IgH Clonotype Sequencing for B-ALL Relapse Detection
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Solution Overview
Problem
Current methods for monitoring leukemia clonotypes in acute lymphoblastic leukemia (ALL) are inadequate for detecting sequence changes or evolution, leading to potential false negative assessments of disease remission and increased risk of relapse.
Innovation Solution
A sequencing-based method that involves obtaining B-cell samples, amplifying nucleic acid molecules from immunoglobulin genes, and determining clonotype profiles to detect patient-specific clonotypes and their evolved progeny, allowing for modified treatment regimens based on clonal evolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional monitoring methods are used, then the process is simple, but sequence changes and clonal evolution cannot be detected
Solution Approach 1:
The patent segments the IgH gene into specific regions (V, D, J segments) and focuses sequencing on the hypervariable CDR3 region. This segmentation allows detection of clonal evolution through targeted analysis of specific genomic segments, resolving the contradiction between simple monitoring and precise sequence change detection.
Solution Approach 2:
The patent transitions from conventional single-point monitoring to high-dimensional sequence profiling by capturing nucleotide-level variations across multiple gene segments. This dimensional expansion enables detection of subtle clonal evolution patterns that conventional methods miss, achieving precise measurement without excessive complexity.
2Reliability
If clonal evolution is not monitored, then the monitoring process remains simple, but false negative assessments of disease remission occur
Solution Approach 1:
The patent implements feedback by continuously monitoring clonotype sequences and comparing them against reference profiles to detect evolution. This feedback mechanism alerts clinicians to emerging resistant clones, improving reliability of remission assessment while managing complexity through automated comparison algorithms.
Solution Approach 2:
The patent performs preliminary sequencing and profiling at diagnosis to establish baseline clonotypes. This preliminary action creates reference data that enables subsequent detection of evolution, improving reliability of remission monitoring by having advance knowledge of the disease's molecular fingerprint.
3Reliability
If traditional monitoring is used, then the approach is straightforward, but relapse risk increases due to undetected resistant cells
Solution Approach 1:
The patent replaces conventional mechanical/cell-based monitoring with molecular sequencing technology. This substitution enables detection of minimal residual disease at the nucleotide level, dramatically improving reliability while the automated nature of sequencing maintains operational simplicity through standardized protocols.
Data Source
AI summary
The invention is directed to methods of monitoring B-cell lymphoid proliferative disorders, such as B-cell acute lymphoblastic leukemias, by measuring the presence, absence and/or levels of correlating, or index, clonotypes and related clonotypes that have evolved therefrom, for example, as part of the disease condition. In one aspect, such methods are implemented by generating sequencing-based clonotype profiles and determining frequencies of correlating, or index, clonotypes present, including new clonotypes that have evolved therefrom, particularly, in the case of B-cell ALL, by VH substitution. The invention also includes use of such monitoring information to modify treatment status of a patient.