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State-of-the-art residual disease assessment

The challenge of residual disease detection: finding the few among the many

For patients with lymphoid malignancies the presence of measurable residual disease (MRD), even at very low levels, can be clinically meaningful. Because MRD is a direct measure of disease, assessing its presence and level becomes a powerful way to understand risk, evaluate response to treatment, and detect early signs of potential disease recurrence.[1]

However, MRD assessment is complicated by the fact that cancerous B and T cells exist amidst a vast array of normal B and T cells. Finding a malignant cell among the huge number of normal ones is like finding one specific snowflake in a blizzard.

The Adaptive Immune System

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Much like a snowflake, each B or T cell has a specific structure which makes it different from other B or T cells in the adaptive immune system.[2]

These differences among B and T cells stem from rearrangements that occur in the DNA within a specific region of a B- or T-cell receptor called the CDR3 region.[2]

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Within this region, there are 3 types of sequences — Variable (V), Diversity (D), and Joining (J) — that recombine with other random DNA sequences to create a novel sequence that uniquely identifies each B- or T-cell receptor.[2]

This process of VDJ rearrangement creates a nearly limitless potential for diversity among B- and T-cell populations.[3] The diversity of each individual’s B- and T-cell receptors is what enables a powerful immune response to a wide array of pathogens.

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When a B or T cell becomes malignant, the DNA that encodes the CDR3 region of that lymphocyte serves as a precise and unique marker of the malignancy.[2]

That marker remains useful as a means to identify disease and quantify disease burden over the course of a patient’s treatment journey.[2]

To be optimally useful in the clinic, an MRD assay should offer:

  • Precise specificity for the DNA sequences that uniquely identify cancerous cells.
  • Deep sensitivity to detect tiny numbers of cancer cells among millions of healthy cells.
  • Refined quantitation to accurately assess and trend a patient’s disease burden over time.
  • Robust standardization to ensure consistency and reliability of clinical results across patients and time.

Built on the foundational innovations of Adaptive Biotechnologies’ proprietary immunosequencing platform, the clonoSEQ® Assay is designed to address these needs.[1]

WHAT MAKES CLONOSEQ UNIQUE

clonoSEQ Technical Innovations

The clonoSEQ Assay sets itself apart from other MRD assays through a series of innovations that are critical to its value in the clinic.

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Ability to Handle SHM

Assay Design Increases Resilience to Somatic Hypermutation (SHM)
Corrects for naturally-occurring changes in MRD markers.

Somatic hypermutation (SHM) can cause clinical assays to underestimate MRD or even miss it entirely. The clonoSEQ Assay is engineered to minimize the impact of SHM on clonoSEQ MRD results.[4,5]

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Avoidance of False Negatives

Synthetic Immune Repertoire Provides Step-by-step Process Controls
Provides confidence in clonoSEQ MRD results.

Each distinct step in the clonoSEQ Assay is monitored by a corresponding control molecule. That’s why when clonoSEQ produces an MRD-negative result, it is clear to a clinician that the test output is accurate and not the result of an assay failure.[1]

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Sophisticated Bioinformatics

Expert-developed Algorithms Maximize Assay Sensitivity and Accuracy
Generates clinically meaningful outputs from complex datasets.

The algorithms that are used to transform raw sequencing data into clonoSEQ results are designed to maximize the assay’s ability to distinguish signal vs. noise and to optimally translate raw sequencing reads into contextualized information for clinical use.[1]

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Advanced Bias Control

Built-in Synthetic Immune Repertoire Helps Solve for Amplification Bias
Makes clonoSEQ results quantitative and clinically relevant.

clonoSEQ is the first MRD assay to leverage a synthetic immune repertoire to address the inherent bias that occurs when DNA sequences are amplified using multiplex PCR. These synthetic molecules enable highly accurate and reproducible quantitation of residual disease.[1,6,7]

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Enhanced Quantitation

Precise Measurement of “MRD Denominator” Maximizes Accuracy of Results
Contextualizes clonoSEQ MRD results.

clonoSEQ uses a robust internal measure to quantify the total nucleated cells (i.e. input DNA) contained in a tested sample. The use of this internal measure ensures the accuracy of a value which is critical to the interpretation of a clinical MRD result.[1]

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Minimal Sample Volumes

Single Tube Design Enables High Sensitivity with Minimal Sample Volumes
Enables efficient and consistent evaluation of all B-cell receptor loci.

By evaluating all B-cell receptor loci together in a single PCR reaction, the clonoSEQ Assay conserves sample material, enabling maximum sensitivity to be achieved with minimal sample material.[1]

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Increased ID Success Rates

Coverage of all Relevant Loci Enables High Malignant Clones Identification Rates
Makes clonoSEQ applicable to broad populations of patients with B-cell malignancies.

With the inclusion of primer sets for IGH, IGK, and IGL, as well as IGH-BCL1 / IGH-BCL2 translocations, the clonoSEQ Assay provides a comprehensive assessment of immune receptors in a single assay for patients with B-cell malignancies.[1]


This page is intended for use by healthcare professionals of the United States.

clonoSEQ® is available as a FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect minimal residual disease (MRD) in bone marrow samples from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL). clonoSEQ is also available for use in other lymphoid cancers as a CLIA-regulated laboratory developed test (LDT) service. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit clonoSEQ.com/technical-summary.

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Citations

  1. clonoSEQ®. https://clonoseq.com/technical-summary. Seattle, WA: Adaptive Biotechnologies; 2018.
  2. Kirsch I, et al. Molec Oncol. 2015;9(10):2063-70.
  3. Abbas A, et al. Cell and Molec Immuno. Philadelphia, PA: Elsevier. 2015:176-177.
  4. Data on file. Clinical Study Reports REP-01038 and REP-01041. Seattle, WA; Adaptive Biotechnologies Corp; 2017.
  5. Carlson C, et al. Nat Commun. 2013;4:2680.
  6. Robins H, et al. Adaptive Biotechnologies Corporation. US patent 9,150,905. October 6, 2015.
  7. Robins H, et al. Adaptive Biotechnologies Corporation. US patent 9,371,558. June 21, 2016.