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Blood Jun 2018The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by...
The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
Topics: Clinical Trials as Topic; Disease Management; Genetic Testing; Humans; Immunophenotyping; Karyotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Staging; Neoplasm, Residual; Prognosis
PubMed: 29540348
DOI: 10.1182/blood-2017-09-806398 -
International Journal of Molecular... Feb 2020Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD... (Review)
Review
Minimal residual disease (MRD) refers to a chemotherapy/radiotherapy-surviving leukemia cell population that gives rise to relapse of the disease. The detection of MRD is critical for predicting the outcome and for selecting the intensity of further treatment strategies. The development of various new diagnostic platforms, including next-generation sequencing (NGS), has introduced significant advances in the sensitivity of MRD diagnostics. Here, we review current methods to diagnose MRD through phenotypic marker patterns or differential gene patterns through analysis by flow cytometry (FCM), polymerase chain reaction (PCR), real-time quantitative polymerase chain reaction (RQ-PCR), reverse transcription polymerase chain reaction (RT-PCR) or NGS. Future advances in clinical procedures will be molded by practical feasibility and patient needs regarding greater diagnostic sensitivity.
Topics: Flow Cytometry; High-Throughput Nucleotide Sequencing; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplastic Cells, Circulating; Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 32033444
DOI: 10.3390/ijms21031054 -
Journal of Hematology & Oncology Dec 2019The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most... (Review)
Review
The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
Topics: Biomarkers, Tumor; Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Lung Neoplasms; Neoplasm, Residual; Prognosis; Protein Kinase Inhibitors
PubMed: 31815659
DOI: 10.1186/s13045-019-0818-2 -
Annals of Oncology : Official Journal... Feb 2023Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.
BACKGROUND
Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)].
PATIENTS AND METHODS
c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961).
RESULTS
Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance.
CONCLUSIONS
c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.
Topics: Humans; Biomarkers, Tumor; Mutation; Neoplasm Recurrence, Local; Prospective Studies; Triple Negative Breast Neoplasms; Neoplasm, Residual; Antineoplastic Agents, Immunological; Circulating Tumor DNA
PubMed: 36423745
DOI: 10.1016/j.annonc.2022.11.005 -
Clinical Cancer Research : An Official... Nov 2016Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to... (Review)
Review
Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to monitor treatment response. In 2014, the updated International Myeloma Working Group (IMWG) diagnostic criteria changed the definition of multiple myeloma from being a disease defined by symptoms to a disease defined by biomarkers. Today, modern combination therapies have reported up to 60% to 80% of patients reaching a complete response. As a logical and necessary step forward, investigators have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. Recent meta-analysis data show that MRD negativity is associated with longer progression-free survival and overall survival. In 2016, the updated IMWG response criteria include MRD as the deepest level of treatment response in multiple myeloma. Simultaneously, we are still quite behind in our understanding of the heterogeneous biology of multiple myeloma and its implications for therapy. Emerging DNA sequencing data show that newly diagnosed multiple myeloma patients have a broad range of mutations, which are distributed unevenly in multiple parallel subclones already present at diagnosis. To move beyond the ill-defined category of "high-risk multiple myeloma," which confers to approximately 25% of all newly diagnosed patients, prospective studies are needed to dissect tumor biology and define multiple myeloma subtypes, and, based on biology, seek to define rational therapies for individual subtypes. This article discusses novel insights and gives perspectives on diagnosis and MRD monitoring and future directions for prognosis and clinical management of multiple myeloma. Clin Cancer Res; 22(22); 5428-33. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "MULTIPLE MYELOMA MULTIPLYING THERAPIES".
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Meta-Analysis as Topic; Multiple Myeloma; Mutation; Neoplasm, Residual; Prognosis; Prospective Studies; Remission Induction
PubMed: 28151710
DOI: 10.1158/1078-0432.CCR-16-0866 -
Nature Biotechnology Dec 2021Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for...
Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neoplasm, Residual
PubMed: 34294911
DOI: 10.1038/s41587-021-00981-w -
JAMA Mar 2023Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The... (Observational Study)
Observational Study
IMPORTANCE
Preventing relapse for adults with acute myeloid leukemia (AML) in first remission is the most common indication for allogeneic hematopoietic cell transplant. The presence of AML measurable residual disease (MRD) has been associated with higher relapse rates, but testing is not standardized.
OBJECTIVE
To determine whether DNA sequencing to identify residual variants in the blood of adults with AML in first remission before allogeneic hematopoietic cell transplant identifies patients at increased risk of relapse and poorer overall survival compared with those without these DNA variants.
