allowed us to track the response of individual B-ALL clones throughout the course of treatment for each patient. Detection of cell-free DNA predicted the clinical diagnosis of MRD and CNS disease. We also identified patients diagnosed as CNS negative who had low levels of cell-free DNA in their CSF sample. These data suggest that cell-free DNA assays may be useful in detecting the presence of ALL in the patient even when blasts are not in the biofluid sample. In total, nanopore analysis of cell-free DNA is a simple, rapid, and inexpensive assay that can serve as a useful complement to traditional clinical diagnostic approaches in the treatment of ALL.

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Acute lymphoblastic leukemia clonal distribution between bone marrow and peripheral blood

Cited by 7 publications

References 22 publications

Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

Myeloid NGS Analyses of Paired Samples from Bone Marrow and Peripheral Blood Yield Concordant Results: A Prospective Cohort Analysis of the AGMT Study Group

Nanopore sequencing of clonal IGH rearrangements in cell-free DNA as a biomarker for acute lymphoblastic leukemia

Nanopore sequencing methods detect cell-free DNA associated with MRD and CNS infiltration in pediatric Acute Lymphoblastic Leukemia

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