DESIGN, SETTING, AND PARTICIPANTS
In this retrospective observational study, DNA sequencing was performed on pretransplant blood from patients aged 18 years or older who had undergone their first allogeneic hematopoietic cell transplant during first remission for AML associated with variants in FLT3, NPM1, IDH1, IDH2, or KIT at 1 of 111 treatment sites from 2013 through 2019. Clinical data were collected, through May 2022, by the Center for International Blood and Marrow Transplant Research.
EXPOSURE
Centralized DNA sequencing of banked pretransplant remission blood samples.
MAIN OUTCOMES AND MEASURES
The primary outcomes were overall survival and relapse. Day of transplant was considered day 0. Hazard ratios were reported using Cox proportional hazards regression models.
RESULTS
Of 1075 patients tested, 822 had FLT3 internal tandem duplication (FLT3-ITD) and/or NPM1 mutated AML (median age, 57.1 years, 54% female). Among 371 patients in the discovery cohort, the persistence of NPM1 and/or FLT3-ITD variants in the blood of 64 patients (17.3%) in remission before undergoing transplant was associated with worse outcomes after transplant (2013-2017). Similarly, of the 451 patients in the validation cohort who had undergone transplant in 2018-2019, 78 patients (17.3%) with residual NPM1 and/or FLT3-ITD variants had higher rates of relapse at 3 years (68% vs 21%; difference, 47% [95% CI, 26% to 69%]; HR, 4.32 [95% CI, 2.98 to 6.26]; P < .001) and decreased survival at 3 years (39% vs 63%; difference, -24% [2-sided 95% CI, -39% to -9%]; HR, 2.43 [95% CI, 1.71 to 3.45]; P < .001).
CONCLUSIONS AND RELEVANCE
Among patients with acute myeloid leukemia in first remission prior to allogeneic hematopoietic cell transplant, the persistence of FLT3 internal tandem duplication or NPM1 variants in the blood at an allele fraction of 0.01% or higher was associated with increased relapse and worse survival compared with those without these variants. Further study is needed to determine whether routine DNA-sequencing testing for residual variants can improve outcomes for patients with acute myeloid leukemia.
Topics: Female; Humans; Male; Middle Aged; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Neoplasm, Residual; Nuclear Proteins; Preoperative Care; Retrospective Studies; Sequence Analysis, DNA; Recurrence; Survival Analysis
PubMed: 36881031
DOI: 10.1001/jama.2023.1363 -
Cancer Discovery Dec 2017Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies....
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest. This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. .
Topics: Circulating Tumor DNA; Female; Humans; Lung Neoplasms; Male; Neoplasm, Residual
PubMed: 28899864
DOI: 10.1158/2159-8290.CD-17-0716 -
Cytometry. Part B, Clinical Cytometry Jan 2016In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal... (Review)
Review
In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal residual disease (flow-MRD) in bone marrow (BM), for improved assessment of response to therapy and prognostication. However, disturbing levels of variability exist regarding the specific protocols and antibody panels used in individual laboratories. Overall, consensus exists about the utility of combined assessment of CD38 and CD138 for the identification of BM plasma cells (PC); in contrast, more heterogeneous lists of markers are used to further distinguish between normal/reactive PCs and myeloma PCs in the MRD settings. Among the later markers, CD19, CD45, CD27, and CD81, together with CD56, CD117, CD200, and CD307, have emerged as particularly informative; however, no single marker provides enough specificity for clear discrimination between clonal PCs and normal PCs. Accordingly, multivariate analyses of single PCs from large series of normal/reactive vs. myeloma BM samples have shown that combined assessment of CD138 and CD38, together with CD45, CD19, CD56, CD27, CD81, and CD117 would be ideally suited for MRD monitoring in virtually every MM patient. However, the specific antibody clones, fluorochrome conjugates and sources of the individual markers determines its optimal (vs. suboptimal or poor) performance in an eight-color staining. Assessment of clonality, via additional cytoplasmic immunoglobulin (CyIg) κ vs. CyIgλ evaluation, may contribute to further establish the normal/reactive vs. clonal nature of small suspicious PC populations at high sensitivity levels, provided that enough cells are evaluated.
Topics: Antibodies; Antigens, CD; Antineoplastic Agents; Clone Cells; Flow Cytometry; Gene Expression; Humans; Immunophenotyping; Multiple Myeloma; Neoplasm, Residual; Plasma Cells; Prognosis; Remission Induction; Reproducibility of Results; Sensitivity and Specificity; Survival Analysis
PubMed: 26100534
DOI: 10.1002/cyto.b.21265 -
PLoS Medicine Oct 2021Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Topics: Cell-Free Nucleic Acids; Colorectal Neoplasms; DNA, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Liver Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Risk Factors
PubMed: 34637442
DOI: 10.1371/journal.pmed.1003794